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Review

Role of miRNA in head and neck squamous cell carcinoma Expert Rev. Anticancer Ther. 15(2), 183–197 (2014)

Yaghma Masood*1, Cheah Yoke Kqueen2 and Pathmanathan Rajadurai3 1 Faculty of Dentistry, Centre of Oral and Maxillofacial Diagnostics and Medicine Studies, Universiti Teknologi MARA, Level 19, Tower 2, Shah Alam, 40450, Malaysia 2 Faculty of Medicine and Health Sciences, Molecular Biology and Bioinformatics, University Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malaysia 3 Department of Pathology, Monash Medical School, Bandar Sunway, Malaysia *Author for correspondence: Tel.: +60 102 259 941 [email protected]

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields. KEYWORDS: head and neck squamous cell carcinoma • HNSCC • metastasis • miRNA • prognosis and survival

Background

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and accounts for 5 million new cases annually [1]. Tobacco smoking, alcohol consumption and human papilloma virus infections have been associated with the occurrence of HNSCC [2,3]. Despite considerable advances in multimodality therapy, the overall 5-year survival rate for patients with HNSCC is only 40–50% [4–6]. This has remained relatively unchanged over the last three to four decades because of the intricate anatomy of the primary tumor sites, distant metastasis, locoregional spread, recurrences, secondary primary tumors and the tendency to be detected at late-stage [4,7]. Several attempts have been made to identify genetic biomarkers for HNSCC, and none have proven to be useful clinically as a guide to treatment selection at initial diagnosis [8]. Evidences suggest that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of cancer, including HNSCC, and their deregulation can lead to cancer [9–11]. Constant attempts are going on to discover novel cancer-associated miRNAs and to identify the biology of these small RNAs in malignant processes. Many studies have investigated the utility

10.1586/14737140.2015.978294

of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of those with HNSCC. This study reviews the literature published in past 10 years on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. miRNAs: biogenesis & transcriptional regulation

miRNAs are small endogenous non-coding, 19–25 nucleotides single-stranded RNA molecules [12]. Multiple proteins and RNAs are involved in the function and biogenesis of miRNAs. They are initially transcribed by RNA polymerase II into primary miRNA and then cleaved to pre-miRNAs in a nuclear multiprotein complex composed primarily of Drosha and Pasha [13]. They are then exported into the cytoplasm by exportin-5, where they are further processed by Dicer and produce miRNA/miRNA* duplex [12]. Subsequently, one strand of this miRNA duplex is incorporated into RNA-induced silencing complex. It then binds to complementary 3´ untranslated regions of target mRNAs and downregulate protein expression through either mRNA

 2014 Informa UK Ltd

ISSN 1473-7140

183

Review

Masood, Kqueen & Rajadurai

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Epigenetic changes (e.g., methylation)

Chromosomal alteration (e.g., translocation, loss, amplification)

Polymorphisms (e.g., SNP)

Defect in miRNA processing machinery

↓ Tumour suppressor protein

↑ Cell proliferation ↑ Metastasis

↑ Oncogenic miRNAs ↓ Senescence

miRNA deregulation

Cancer cell

↑ Apoptosis

↑ Angiogenesiss ↓ Tumour suppressor miRNAs ↑ Invasion

Altered behavior of transcription factors

↑ Oncogenic protein

↓ Drug resistance

Figure 1. Mechanism of miRNA deregulation and cancer cell development. Chromosomal alterations, epigenetic changes, polymorphisms, defect in miRNA processing machinery and altered behavior of transcription can cause miRNA deregulation. This miRNA deregulation may lead to either loss of tumor suppressor miRNA or over-expression of oncogenic miRNA that may cause increase in production of oncogenic proteins and elevate the levels of tumor suppressor proteins, respectively. This process may ultimately transform the normal cell into cancer cell. The final outcome may lead to increase cell proliferation, apoptosis, invasion, metastasis, angiogenesis and decrease in drug resistance and senescence. SNP: Single nucleotide polymorphisms.

degradation or translational repression and affect almost every cellular process [9,10]. In addition, alterations of miRNAs have been significantly associated with specific clinical phenotypes including cancer [14]. Single miRNA can bind to posttranscriptional regulators of as many as 200 proteins coding gene-related functions; on the other hand, many miRNAs can bind to a single gene promoter [15]. Approximately, 2000 miR genes have been described in the human genome. miRNAs now constitute one of the largest gene families known, accounting for approximately 1% of the genome [14]. Mechanism of miRNA deregulation in cancer

Some downregulated miRNAs function as tumor suppressors by negatively regulating oncogenic proteins, whereas upregulated miRNAs could function as oncogenes by repressing tumor suppressor proteins and contribute to cancer development [12]. A single miRNA can target numerous genes and involve in distinct pathways. Each miRNA can contribute to different biological downstream effects in different cells or tissue types, influencing the suppressive/oncogenic function of any miRNA in a given tissue. For example, conflicting findings have been observed for miR-221/miR-222 [16]. miRNA deregulation in cancer should be governed by either of the following: First, epigenetic changes, where DNA 184

hypermethylation of tumor suppressor genes is the most common and readily noticeable epigenetic event in cancer, whereas hypomethylation-associated activation of oncogenes is less frequently observed [17]. DNA methylation is also considered an ideal approach for screening and early detection of many cancers including HNSCC [18]. Second, a chromosomal alteration is another mechanism for miRNA deregulation in oncogenic processes. For instance, the let-7 family map to chromosomal loci that are often deleted in solid tumors [16]. Third, it has been reported that the presence of polymorphisms, mainly single nucleotide polymorphisms in pri-, pre- and mature miRNA genes, affect the processing machinery or target binding sites and increase the susceptibility to cancers [19]. Single nucleotide polymorphisms within miR-196a2 (rs11614913) is currently detected in multiple solid neoplasms, including HNSCC, and homozygosity for this variant lead to a higher risk of developing multiple cancer types in the patients [20]. Fourth, altered behavior of transcription factors can also contribute to altered miRNA behavior. P53-induced expression of miR-34 via binding to the miRNA promoter offers an example for altered behavior [16]. Finally, defects in miRNA processing machinery can also govern miRNA deregulation in cancer. Elevated expression levels of Dicer protein are found in HNSCC, and are consistent with reports found in lung, prostate and ovarian carcinomas [21].

Expert Rev. Anticancer Ther. 15(2), (2014)

Role of miRNA in HNSCC

let-7b-mediated reduction of Dicer protein is associated with translational repression of cell proliferation, another example of defect in miRNA processing machinery (FIGURE 1) [22].

Paper screened by titles and abstract n = 212 Rejected papers by titles and abstract n = 167 did not fulfill the inclusion criteria

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Materials & methods

A careful systematic search was done independently by two authors using PubMed and Ovid to identify relevant studies published in English language from July 2003 to June 2013. The following search terms were used and combined using the logical operator OR: HNSCC, oral squamous cell carcinoma, head and neck carcinoma, oral carcinoma, upper aerodigestive tract cancer, mouth cancer, head and neck cancer, oral cancer, nasopharynx carcinoma, oropharynx carcinoma, hypopharynx carcinoma, paranasal carcinoma, larynx carcinoma, lip carcinoma, nose carcinoma, salivary gland carcinoma, nasopharynx cancer, oropharynx cancer, paranasal cancer, hypopharynx cancer, larynx cancer, lip cancer, nose cancer, nasal cancer and salivary gland cancer. These search terms were further combined with the terms miRNA OR miRNA using the logical operator AND. This search strategy identified 212 articles published on the relevant topic in English language journals in 10 years’ time between July 2003 and June 2013 (FIGURE 2). Title and abstracts of all these identified articles were screened for inclusion and exclusion criteria. Studies were considered eligible if they met the following criteria: they studied the patients with any type of head and neck cancer; they measured the expression of miRNA in tissue with normal tissue as a control; English language studies. Articles were excluded based on the following criteria: review articles or letters; nonEnglish articles; miRNA expressed in cell lines, serum, plasma, saliva and fine needle aspiration biopsy; human papilloma virus infection and response to therapy from non-human papilloma virus-related HNSCC. A total of 167 articles were excluded from the study on the basis of exclusion and inclusion criteria, and 45 articles were selected for full text review. After full text review, six articles were excluded again on the basis of exclusion and inclusion criteria and finally 39 articles were included in this study. HNSCC & miRNA

Based solely on the literature contained in this review, it appears that the dysregulation of miRNA in HNSCC is either overexpression, under expression or both. Some of the effects have been intensively investigated with respect to miRNA expression and functionality, but the functional properties of the vast majority of miRNA remains completely unknown (TABLE 1). In the following sections, miRNAs that are particularly interesting, extensively investigated or have been examined in multiple studies or validated by independent means within a single report in HNSCC tumor samples are discussed.

Review

Full papers screened n = 45

Rejected full papers n = 6 Papers appraised in the study n = 39

Figure 2. Flowchart showing the retrieval of papers for appraisal.

inhibited cell proliferation and induced the apoptosis and inhibited mammalian target of rapamycin in oral cancer cells [23]. Studies are required to further understand the functions of miR-99a in HNSCC carcinogenesis, as other signaling pathways or molecules may be targeted by miR-99a [23]. miR-375

miRNA-375 is found to have a putative tumor suppressive role in HNSCC [24]. It has been shown to possess oncogenic properties, including cancer cell progression, invasion, metastasis and chemoresistance by directly upregulating metadherin (AEG-1/ MTDH) [25]. Downregulation of miR-375 and poor prognosis may be associated with a tendency to increased invasiveness in HNSCC [8]. Conversely, increased level of miR-375 expression is observed in HNSCC patients with alcohol consumption (independent from tobacco smoking) [24]. This is consistent with findings that miRNA profiles are cell type and tumor specific, may reflect the etiology and could even precisely differentiate tumor subtypes. However, no association has been found between miR-375 silencing and DNA hypermethylation in HNSCC [26]. Moreover, the miR-221:miR-375 ratio also demonstrated a high discriminatory potential, with a sensitivity of 92% and specificity of 93% in distinguishing HNSCC tumor from normal tissue [27]. miR-133a

miR-133a is established as being downregulated and act as tumor suppressor in HNSCC and found to inhibit cell proliferation, migration and invasion [28–31]. Furthermore, it has been demonstrated that miR-133a directly downregulates actinrelated protein 2/3 complex subunit 5 (ARPC5), caveolin-1 (CAV1), GSTP1, transgelin-2 (TAGLN2) and pyruvate kinase muscle isozyme (PKM2) [31–33]. More recently, it was shown that moesin is also targeted by miR-133a in HNSCC, and participates in cancer invasion and metastasis [34].

miRNA-99

Lower miR-99a expression is found in HNSCC tissues, when compared with the adjacent non-tumor tissues derived from cancer patients. Moreover, miR-99a overexpression distinctly informahealthcare.com

miR-218

Several reports have reported significant miR-218 repression in HNSCC tumor samples. It is capable of suppressing cancer cell 185

186 RICTOR, survivin, ROBO1 and laminin332 E2F3, survivin, SIRT1, CDK4, VEGF

Tumor suppressor

Tumor suppressor

Tumor suppressor

#

#

#

#

mi-R 133a

miR-218

miR-34a

miR-9

Cervical cancer, colorectal cancer, lung cancer and pancreatic cancer

#: Down regulation; ": Up regulation; CSC: Cancer stem cells; EMT: Epithelial mesenchymal transition; HNSCC: Head and neck squamous cell carcinoma.

"

Cell proliferation apoptosis, invasion and migration

HNSCC, breast, pancreas, colon, melanoma, lung and kidney cancer

HNSCC and lung cancer

SNX1

Cell proliferation and apoptosis

HNSCC, medulloblastoma, colon cancer, and pancreatic cancer, lung cancer, prostate cancer, hepatocellular carcinoma, neuroblastoma and colon cancer

HNSCC and gastric cancer

HNSCC, breast cancer, hepatocellular carcinoma and bladder cancer

HNSCC, gastric cancer, hepatocellular carcinoma and breast cancer

HNSCC, liver, lung, prostate cancer, serous ovarian carcinoma and bladder cancer

Tumors

#

NF-jB, p53

Apoptosis, cell proliferation, senescence, angiogenesis, invasion, metastasis and drug resistance

Cell migration and invasion

Cell proliferation, migration and invasion

Cell proliferation, invasion, poor prognosis distant metastasis, cancercell progression and chemoresistance

Cell growth, cell apoptosis

Pathways/ significance

Breast, cervical, brain and endometrial cancers

PTEN

TP53, p53, MYCN, CDK4, cyclin D1, SIRT1, VEGF and Bcl-2

LAMA3, LAMB3 and LAMC2

PRELID1, TPM2, TPM3, SEC61B, PTMA, COX6A1, GSTP1, EFEMP1, CMTM6, DYNC1LI2, ATP5L, INHBA, AP2M1, ADA, EIF4A1, PTRF,PTPMT1, FTL, SLC25A39, SQLE, FSCN1, LASP1, TAGLN2 and ARPC5

JAK2, YAP

Validated/putative targets in other cancers

"

Tumor suppressor

Metadherin, AEG-1/ MTDH, PDK1

Tumor suppressor

#

miR-375

miR-95

mTOR

#

miR-99a

ARPC5, CAV1, GSTP1, TAGLN2, PKM2 and MSN

Validated/ putative targets in HNSCC

Expression

miRNA

Table 1. Studies of miRNA expression in head and neck squamous cell carcinoma.

Microarray

qRT-PCR

Microarray qRT-PCR

RT-PCR

RT-PCR

Microarray qRT-PCR

qRT-PCR

Type methods

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[41,49,100–102]

[39,41,80,93–99]

[37,38,78,79,92]

[35,36,77]

[28–34]

[8,24–27,76,90]

[23]

Ref.

Review Masood, Kqueen & Rajadurai

Expert Rev. Anticancer Ther. 15(2), (2014)

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#

miR-27b

Tumoral angiogenesis, lymphangiogenesis, tumor progression, nodal metastasis, poor prognosis, proliferation and invasion

Cell proliferation, migration, and invasion and promoted apoptosis and cell cycle arrest

HNSCC, hepatocellular carcinoma, lung cancer and rhabdomyosarcoma

#: Down regulation; ": Up regulation; CSC: Cancer stem cells; EMT: Epithelial mesenchymal transition; HNSCC: Head and neck squamous cell carcinoma.

Mcl-1, c-Met

Oncogene

#

miR-1

TAGLN2, SERP1, SLC44A1, NRG2, MMD, TWF1, PVRL2, C4orf34, LASP1, TSPAN4, NP, PTMA, EBPL, ANXA2P1, SFRS9, FAM101B, CAPN5, SUSD1, TRANK1, C12orf49

HNSCC

Cell proliferation, survival

Tumor suppressor

#

miR-489

PTPN11, EGFR

Acute myeloid leukemia, gastric carcinogenesis, gastric carcinogenesis and prostate cancer

Breast cancer Mitogen-activated protein kinase and Akt, VEGF-A, KRas, Crk,

HNSCC, adenoma, pancreatic cancer, non-small cell lung carcinoma and renal cell carcinoma

VEGF-A

HNSCC

HNSCC, leiomyoma, melanoma, ovarian cancer, colon cancer, gastric cancer and lung cancer

"

Tumor suppressor

RAS, HMGA2, C-myc, Oct4, Nanog, dicer

#

TCPT, TPT1

Oct4 and Nanog, C-myc, RAS, Dicer

"

miR-126

Prognosis, metastasis, recurrence, apoptosis, survival and cell proliferation

Tumor suppressor

#

miR-7 family

HNSCC, renal cell carcinoma, prostate carcinoma, astrocytoma and gastric carcinoma

Invasion or metastasis, apoptosis, tumor progression and poor prognosis

#

miR-149

Cell cycle arrest at the G1 phase, cell proliferation and cell differentiation

HNSCC, gastric, colorectal cancer and gliomas

Cdk6, Mib1, Jard1b, VKORC1 and Ezh2

#

miR-137

Cdk6

HNSCC

#

miR-494

Tumors

HNSCC

Pathways/ significance

#

Validated/putative targets in other cancers

miR-124

Validated/ putative targets in HNSCC

Expression

miRNA

Table 1. Studies of miRNA expression in head and neck squamous cell carcinoma (cont.).

Microarray

Microarray

qRT-PCR

qRT-PCR

qRT-PCR Microarray

Direct sequencing

qRT-PCR

Microarray

Type methods

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[117–120]

[117]

[82–84,113–116]

[41,70]

[43–46,52,90,111,112]

[63,64,86,106–110]

[26,39–42,103–105]

[47]

[38]

Ref.

Role of miRNA in HNSCC

Review

187

188 PKCe, PDCD4

#

miR-107

Oncogene

"

miR-221/ miR-222

c-kit cytokine receptor, estrogen receptor-a, PTEN, TIMP3, Bim, PUMA, p27, p57, Cip/Kip family members

ILK, GNAS, Wnt signaling pathway

Cell cycle progression, oncogenesis, apoptosis and drug resistance

HNSCC, thyroid papillary carcinomas, glioblastoma, hepatocellular cancer, nonsmall cell lung cancer, breast cancer and some prostate cancers

HNSCC, bladder, prostate and breast cancer

HNSCC and endometrial cancer

#: Down regulation; ": Up regulation; CSC: Cancer stem cells; EMT: Epithelial mesenchymal transition; HNSCC: Head and neck squamous cell carcinoma.

Oncogene

"

miR-127

"

HNSCC, breast, B-cell lymphomas, DLBCL lymphomas, colon and lung cancer

miR-744

APC

Oncogene

"

Apoptosis and cell proliferation, tumor angiogenesis, cell survival, invasion, metastasis, cell growth, chemosensitivity and chemoresistance

miR-155

Cytochrome C, TPM1 and bcl-2, PDCD4, CCNB1, VEGF, p53, PTEN, p63

HNSCC, CLL, lung adenocarcinoma, pancreatic cancer, hepatocellular and papillary thyroid carcinoma, multiple myeloma, B-cell lymphoma, uterine, leiomyomas, breast cancer lesions, colorectal cancer, esophageal carcinoma and oral carcinoma, cervical, ovarian and breast tumors

PTEN, BTG-2, PDCD4, p53, p63, TPM1, P12

Oncogene

"

miR-21

HNSCC, breast, ovarian cancer, hepatocellular carcinoma and thyroid papillary carcinoma B-cell chronic lymphocytic leukemia

Cell survival and cell cycle progression, vascular invasion and tumor metastasis

#

CDX2, GATA6, Wnt/ b-catenin signaling, p27Kip1 and Bcl-2

"

miR-181

HNSCC

DNp63 [31]

#

miR-203

Genotoxic damage

HNSCC

Cell proliferation

P53

#

HNSCC, bladder, colon and pancreatic cancer

Tumors

miR-125b

Distant metastasis and poorer clinical outcome

Pathways/ significance

Breast and gastric cancer P53

HIF1-b and CDK6

Validated/putative targets in other cancers

"

Tumor suppressor

Validated/ putative targets in HNSCC

Expression

miRNA

Table 1. Studies of miRNA expression in head and neck squamous cell carcinoma (cont.).

qRT-PCR Microarray

qRT-PCR

Microarray

Microarray qRT-PCR

Microarray qRT-PCR

Microarray qRT-PCR

qRT-PCR

qRT-PCR

qRT-PCR

Type methods

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[27,73–75]

[26,58,60]

[49]

[52,90]

[24,27,45,47–55,90,106,127]

[41,49,64,81,124–126]

[48]

[48,90]

[52,64,121–123]

Ref.

Review Masood, Kqueen & Rajadurai

Expert Rev. Anticancer Ther. 15(2), (2014)

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Oncogene

Tumor suppressor

"

#

miR-141

"

miR-130b

CCNB1, GSS RUNX3, TP53INP1, Wnt signaling, mTOR signaling, TGF-b and MAPK signaling pathway

Cell growth, self-renewal, senescence, cell proliferation and survival

Survival, apoptosis and metastasis

HNSCC, liver cancer, gastric cancer, renal cell carcinoma

HNSCC, metastatic breast cancer, gastric carcinoma and prostate carcinoma

#: Down regulation; ": Up regulation; CSC: Cancer stem cells; EMT: Epithelial mesenchymal transition; HNSCC: Head and neck squamous cell carcinoma.

#

#

TIAM1, LATS2, RhoA

HNSCC

HNSCC, colorectal carcinoma, esophageal carcinoma lung carcinoma, hepatocellular carcinoma, colorectal carcinoma and breast carcinoma

FIH

Invasion, metastasis, EMT, inducing CSC formation, survival, self-renewal and radiochemoresistance in CSC

HNSCC, gastric cancer and prostate cancer

Gastric and renal cell carcinoma

HNSCC, ovarian carcinoma, prostate cancer, adrenocorticotropic hormone pituitary tumor and cholangiocarcinoma

HNSCC, ovarian cancer, hepatocellular carcinoma, gastric cancer, breast cancer, bladder cancer, pancreatic cancer and colorectal cancer

Tumors

"

miR-31*

miR-31

ZEB1 ZEB2, E-cadherin, BMI1, p53, MDM2, p14ARF and DHFR

Cell proliferation and apoptosis

Cell cycle, apoptosis, cell growth, migration and invasion

Growth, invasion, metastasis and cell proliferation

Pathways/ significance

HNSCC, bladder, prostate and breast cancer

BMI1, ZEB1/ZEB2

#

miR-200/205

c-MYC, SPLUNC1, BRD3, UBAP1 and PTEN

Dicer1, E-cadhein, c-MYC

Validated/putative targets in other cancers

"

c-myc,

"

miR-184

Oncogene

Dicer1, K-Ras

Oncogene

"

MiR-18a

c-MYC, SPLUNC1, BRD3, UBAP1 and PTEN. Rb/E2F, JNK2 and AKT pathways

Validated/ putative targets in HNSCC

Expression

miRNA

Table 1. Studies of miRNA expression in head and neck squamous cell carcinoma (cont.).

qRT-PCR

qRT-PCR

qRT-PCR

qRT-PCR Microarray

qRT-PCR

Microarray

Microarray

Type methods

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[27,63,138–140]

[66]

[27,63,64,66,135–137]

[26,45,58–62]

[64,133,134]

[49,57,132]

[24,27,56,128–131]

Ref.

Role of miRNA in HNSCC

Review

189

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Masood, Kqueen & Rajadurai

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migration and invasion through regulating focal adhesion pathway [35]. Furthermore, DNA hypermethylation has been found in head and neck carcinoma that silence miR-218 [35]. Other oncogenic targets of MiR-218 include roundabout homolog 1 (ROBO1), RICTOR, and survivin and laminin-332 in HNSCC [35,36]. Elucidation of tumor suppressive miR-218-mediated novel cancer pathways could provide new insights into the potential mechanisms of HNSCC invasion [36].

expression of let-7a, the incidence of regional metastatic lymph nodes and the risk of local recurrences. Furthermore, let-7a treatment increased the apoptotic activities of aldehyde dehydrogenase 1 (ALDH1+) cells isolated from HNSCC tissues [43,46]. Decreased levels of this miRNA family have also been documented to result in both increased Dicer expression and altered miRNA expression patterns [10]. Future research could reveal further promising therapeutic characteristics in HNSCC.

miR-34a

Studies have suggested that miR-34a has a tumor suppressive role in HNSCC by targeting p53, MYCN, cyclin-dependent kinase 4 (CDK4), cyclin D1, SIRT1, E2F3, survivin, VEGF and Bcl-2 [37]. This miRNA has been shown to affect tumor cell proliferation, apoptosis, senescence, angiogenesis, invasion, metastasis and drug resistance [37,38]. It is strongly proposed that miR-34a is an important independent biomarker for detecting cis-diamminedichloroplatinum resistance and could be used a prognostic marker in HNSCC patients treated with cis-diamminedichloroplatinum. Further genetic and epigenetic studies of the miR-34a are necessary that could help in managing HNSCC patients [38]. miRNA-137

Several studies have shown that miR-137 is downregulated in HNSCC compared to normal tissues, but no scientific expression pattern has been noted between non-metastatic and metastatic tumors [26,39,40]. This downregulation is associated with promoter methylation [26,40,41]. It targets Cdk6 that is an important regulator of cell cycle progression [41,42]. Moreover, studies indicate that miR-137 methylation is associated with a poorer overall survival in HNSCC patients, and also related with tumor grade [40]. CpG methylation silencing in HNSCC may not be detectable in total, heterogeneous tumor samples. This is in line with another study, where CpG methylation was undetected in all the HNSCC tissues. Whereas, in purified populations of cancer stem cells (CSCs) with CD44 high, mature miR-137 was readily detectable. Similar increase in CD44 high CSCs was observed that was epigenetically independent. This demonstrates that miR-137 expression is regulated by other mechanisms, which could account for the undetected methylation silencing [26]. miRNA-let7

Studies have documented miR-7 as tumor suppressor in HNSCC. Reports have claimed that let-7 targets a number of genes such as RAS or high mobility group (HMGA2). Interestingly, decreased let-7 expression levels are associated with KRAS-LCS6 variant allele associated with poor prognosis in HNSCC patients [43,44]. More recently, it has been shown that oncogene C-myc overexpression might be a reason for let-7 miRNA repression in HNSCC and has been correlated with poor prognosis, reduced survival and increased frequency of metastasis [45,46]. Another study has demonstrated that increased expression of Oct4 and Nanog is associated with decreased 190

miR-21

miR-21 is one of the widely studied miRNAs with a clear role as a putative oncogene in HNSCC [27,47,48]. However, it is reported that miR-21 is not differentially expressed between cancer and normal tissues in prostate, gastric, male breast cancer and head and neck cancer [49–51]. This could be due to siteand tissue-specific differences, subject ethnicity and also varied methods used for miRNA profiling and data analysis [49]. miR-21 is found to target the expression of tropomyosin 1 (TPM1), bcl-2 expression, p63 isoforms, B-cell translocation gene 2 (BTG2), TAp63 and p53 [45,48]. Other studies have reported that it also targets programmed cell death 4 (PDCD4) that regulates cellular proliferation, apoptosis, invasion, metastasis, tumor angiogenesis and survival [24,52–55]. Child et al. suggested that miR-21 causes translational inhibition of phosphatase and tensin homolog in HNSCC that is responsible for loss of heterozygosity and mutation [45]. Chang et al. provided the evidence that miR-21 decrease the cytochrome C release that exerts a growth advantage. This supports the possibility that miR-21 inhibits several mRNAs that give rise to many events that prevent apoptosis and increase cellular proliferation [47]. In addition, it is reported that HNSCC patients with high miR-21 expression had worse survival [27]. Relationship between miR-21 and these molecules should be explored further and could be used as an indicator of prognosis and a potential therapeutic target for HNSCC. miR-18a

The expression of miR-18a is a member of the oncogenic miR 17-92 cluster and has been shown to be associated with occurrence and progression of HNSCC [24,56]. It is also demonstrated that Dicer1 is a direct target of miR-18a and a higher expression level of miR-18a is inversely correlated to the expression levels of Dicer1 and also associated with advanced stage and lymph node metastasis. Moreover, results have revealed that miR-18a also downregulates many miRNAs, for example, the miR-200 family and miR-143 through Dicer1 [56]. Hence, inhibition of miR-18a could help in decreasing metastatic risk and progression of HNSCC. miR-141

The expression of miR-141 is upregulated and it acts as an oncogene in HNSCC tumor samples. It has been shown to directly target bromodomain-containing protein 3 (BRD3), ubiquitin-associated protein 1 (UBAP1) and phosphatase and Expert Rev. Anticancer Ther. 15(2), (2014)

Role of miRNA in HNSCC

tensin homolog, and is associated with reduced apoptosis and increased cell cycle, cell growth, migration and invasion. miR-141 inhibition does also result in the modulation of some molecules in the Rb/E2F, c-Jun N-terminal kinases (JNK2) and AKT pathways [57].

Review

reported that miR-31* targets many oncogenes, including G2/Mspecific cyclin-B1, glutathione synthetase (GSS) and RhoA [66]. Future studies are required to exploit the therapeutic implications of these findings for treatment of HNSCC. Discussion

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miRNA-200/205

One of the miRNAs with disputed findings in expression levels between nonmalignant head and neck tissue and HNSCC tumor samples is miR-200/205. miR-205 acts as tumor suppressor gene. Its downregulation is associated with locoregional recurrence in HNSCC. Combined lower expression of miR-205 and let-7d was also observed with poor head and neck cancer survival and distant metastasis, that were independent of anatomical site, stage of tumor and treatment. miR-205 is found to target p53, mouse double minute 2 homolog, p14ARF and dihydrofolate reductase [45]. However, contradictory to this, it is speculated that the miR-200 family and miR-205 are coordinately regulated and they are epigenetically activated by hypomethylation but no obvious change was found between metastatic and non-metastatic tumors [26,58–60]. miR-200/205 also targets ZEB1 and ZEB2 [61]. miR-200c expression is downregulated in HNSCC and by negatively regulating the expression of BMI1 [62]. Repression of the miR-200s and miR-205 could lead to silencing of E-cadherin and BMI1, followed by epithelial mesenchymal transition, thereby inducing CSC formation [59,61]. It is revealed that miR-200/miR-205 are epithelial-specific and they are found to be activated all the way from normal tissue transformation to carcinoma in situ, but becomes specifically repressed during epithelial mesenchymal transition. The specific silencing of miR-200/miR-205 is epigenetically independent in mesenchymal-like oral CSC with CD44 high. Thus, other mechanisms may be responsible for initiation of the primary repression, and epigenetic silencing could play a secondary and more definitive event in progression of the tumor mass. By targeting BMI1 and ZEB1/ZEB2, miR-200c may suppress self-renewal, radiochemoresistance and metastatic properties of CSCs as well as progression in HNSCC [62]. miR200/205 may be important for tumor invasion and recurrence and may provide powerful complementary therapeutic cancer targets [26]. miR-31

Over-expression of miR-31 is found in HNSCC by transactivating hypoxia-inducible factor in normoxia by targeting factorinhibiting hypoxia-inducible factor, that resulted in increased level of VEGF and several other factors that augment pathogenesis [27]. However, the oncogenic potential of miR-31 is known to be diminished in the state of hypoxia [63]. These effects involve targeting of T-cell lymphoma invasion and metastasis 1 and large tumor suppressor kinase 2 (LATS2) [64–66]. In contrast, low expression is also reported in HNSCC, and loss of heterozygosity at 9p21 could be the cause [63]. Recently, it was found that passenger strand miR-31* is also a distinct and functional miRNA and may counteract the function of miR-31 in HNSCC. It is informahealthcare.com

HNSCC are the most frequent malignancies of the upper aerodigestive tract [4]. The poor prognosis and the survival rate have not improved significantly over the last few decades, despite more aggressive surgical treatment, radiotherapy and chemotherapy [4,7]. This high mortality rate is due to tissue invasion as well as tumor resistance to radiation treatment and chemotherapy. Therefore, it is vital to develop new therapeutic approaches to increase the patient survival and decrease the adverse effects associated with chemoradiation. Recent studies have demonstrated that some of the miRNAs found differentially expressed in HNSCC may play an important role in initiation or progression of the disease [37]. miRNA has been considered a more suitable potential biomarker than protein biomarkers for clinical applications in cancer prognosis because they have unique expression profiles in cancerous tissue compared to normal tissue, have more stable expression than mRNA and can be easily accessed by qRT-PCR [67]. miRNA genes represent about 1% of the genome but are estimated to regulate up to 30% of human genes [14,15]. Given their capacity for targeting up to 200 different mRNAs simultaneously, and thus biological pathways, miRNAs are particularly attractive candidates [68]. In addition to this, single miRNA reversion in the malignant expression could have beneficial effects on hundreds of genes and affect numerous key pathways [69]. miRNA may function as an oncogene or as a tumor suppressor gene and are tumor, and cell-type specific and can even precisely differentiate tumor subtypes and also depend on patient organization, tumor site, status or histologic tumor grade, and so on [24,70]. Besides the up- and downregulated miRNAs, a number of studies dispute the expression levels of miRNAs, for example, miR31 (TABLE 1). These contrary findings may be attributed to the experimental framework of the studies, different models and the recognized fact that the tumor niche is a governing factor with respect to gene expression and regulation [71]. Further resolution and characterization of the key regulatory determinants should be undertaken. Out of 38 studies reviewed in this article, 26 studies used qRT-PCR and 12 used microarray for profiling the miRNA. Although qRT-PCR is often considered as the ‘gold standard’ in the detection and quantitation of gene expression, it is probably better used as a validation rather than a profiling tool because of rapid increase in number of miRNAs that makes qPCR inefficient. Currently, next-generation sequencing is considered as the most preferable for miRNA profiling due to advances in sequencing technology, that have accelerated the discovery rate of new miRNAs and modifications to existing miRNA entries and identification of novel miRNAs [72]. Numerous studies have indicated that miRNA alterations associated with HNSCC play important roles in regulating cell proliferation, apoptosis, metastasis, drug resistance and prognosis. Hence, these miRNAs could play potential role as diagnostic and 191

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Masood, Kqueen & Rajadurai

prognostic biomarkers [68]. Among them, miR-21 is most extensively studied in many cancers and may be the most attractive biomarker for clinical application and has been considered as very promising for prediction of prognosis [69]. Its overexpression is positively correlated with metastasis and reduced survival in HNSCC patients [24,27,52]. It is found that many miRNAs, for example, 375, 200c, 221/222 play important roles in resistance against certain drugs [25,62,73–76]. Other groups have reported an association between downregulation of miR-133a and miR-218 and migration and invasion in HNSCC and other cancers [28–30,35,77]. Studies have also shown that miR-34a downregulation has been found to induce tumor cell proliferation, apoptosis, senescence, angiogenesis, invasion, metastasis and drug resistance in prostate, hepatocellular cancer and HNSCC [37,78,79]. In addition, methylation of miR-9 appears to suppress tumor progression and metastasis in recurrent hepatic cell carcinoma and HNSCC [39,41,80]. Furthermore, results from one study suggest that upregulation of miR-181 is associated with vascular invasion, lymph node metastasis and poor prognosis in HNSCC patients [81]. Moreover, studies indicate that miR-137 methylation is also associated with a poorer overall survival in HNSCC patients and related with tumor grade [40]. Some reports have demonstrated that higher expression level of miR-18a is related with advanced stage and lymph node metastasis in nasopharyngeal cancer samples [56]. In addition to this, previous reports have shown that miR-126 acts as a tumor suppressor gene in many malignant tumors, including HNSCC tissues and is associated with the induction of tumor angiogenesis, lymphangiogenesis, tumor progression, nodal metastasis and poor prognosis in oral cancer patients [82–84]. As far as let-7 family is concerned, it is reported that tumor suppressor role of let-7a is associated with increased expression of the stemness genes Oct4 and Nanog, regional lymph nodes metastasis and local recurrences of head and neck cancer [43,46]. Reduced level of this family in tumors is also related to poor prognosis, reduced survival in lung cancer and HNSCC [45,46,85]. Furthermore, combined lower expression of miR-205 and let-7d are also associated with poor survival and distant metastasis that are independent of anatomical site, stage of tumor and treatment [46]. Evidences have proposed that some miRNA expression ratios distinguish diseased tissue from nondiseased tissue and may be utilized in diagnosing HNSCC at an early stage [27]. Li et al. have identified that a panel of miRNAs may be a stronger predictor for survival than a single miRNA [69]. In line with this, the ratio of miR-221:miR-375 demonstrated high discriminatory potential, with a sensitivity of 92% and specificity of 93% in distinguishing HNSCC tumor from normal tissue [27]. Recently, few studies have claimed that miRNA regulate the metastatic properties of CSC and epithelial mesenchymal transition. For instance, miR-375 and MiR-200c may suppress self-renewal, invasion and metastatic properties of CSCs as well as cancer progression in HNSCC [62,76,86]. Novel therapies are perhaps the most exciting aspect in the developing field of miRNAs in HNSCC. The successful targeting and regulation of miRNA in vivo is exciting, followed by in vitro strategies for determining gain of function and the 192

silencing of select miRNA. Many studies have utilized in vivo and in vitro models that are the first important steps, followed by miRNA delivery for clinical application as the next step to therapeutic development [68]. Technological advances are enabling the synthesis of pre- or anti-RNA molecules within carrier vehicles that can be safely delivered into patients [87]. For example, ectopic transfection of miR-137 and miR-193a into HNSCC cell lines lacking expression of these miRNAs readily reduced cell growth [41]. These molecules can be administered topically or systematically to induce generalized cell targeting. If the targeted event is cell specific, then the affects should be harmless to normal cells and antineoplastic [87]. For instance, a study done by Kota et al. demonstrated that systemic delivery of miR-26a in a murine model of hepatocellular carcinoma could reduce liver tumor size by inhibiting the cancer cell proliferation, induction of tumor-specific apoptosis and surprisingly, protection from disease progression without toxicity. This suggests that administration of miRNAs that are overexpressed and therefore well accepted in normal tissues [88]. Furthermore, inhibiting the expression of oncogenic miRNAs and increasing the expression of tumor suppressor miRNAs in HNSCC could be successful therapeutic approaches [89]. However, limited data is available on specific miRNA expression signatures in HNSCC clinical specimens [45,52,90]. Therefore, future studies are essential to examine the potential for associations between miRNA expression and clinical parameters such as tumor stage, the presence of metastasis and prognosis in a larger series of HNSCC [27]. Summary

MiRNAs are important modulators of gene expression. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They are frequently altered in HNSCC and as such offer the potential to be used as biomarkers or novel therapeutic targets. Future study is required to test their use in both of these fields. Expert commentary

It is important to note that HNSCC constitutes an anatomically heterogeneous group arising most often from the oral cavity, lip, nose and paranasal sinuses and nasopharynx, larynx hypophaynx oropharynx, thyroid and salivary glands. Although it is a common disease, there is not much improvement in the survival of patients. miRNAs are important modulators of gene expression and their deregulation in HNSCC may serve as important biomarkers for early diagnosis, treatment evaluation, recurrence and prognosis, and also used as novel therapeutic targets. Extensive studies of specific roles of miRNAs are required that will further help to understand the complexity of HNSCC progression and behavior. Five-year view

MiRNAs play an important role in several cellular processes of HNSCC and their deregulation can lead to cancer. Many studies have investigated the utility of miRNAs as diagnostic/ Expert Rev. Anticancer Ther. 15(2), (2014)

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Role of miRNA in HNSCC

prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. Although the in vivo delivery of miRNA has proved challenging, recently there have been significant advances, for example: the use of a nanoparticle system to successfully deliver siRNA in melanoma [91]. This suggests that the design of a similar system to deliver miRNA for HNSCC may not be beyond the realms of possibility in the future. Further studies are necessary to elucidate the precise role of miRNAs as pathways on apoptosis, cellular progression, resistance and metastasis; this

Review

could provide even further prognostic/therapeutic values of miRNAs in HNSCC. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. • Based on the literature, it appears that the dysregulation of miRNA in HNSCC is either over-expression, under expression or both. • miRNA has been considered as more suitable potential biomarker than protein biomarkers for clinical applications in cancer prognosis. • Next-generation sequencing is considered as the most preferable for miRNA profiling due to advances in sequencing technology. • Evidences have proposed that some miRNA expression ratios distinguish diseased tissue from non-diseased tissue and may be utilized in diagnosing HNSCC at an early stage. • Few studies have claimed that miRNA regulate the metastatic properties of cancer stem cells and epithelial mesenchymal transition. • Novel therapies are perhaps the most exciting aspect in the developing field of miRNAs in HNSCC.

altering the invasive properties of head and neck squamous cell carcinomas. Am J Pathol 2012;180(3):917-28

References 1.

2.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62(1):10-29 Petersen PE. Oral cancer prevention and control–the approach of the World Health Organization. Oral Oncol 2009;45(4-5): 454-60

3.

Petti S, Mohd M, Scully C. Revisiting the association between alcohol drinking and oral cancer in nonsmoking and betel quid non-chewing individuals. Cancer Epidemiol 2012;36(1):e1-6

4.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2):71-96

5.

Petti S, Masood M, Scully C. The magnitude of tobacco smoking-betel quid chewing-alcohol drinking interaction effect on oral cancer in South-East Asia. A metaanalysis of observational studies. PLoS One 2013;8(11):e78999

6.

7.

8.

9.

Petti S, Masood M, Scully C. Alcohol is not a risk factor for oral cancer in non-smoking, betel quid non-chewing individuals. A meta-analysis update. Annali Di Igiene 2013;25(1):12 Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011;11(1):9-22 Harris T, Jimenez L, Kawachi N, et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while

informahealthcare.com

Guo X, Liao Q, Chen P, et al. The microRNA-processing enzymes: Drosha and Dicer can predict prognosis of nasopharyngeal carcinoma. J Cancer Res Clin Oncol 2012;138(1):49-56

10.

Jakymiw A, Patel RS, Deming N, et al. Overexpression of dicer as a result of reduced let-7 microRNA levels contributes to increased cell proliferation of oral cancer cells. Genes Chromosomes Cancer 2010; 49(6):549-59

11.

Siriwardena BS, Rasnayaka RM, Masood Y, et al. A predictive model of oral cancer metastasis for different cancer sites and age groups. J Invest Clin Dentistry 2014;In press

12.

Esquela-Kerscher A, Slack FJ. Oncomirs microRNAs with a role in cancer. Nat Rev Cancer 2006;6(4):259-69

13.

Lee Y, Ahn C, Han J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425(6956):415-19

14.

de la Chapelle A, Jazdzewski K. MicroRNAs in thyroid cancer. J Clin Endocrinol Metab 2011;96(11):3326-36

15.

Nohata N, Hanazawa T, Kinoshita T, et al. MicroRNAs function as tumor suppressors or oncogenes: aberrant expression of microRNAs in head and neck squamous cell

carcinoma. Auris Nasus Larynx 2013;40(2): 143-9 16.

Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009;10(10):704-14

17.

Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31(1):27-36

18.

Carvalho AL, Jeronimo C, Kim MM, et al. Evaluation of promoter hypermethylation detection in body fluids as a screening/ diagnosis tool for head and neck squamous cell carcinoma. Clin Cancer Res 2008;14(1): 97-107

19.

Gorenchtein M, Poh CF, Saini R, Garnis C. MicroRNAs in an oral cancer context - from basic biology to clinical utility. J Dent Res 2012;91(5):440-6

20.

Christensen BC, Avissar-Whiting M, Ouellet LG, et al. Mature microRNA sequence polymorphism in MIR196A2 is associated with risk and prognosis of head and neck cancer. Clin Cancer Res 2010;16(14):3713-20

21.

Flavin RJ, Smyth PC, Finn SP, et al. Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients. Mod Pathol 2008;21(6):676-84

22.

Selbach M, Schwanhausser B, Thierfelder N, et al. Widespread changes in protein synthesis induced by microRNAs. Nature 2008;455(7209):58-63

193

Review 23.

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

Masood, Kqueen & Rajadurai

Yan B, Fu Q, Lai L, et al. Downregulation of microRNA 99a in oral squamous cell carcinomas contributes to the growth and survival of oral cancer cells. Mol Med Rep 2012;6(3):675-81 Avissar M, McClean MD, Kelsey KT, Marsit CJ. MicroRNA expression in head and neck cancer associates with alcohol consumption and survival. Carcinogenesis 2009;30(12):2059-63

carcinoma. Int J Oncol 2011;39(5): 1099-107 34.

35.

Nohata N, Hanazawa T, Kikkawa N, et al. Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC). J Hum Genet 2011;56(8):595-601 Wiklund ED, Gao S, Hulf T, et al. MicroRNA alterations and associated aberrant DNA methylation patterns across multiple sample types in oral squamous cell carcinoma. PLoS One 2011;6(11):e27840 Avissar M, Christensen BC, Kelsey KT, Marsit CJ. MicroRNA expression ratio is predictive of head and neck squamous cell carcinoma. Clin Cancer Res 2009;15(8): 2850-5 Kano M, Seki N, Kikkawa N, et al. miR145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer 2010;127(12): 2804-14 Kojima S, Chiyomaru T, Kawakami K, et al. Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer. Br J Cancer 2012;106(2): 405-13 Yoshino H, Chiyomaru T, Enokida H, et al. The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer. Br J Cancer 2011;104(5): 808-18 Kinoshita T, Nohata N, Watanabe-Takano H, et al. Actin-related protein 2/3 complex subunit 5 (ARPC5) contributes to cell migration and invasion and is directly regulated by tumor-suppressive microRNA-133a in head and neck squamous cell carcinoma. Int J Oncol 2012;40(6):1770-8 Nohata N, Hanazawa T, Kikkawa N, et al. Caveolin-1 mediates tumor cell migration and invasion and its regulation by miR-133a in head and neck squamous cell carcinoma. Int J Oncol 2011;38(1):209-17 Nohata N, Hanazawa T, Kikkawa N, et al. Identification of novel molecular targets regulated by tumor suppressive miR-1/miR133a in maxillary sinus squamous cell

194

36.

37.

38.

39.

40.

41.

42.

43.

44.

Kinoshita T, Nohata N, Fuse M, et al. Tumor suppressive microRNA-133a regulates novel targets: moesin contributes to cancer cell proliferation and invasion in head and neck squamous cell carcinoma. Biochem Biophys Res Commun 2012; 418(2):378-83 Uesugi A, Kozaki K, Tsuruta T, et al. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res 2011;71(17):5765-78 Kinoshita T, Hanazawa T, Nohata N, et al. Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion through targeting laminin-332 in head and neck squamous cell carcinoma. Oncotarget 2012; 3(11):1386-400 Kumar B, Yadav A, Lang J, et al. Dysregulation of microRNA-34a expression in head and neck squamous cell carcinoma promotes tumor growth and tumor angiogenesis. PLoS One 2012;7(5):e37601 Ogawa T, Saiki Y, Shiga K, et al. miR-34a is downregulated in cis-diamminedichloroplatinum treated sinonasal squamous cell carcinoma patients with poor prognosis. Cancer Sci 2012; 103(9):1737-43 Langevin SM, Stone RA, Bunker CH, et al. MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. Carcinogenesis 2010;31(5):864-70 Langevin SM, Stone RA, Bunker CH, et al. MicroRNA-137 promoter methylation is associated with poorer overall survival in patients with squamous cell carcinoma of the head and neck. Cancer 2011;117(7): 1454-62 Kozaki K, Imoto I, Mogi S, et al. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res 2008;68(7):2094-105 Shomron N. MicroRNAs and pharmacogenomics. Pharmacogenomics 2010;11(5):629-32 Christensen BC, Moyer BJ, Avissar M, et al. A let-7 microRNA-binding site polymorphism in the KRAS 3’ UTR is associated with reduced survival in oral cancers. Carcinogenesis 2009;30(6):1003-7 Tran N, O’Brien CJ, Clark J, Rose B. Potential role of micro-RNAs in head and

neck tumorigenesis. Head Neck 2010;32(8): 1099-111 45.

Childs G, Fazzari M, Kung G, et al. Low-level expression of microRNAs let-7d and miR-205 are prognostic markers of head and neck squamous cell carcinoma. Am J Pathol 2009;174(3):736-45

46.

Yu CC, Chen YW, Chiou GY, et al. MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation. Oral Oncol 2011;47(3):202-10

47.

Chang SS, Jiang WW, Smith I, et al. MicroRNA alterations in head and neck squamous cell carcinoma. Int J Cancer 2008;123(12):2791-7

48.

Boldrup L, Coates PJ, Wahlgren M, et al. Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins. J Carcinog 2012;11:18

49.

Nurul-Syakima AM, Yoke-Kqueen C, Sabariah AR, et al. Differential microRNA expression and identification of putative miRNA targets and pathways in head and neck cancers. Int J Mol Med 2011;28(3):327-36

50.

Ambs S, Prueitt RL, Yi M, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 2008;68(15):6162-70

51.

Fassan M, Baffa R, Palazzo JP, et al. MicroRNA expression profiling of male breast cancer. Breast Cancer Res 2009; 11(4):R58

52.

Ramdas L, Giri U, Ashorn CL, et al. miRNA expression profiles in head and neck squamous cell carcinoma and adjacent normal tissue. Head Neck 2009;31(5): 642-54

53.

Guo J, Miao Y, Xiao B, et al. Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol 2009;24(4):652-7

54.

Motoyama K, Inoue H, Takatsuno Y, et al. Over- and under-expressed microRNAs in human colorectal cancer. Int J Oncol 2009; 34(4):1069-75

55.

Reis PP, Tomenson M, Cervigne NK, et al. Programmed cell death 4 loss increases tumor cell invasion and is regulated by miR-21 in oral squamous cell carcinoma. Mol Cancer 2010;9:238

56.

Luo Z, Dai Y, Zhang L, et al. miR-18a promotes malignant progression by impairing microRNA biogenesis in

Expert Rev. Anticancer Ther. 15(2), (2014)

Role of miRNA in HNSCC

nasopharyngeal carcinoma. Carcinogenesis 2013;34(2):415-25 57.

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

58.

59.

Zhang L, Deng T, Li X, et al. microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network. Carcinogenesis 2010;31(4):559-66 Vrba L, Jensen TJ, Garbe JC, et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One 2010; 5(1):e8697 Shimono Y, Zabala M, Cho RW, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009;138(3):592-603

60.

Wiklund ED, Bramsen JB, Hulf T, et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer 2011;128(6): 1327-34

61.

Wellner U, Schubert J, Burk UC, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009;11(12):1487-95

62.

63.

64.

65.

66.

67.

68.

69.

Li X, Zhang Y, Zhang Y, et al. Survival prediction of gastric cancer by a sevenmicroRNA signature. Gut 2010;59:579-85

70.

Lo WY, Wang HJ, Chiu CW, Chen SF. miR-27b-regulated TCTP as a novel plasma biomarker for oral cancer: from quantitative proteomics to post-transcriptional study. J Proteomics 2012;77:154-66

71.

72.

Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012;196(4): 395-406 Git A, Dvinge H, Salmon-Divon M, et al. Systematic comparison of microarray profiling, real-time PCR, and next-generation sequencing technologies for measuring differential microRNA expression. RNA 2010;16(5): 991-1006

Review

81.

Yang CC, Hung PS, Wang PW, et al. miR-181 as a putative biomarker for lymph-node metastasis of oral squamous cell carcinoma. J Oral Pathol Med 2011;40(5): 397-404

82.

Jiao LR, Frampton AE, Jacob J, et al. MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS One 2012;7(2):e32068

83.

Donnem T, Fenton CG, Lonvik K, et al. MicroRNA signatures in tumor tissue related to angiogenesis in non-small cell lung cancer. PLoS One 2012;7(1):e29671

84.

Sasahira T, Kurihara M, Bhawal UK, et al. Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. Br J Cancer 2012;107(4):700-6

85.

Osada H, Takahashi T. let-7 and miR-1792: small-sized major players in lung cancer development. Cancer Sci 2011;102(1):9-17

86.

Tu HF, Liu CJ, Chang CL, et al. The association between genetic polymorphism and the processing efficiency of miR-149 affects the prognosis of patients with head and neck squamous cell carcinoma. PLoS One 2012;7(12):e51606

87.

Catto JW, Alcaraz A, Bjartell AS, et al. MicroRNA in prostate, bladder, and kidney cancer: a systematic review. Eur Urol 2011; 59(5):671-81

73.

Zhang J, Han L. Ge Y, et al. miR-221/ 222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol 2010;36(4):913-20

74.

Yang CJ, Shen WG, Liu CJ, et al. miR-221 and miR-222 expression increased the growth and tumorigenesis of oral carcinoma cells. J Oral Pathol Med 2011; 40(7):560-6

75.

Garofalo M, Di Leva G, Romano G, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 2009;16(6):498-509

88.

76.

Wong TS, Liu XB, Wong BY, et al. Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res 2008;14(9): 2588-92

Hui AB, Bruce JP, Alajez NM, et al. Significance of dysregulated metadherin and microRNA-375 in head and neck cancer. Clin Cancer Res 2011;17(24):7539-50

Kota J, Chivukula RR, O’Donnell KA, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009;137(6):1005-17

89.

77.

Zhang T, Wang Q, Zhao D, et al. The oncogenetic role of microRNA-31 as a potential biomarker in oesophageal squamous cell carcinoma. Clin Sci (Lond) 2011;121(10):437-47

Tie J, Pan Y, Zhao L, et al. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet 2010;6(3): e1000879

Liu X, Wang A, Heidbreder CE, et al. MicroRNA-24 targeting RNA-binding protein DND1 in tongue squamous cell carcinoma. FEBS Lett 2010;584(18): 4115-20

90.

78.

Li N, Fu H, Tie Y, et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 2009;275(1): 44-53

Hui AB, Lenarduzzi M, Krushel T, et al. Comprehensive MicroRNA profiling for head and neck squamous cell carcinomas. Clin Cancer Res 2010;16(4):1129-39

91.

Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010; 464(7291):1067-70

92.

Gallardo E, Navarro A, Vinolas N, et al. miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer. Carcinogenesis 2009;30(11):1903-9

93.

Minor J, Wang X, Zhang F, et al. Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas. Oral Oncol 2012;48(1):73-8

Lo WL, Yu CC, Chiou GY, et al. MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells. J Pathol 2011;223(4):482-95 Liu CJ, Tsai MM, Hung PS, et al. miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma. Cancer Res 2010;70(4):1635-44

Chang KW, Kao SY, Wu YH, et al. Passenger strand miRNA miR-31* regulates the phenotypes of oral cancer cells by targeting RhoA. Oral Oncol 2013;49(1): 27-33 Ferracin M, Veronese A, Negrini M. Micromarkers: miRNAs in cancer diagnosis and prognosis. Expert Rev Mol Diagn 2010;10(3):297-308 Nana-Sinkam P, Croce CM. MicroRNAs in diagnosis and prognosis in cancer: what does the future hold? Pharmacogenomics 2010;11(5):667-9

informahealthcare.com

79.

80.

Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011;17(2): 211-15 Hildebrandt MA, Gu J, Lin J, et al. Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene 2010;29(42): 5724-8

195

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

Review

Masood, Kqueen & Rajadurai

94.

Hsu PY, Deatherage DE, Rodriguez BA, et al. Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. Cancer Res 2009;69(14): 5936-45

95.

Guo LM, Pu Y, Han Z, et al. MicroRNA-9 inhibits ovarian cancer cell growth through regulation of NF-kappaB1. FEBS J 2009;276(19):5537-46

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

Li D, Chen P, Li XY, et al. Grade-specific expression profiles of miRNAs/mRNAs and docking study in human grade I–III astrocytomas. OMICS 2011;15(10):673-82

108.

Zhang M, Jin M, Yu Y, et al. Associations of miRNA polymorphisms and female physiological characteristics with breast cancer risk in Chinese population. Eur J Cancer Care (Engl) 2012;21(2):274-80

Wan HY, Guo LM, Liu T, et al. Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma. Mol Cancer 2010;9:16

109.

Hu X, Schwarz JK, Lewis JS Jr, et al. A microRNA expression signature for cervical cancer prognosis. Cancer Res 2010; 70(4):1441-8

110.

Ma L, Young J, Prabhala H, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 2010;12(3):247-56 Kim MS, Lee J, Sidransky D. DNA methylation markers in colorectal cancer. Cancer Metastasis Rev 2010;29(1): 181-206 Huang Z, Huang S, Wang Q, et al. MicroRNA-95 promotes cell proliferation and targets sorting Nexin 1 in human colorectal carcinoma. Cancer Res 2011; 71(7):2582-9

111.

112.

Jin L, Hu WL, Jiang CC, et al. MicroRNA149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma. Proc Natl Acad Sci USA 2011;108(38):15840-5 Vinci S, Gelmini S, Pratesi N, et al. Genetic variants in miR-146a, miR-149, miR-196a2, miR-499 and their influence on relative expression in lung cancers. Clin Chem Lab Med 2011;49(12):2073-80 Nam EJ, Yoon H, Kim SW, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008; 14(9):2690-5 Motoyama K, Inoue H, Nakamura Y, et al. Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res 2008;14(8):2334-40

120.

Nasser MW, Datta J, Nuovo G, et al. Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1. J Biol Chem 2008; 283(48):33394-405

121.

Martello G, Rosato A, Ferrari F, et al. A microRNA targeting dicer for metastasis control. Cell 2010;141(7):1195-207

122.

Feng L, Xie Y, Zhang H, Wu Y. miR-107 targets cyclin-dependent kinase 6 expression, induces cell cycle G1 arrest and inhibits invasion in gastric cancer cells. Med Oncol 2012;29(2):856-63

123.

Datta J, Smith A, Lang JC, et al. microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cvarepsilon. Oncogene 2012;31(36):4045-53

124.

Chen G, Zhu W, Shi D, et al. MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep 2010;23(4): 997-1003

125.

Ji J, Yamashita T, Budhu A, et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009;50(2):472-80

126.

Wang X, Gocek E, Liu CG, Studzinski GP. MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle 2009;8(5):736-41

113.

Otsubo T, Akiyama Y, Hashimoto Y, et al. MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One 2011;6(1):e16617

114.

Meister J, Schmidt MH. miR-126 and miR-126*: new players in cancer. Sci World J 2010;10:11

Li WG, Yuan YZ, Qiao MM, Zhang YP. High dose glargine alters the expression profiles of microRNAs in pancreatic cancer cells. World J Gastroenterol 2012;18(21): 2630-9

115.

Slaby O, Redova M, Poprach A, et al. Identification of MicroRNAs associated with early relapse after nephrectomy in renal cell carcinoma patients. Genes Chromosomes Cancer 2012;51(7):707-16

127.

Bandres E, Agirre X, Bitarte N, et al. Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 2009;125(11):2737-43

116.

Watahiki A, Wang Y, Morris J, et al. MicroRNAs associated with metastatic prostate cancer. PLoS One 2011;6(9): e24950

Zheng J, Xue H, Wang T, et al. miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion. J Cell Biochem 2011;112(3):872-80

128.

Ando T, Yoshida T, Enomoto S, et al. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer 2009; 124(10):2367-74

117.

Tao J, Wu D, Li P, Xu B, Lu Q, Zhang W. microRNA-18a, a member of the oncogenic miR-17-92 cluster, targets Dicer and suppresses cell proliferation in bladder cancer T24 cells. Mol Med Report 2012;5:6

129.

Wu CW, Dong YJ, Liang QY, et al. MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. PLoS One 2013;8(2):e57036

130.

Liu WH, Yeh SH, Lu CC, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009;136(2):683-93

131.

Castellano L, Giamas G, Jacob J, et al. The estrogen receptor-alpha-induced

Miko E, Czimmerer Z, Csanky E, et al. Differentially expressed microRNAs in small cell lung cancer. Exp Lung Res 2009;35(8): 646-64

Smrt RD, Szulwach KE, Pfeiffer RL, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010;28(6): 1060-70 Liu Z, Li G, Wei S, et al. Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck. Cancer 2010;116(20):4753-60

196

118.

119.

Kikkawa N, Hanazawa T, Fujimura L, et al. miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC). Br J Cancer 2010;103(6):877-84 Datta J, Kutay H, Nasser MW, et al. Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 2008;68(13):5049-58 Nohata N, Sone Y, Hanazawa T, et al. miR-1 as a tumor suppressive microRNA targeting TAGLN2 in head and neck squamous cell carcinoma. Oncotarget 2011;2(1-2):29-42

Expert Rev. Anticancer Ther. 15(2), (2014)

Role of miRNA in HNSCC

microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA 2009;106(37):15732-7 132.

Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

133.

134.

Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J Pathol 2008;216(4):418-27 Xu Y, Ma H, Yu H, et al. The miR-184 binding-site rs8126 T>C polymorphism in TNFAIP2 is associated with risk of gastric cancer. PLoS One 2013; 8(5):e64973 Walter BA, Valera VA, Pinto PA, Merino MJ. Comprehensive microRNA Profiling of Prostate Cancer. J Cancer 2013;4(5):350-7

informahealthcare.com

Review

135.

Cottonham CL, Kaneko S, Xu L. miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem 2010;285(46):35293-302

139.

Ma S, Tang KH, Chan YP, et al. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 2010;7(6):694-707

136.

Schaefer A, Jung M, Mollenkopf HJ, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer 2010;126(5):1166-76

140.

137.

Zhang Y, Guo J, Li D, et al. Down-regulation of miR-31 expression in gastric cancer tissues and its clinical significance. Med Oncol 2010;27(3):685-9

Yeung ML, Yasunaga J, Bennasser Y, et al. Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressor in cell growth dysregulation by human T-cell lymphotrophic virus 1. Cancer Res 2008; 68(21):8976-85

138.

Lai KW, Koh KX, Loh M, et al. MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer. Eur J Cancer 2010;46(8):1456-63

197

Role of miRNA in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in p...
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