Review
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Gastrointestinal cancer and drug resistance
2.
MicroRNA and drug resistance
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The effect of miRNAs on CDDP and 5-flu resistance in
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esophageal cancer 4.
The effect of miRNAs on CDDP and 5-flu resistance in gastric cancer
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The effect of miRNAs on CDDP and 5-flu resistance in colorectal cancer
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The effect of miRNAs on paclitaxel resistance in GI cancer
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The effect of miRNAs on other drug-induced resistance in GI cancer
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Conclusion
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Expert opinion
MicroRNAs in gastrointestinal cancer: prognostic significance and potential role in chemoresistance Liu Hong, Yu Han, Jianjun Yang, Hongwei Zhang, Qingchuan Zhao, Kaichun Wu & Daiming Fan† †
Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Xi’an, China
Introduction: Although chemotherapy is an important therapeutic strategy for gastrointestinal cancer, its clinical effect remains unsatisfied due to drug resistance. Drug resistance is a complex multistep process resulting from deregulated expression of many molecules, including tumor suppressor genes, oncogenes and microRNAs (miRNAs). A better understanding of drug resistance-related miRNAs may eventually lead to optimized therapeutic strategies for cancer patients. Areas covered: This review summarizes the recent advances of drug resistance-related miRNAs in esophageal, gastric and colorectal cancer. Furthermore, this study envisages future developments toward the clinical applications of these miRNAs to cancer therapy. Expert opinion: Drug resistance-related miRNAs may be potentially predicting biomarkers that help guide individualized chemotherapy. Specific miRNAs and their target genes can be used as therapeutic targets by reversing drug resistance. More investigations should be performed to promote the translational bridging of the latest research into clinical application. Keywords: colon cancer, drug resistance, esophageal cancer, gastric cancer, microRNA, rectal cancer Expert Opin. Biol. Ther. (2014) 14(8):1103-1111
1.
Gastrointestinal cancer and drug resistance
Current therapeutic approaches for gastrointestinal (GI) cancer rely primarily upon surgery, chemotherapy and radiotherapy [1]. Surgery is the primary treatment for the early stage of GI cancer, but most patients are diagnosed in an advanced stage. For these patients, chemotherapy is the first-line treatment. The most commonly used chemotherapeutic regimens in GI cancer are 5-fluorouracil (5-flu) and cisplatin (CDDP). Chemotherapy is proved effective for improving survival and life quality of GI cancer patients. However, although many novel chemotherapeutic drugs are increasingly invented, chemotherapy fails to kill all cancer cells because of intrinsic or acquired drug resistance [2]. Acquired resistance accounts for > 90% of unsuccessful treatments in advanced cancer patients. Drug resistance is often mediated by drug efflux transporters, such as P-glycoprotein (P-gp) and multidrug resistance-associated protein [3]. Molecular investigations have discovered many mechanisms underlying drug resistance, including redistribution of intracellular accumulation of drugs, enhanced DNA repair activity, defective DNA damage response, the inactivation of apoptosis pathways, stem cell development, etc [4-6]. 10.1517/14712598.2014.907787 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Drug resistance is one of clinical obstacles to the successful treatment of gastrointestinal (GI) cancer. MicroRNAs (miRNAs) play important roles in drug resistance by regulating many signal pathways. Drug resistance-related miRNAs and their targets may be used as predicting biomarkers and therapeutic targets for GI cancer. Continued basic studies are needed to investigate the mechanisms of miRNA-mediated drug resistance. More clinical studies should be performed to promote the clinical use of drug resistance-related miRNAs and their targets in the management of GI cancer.
This box summarizes key points contained in the article.
So far, the precise mechanisms of drug resistance remain largely unclear. Therefore, there is a dire need for totally understanding the molecular mechanisms involved in drug resistance of GI cancer. 2.
MicroRNA and drug resistance
MicroRNAs (miRNAs) are an evolutionarily conserved group of small RNAs that function as negative gene regulators at the posttranscriptional level [7]. A mature functional miRNA can negatively regulate the expression of specific protein-coding genes by silencing the translation of messenger RNAs [8]. Since their initial discovery in 1993, emerging reports have shown that alterations of miRNAs are correlated with the pathogenesis of many types of human cancers, suggesting their potential to become diagnostic, prognostic and therapeutic targets [9-11]. An miRNA exhibits altered expression levels in different cancer tissues, affecting fundamental biological processes, such as cell apoptosis, proliferation, migration and differentiation [12-14]. Some miRNAs can act as tumor suppressors by preventing the development of the tumor state [15]. Some miRNAs are called oncomiRs that generally modulate the expression of tumor suppressor genes and contribute to tumor development [11,15]. miRNAs are involved in drug resistance by targeting hundreds of tumor-related gene transcripts, including drug resistance-related genes [8]. Regulating the level of one individual miRNA can eventually affect many complex molecular pathways at the same time [16]. Thus, the mechanisms of miRNA-mediated drug resistance are produced in a complicated series of biological, physiological and pathological processes. A number of investigators have reported the important roles of miRNAs in the establishment of drug resistance (Table 1). Some drug resistance-related miRNAs may have the value of predicting the prognosis of GI cancer (Table 2). The effort to elucidate the functions of drug resistance-related miRNAs may lead to improved clinical strategies for cancer therapy. 1104
The effect of miRNAs on CDDP and 5-flu resistance in esophageal cancer
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Article highlights.
Esophageal cancer (EC) is the eighth most common cancer worldwide, and its incidence is increasingly higher in the Western countries [17]. EC consists of two predominant histological subtypes, squamous cell carcinoma and adenocarcinoma [18]. The prognosis of EC is poor due to lack of effective chemotherapy. Ko et al. have detected the miRNA expression profiling of EC before and after induction chemoradiotherapy [19]. The pretreatment and posttreatment specimens from 25 patients who underwent trimodal therapy using concurrent irinotecan/ CDDP and radiotherapy were collected. After induction therapy, patients with high levels of miR-145 or miR-135b in the posttreatment biopsy specimens had significantly shorter median disease-free survival than those with low levels. Imanaka et al. have found that miR-141 could confer resistance of esophageal squamous cell carcinoma (ESCC) cells to CDDP-induced apoptosis by targeting YAP1 [20]. They detected the miRNA profiles of the CDDP-sensitive and resistant ESCC cell lines by miRNA microarray analysis. miR-141, the most highly expressed miRNA in the CDDP-resistant cell lines, showed increased cell viability after CDDP treatment. Wu et al. have found that an miR-200b/200c/429-binding site polymorphism in the 3¢ untranslated region of the AP-2a gene was associated with CDDP resistance of EC [21]. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3¢ UTR of AP-2a, which upregulated AP-2a protein expression and increased CDDP sensitivity. Upregulation of miR-200c could induce chemoresistance in EC through activation of the Akt signaling pathway [22]. The expression of miR-200c was significantly increased in CDDP-resistant cells as compared with their parent cells. Downregulation of miR-200c could increase chemosensitivity of ESCC cells to CDDP by targeting PPP2R1B. High expression of miR-200c was associated with shortened progressionfree survival of EC patients [23]. Downregulation of miR-27a could increase sensitivity of EC cells to both CDDP and 5-flu, and could promote Adriamycin (ADR)-induced apoptosis [24]. miR-148a could sensitize chemotherapy-sensitive EC cells to CDDP and 5-flu, and could attenuate resistance in chemotherapy-resistant variants [25]. Some drug resistance-related miRNAs, such as Let-7c, miR-296, miR-483 and miR-214, have the value of predicting prognosis of EC patients. Sugimura et al. have found that Let7c was involved in drug resistance of ESCC through regulation of IL-6/STAT3 pathway [26]. Low expression of Let-7c in before-treatment biopsies from 74 patients was significantly correlated with poor response to chemotherapy and poor prognosis. Upregulation of Let-7c in ESCC cells could restore sensitivity to CDDP and increase apoptosis rate after exposure to CDDP. The expression of miR-296 was increasingly upregulated in esophagitis tissues, esophageal carcinoma in situ
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Table 1. Summary of selected drug resistance-related microRNAs in gastroenteric cancer. MicroRNA
Tumor type
Effect on drug resistance
Let-7c miR-141 miR-200c miR-148a
ESCC ESCC EC GC EC
miR-27a miR-296
EC, GC ESCC
Upregulation of let-7c restores sensitivity to cisplatin (CDDP) Upregulation of miR-141 confers drug resistance Upregulation of miR-200c induces chemoresistance Upregulation of miR-200c inhibits chemoresistance Upregulation of miR-148a restores sensitivity to CDDP and 5-fluorouracil Downregulation of miR-27a reverses drug resistance Downregulation of miR-296 confers drug sensitivity of cells
miR-200bc/429 miR-21 miR-106a miR-181b miR-497 miR-15b/16 miR-19a/b miR-34
EC GC, CRC GC GC GC GC GC GC
Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation
miR-34a miR-140 miR-20a miR-143
CRC CC CC CC
Upregulation of miR-34 reverses drug resistance Downregulation of miR-140 reverses drug resistance Downregulation of miR-20a reverses drug resistance Upregulation of miR-143 reverses drug resistance
miR-222 miR-195 miR-125a/b miR-22 miR-451 miR-224 miR-203
CRC CC CC CC CC CC CC
Upregulation of miR-222 reverses drug resistance Upregulation of miR-195 reverses drug resistance Upregulation of miR-125a/b inhibits chemoresistance Upregulation of miR-22 reverses drug resistance miR-451 restoration reverses drug resistance Downregulation of miR-224 induces drug resistance Upregulation of miR-203 reverses drug resistance
miR-1915 miR-506
CRC CC
Upregulation of miR-1915 reverses drug resistance Upregulation of miR-506 confers drug resistance
of of of of of of of of
miR-200bc/429 reverses drug resistance miR-21 induces chemoresistance miR-106a promotes chemoresistance miR-181b reverses drug resistance miR-497 reverses drug resistance miR-15b/16 reverses drug resistance miR-19a/b promotes chemoresistance miR-34 reverses drug resistance
Target
Ref.
IL-6/STAT3 YAP1 PPP2R1B E-cadherin NA
[26] [20] [22] [34] [25]
MDR1, p21 P-glycoprotein (P-gp), Bcl-2, cyclin D1, Bax, p27 Bcl-2, XIAP PTEN, hMSH2 PTEN, RUNX3 Bcl-2 Bcl-2 Bcl-2 P-gp, PTEN, Bcl-2, Bax MAPT, Bcl-2, Notch, HMGA2 Sirt1, E2F3 HDAC4 BNIP2 Bcl-2, caspase -3,8, 9 NF-kB ADAM-17 Bcl-2-L2 ALDH1A3, Mcl1 PTEN COX-2, ABCB1 CDS2, HSPC159 Akt2, Bcl-xL, Bax, caspase-3 Bcl-2 PPARa
[24,38] [27]
[21] [35,36,46] [31,32] [33] [58] [59] [60] [54] [42] [43] [44] [50,51] [61] [62] [55] [56] [63] [64] [57] [66] [68]
CC: Colon cancer; CRC: Colorectal cancer; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; NA: Not applicable.
Table 2. Effect of drug resistance-related microRNAs on prognosis of gastroenteric cancer. MicroRNA
Tumor type
miR-145 miR-135b miR-200c miR-296 Let-7 miR-483 miR-214 miR-143
EC EC EC ESCC ESCC, GC ESCC ESCC CC
Effect on prognosis
Ref.
High miR-145 expression predicts poor survival High miR-135b expression predicts poor survival High miR-200c expression predicts poor survival Low miR-296 expression predicts better survival Low Let-7c, 7i expression predicts poor prognosis High miR-483 expression predicts poor survival High miR-214 expression predicts poor survival Low miR-143 expression predicts poor survival
[19] [19] [23] [27] [26,49] [28] [28] [49]
CC: Colon cancer; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer.
and ESCC tissues [27]. Low expression of miR-296 predicted better survival. Downregulation of miR-296 could confer sensitivity of vincristine (VCR), ADR, CDDP and 5-flu on EC cells by decreasing the expression of P-gp, Bcl-2, cyclin D1 as well as upregulating the expression of Bax and p27. Zhou et al. have investigated the expression of miR-483 and miR-214 in 104 cases of EC tissues and matched adjacent
benign esophageal tissues [28]. The expression of miR-483 and miR-214 was found significantly upregulated in ESCC tissues, and high expression of them might predict poor survival. The expression levels of miR-483 and miR-214 showed an inverse correlation with chemotherapy effect. Downregulation of miR-483 and miR-214 could confer sensitivity of ADR, 5-flu and CDDP to EC cells.
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The effect of miRNAs on CDDP and 5-flu resistance in gastric cancer
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Gastric cancer (GC) is the second most common cause of death from cancer in the world [29]. Wang et al. have detected the miRNA expression profiles associated with drug resistance in the 5-flu-induced GC cell line SGC7901 [30]. The expression of nine miRNAs, including miR-10b, -22, -31, -133b, -190, -501, -615, -501-5p and -615-5p, was found upregulated, while the expression of 18 additional miRNAs (miR-32, -197, -210, -766, -1229, -1238, -3131, -3149, -1224-3p, -3162-3p, -532, -877, -4701-5p, -5096, -4728-3p, -1273d, -486-3p and4763-3p) was downregulated in the SGC-7901/5-flu cell line compared with its parental cell line. miR-106a could confer CDDP resistance by regulating PTEN/Akt pathway and RUNX3 in GC cells [31,32]. miR106a was overexpressed in GC, and its expression was upregulated in the SGC7901/CDDP cells compared with its parental line SGC7901. miR-106a could promote CDDP resistance in SGC7901, while suppression of miR-106a in the CDDP resistant GC cell line SGC7901/CDDP led to enhanced CDDP-induced apoptosis. miR-181b could modulate multidrug resistance of GC by targeting Bcl-2 [33]. Overexpression of miR-181b might sensitize SGC7901/VCR cells to VCR and CDDP. miR-200c could inhibit chemotherapy resistance and cell proliferation of the SGC7901/CDDP cells by regulating E-cadherin [34]. Recent studies have provided supporting evidence for miR-21 as an oncogene [35]. Yang et al. have found that miR-21 could confer CDDP resistance in GC cells by regulating PTEN and activation of Akt pathway [36]. The expression of miR-21 was upregulated in the SGC7901/CDDP cells compared to its parental line. Upregulation of miR-21 could significantly decrease CDDP-induced apoptosis, while knockdown of miR-21 could dramatically increase antiproliferative effects and CDDP-induced apoptosis. Inhibition of Akt using PI3K inhibitor LY 294002 could abrogate miR-21-induced cell survival. Liu et al. have found that miR-27a inhibitors alone or in combination with perifosine could suppress the growth of GC cells [37]. miR-27a expression was significantly upregulated in GC tissues, compared with their nontumor adjacent tissues. High expression levels of miR-27a were associated with poor tumor histological grade. Downregulation of miR-27a might reverse drug resistance of GC cells toward CDDP and 5-flu by decreasing the expression of P-gp, and upregulating the expression of p21 [38]. Kim et al. have identified miRNA signature associated with outcome of GC patients following chemotherapy [39]. Biopsy samples were collected prior to chemotherapy from 90 GC patients treated with CDDP/5-flu and from 34 healthy volunteers. Several apoptosis-related miRNAs, including let7g, miR-342, miR-16, miR-181, miR-1 and miR-34, were associated with time to progression. Liu et al. have detected 1106
the expression of Let-7i in 86 cases of GC patients who underwent preoperative chemotherapy (FOLFOX 4) and radical resection [40]. Let-7i was significantly downregulated in most GC tissues, and low levels of let-7i were significantly correlated with local invasion, lymphatic metastasis and poor pathologic tumor response. Low Let-7i expression was an unfavorable prognostic factor of survival, indicating that Let-7i might be a potential tissue marker for the prediction of chemotherapeutic sensitivity in GC patients.
The effect of miRNAs on CDDP and 5-flu resistance in colorectal cancer
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Colorectal cancer (CRC) is the third leading cause of cancer in males and the fourth leading cause of cancer in females worldwide [41]. miR-34a could negatively regulate the resistance to 5-flu in human CRC DLD-1 cells by targeting the Sirt1 and E2F3 genes [42]. miR-34a was downregulated in 5-flu-resistant DLD-1 cells compared with the parental cells. The ectopic expression of miR-34a in the 5-flu-resistant cells could attenuate the resistance to 5-flu. The expression of miR-140 was significantly elevated in colon cancer stem-like cells that exhibit chemoresistance [43]. Blocking endogenous miR-140 could partially sensitize resistant colon cancer stem-like cells to 5-flu treatment through suppression of HDAC4. Knockdown of miR-20a could sensitize CRC cells SW620 and SW480 to 5-flu, oxaliplatin and teniposide by targeting BNIP2 [44]. miR-192/miR-215 might influence 5-flu resistance through cell cycle-mediated mechanisms complementary to its posttranscriptional thymidylate synthase regulation [45]. miR-21 induced resistance of CRC to 5-flu by downregulating human DNA MutS homolog 2 [46]. CRC cells overproducing miR-21 exhibited significantly reduced 5-flu-induced G2/M damage arrest and apoptosis. miR-21 could induce stemness by downregulating TGFbR2 and PDCD4 in colon cancer cells [47]. miR-143 might function as one anti-oncomir [48]. Downregulation of miR-143 predicted poor prognosis in Kirsten rat sarcoma viral oncogene homolog wild-type CRC patients [49]. Borralho et al. have found that miR-143 reduced viability and increased sensitivity to 5-flu in HCT116 CRC cells through extracellular-regulated protein kinase 5/ NF-kB-regulated pathways [50]. miR-143 could increase caspase -3, -8 and -9 activities, and decrease the expression of NF-kB and Bcl-2. Adrenaline could increase chemoresistance toward CDDP in colon cancer cells HT29 through induction of miR-155 [51]. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to CDDP-induced apoptosis. Svoboda et al. have evaluated the miRNA expression profile associated with response to neoadjuvant chemoradiotherapy (capecitabine or 5-flu) in 20 cases of locally advanced rectal cancer patients [52]. miR-215, miR-190b and miR-29b2 were found overexpressed in nonresponders, and Let-7e, miR-196b, miR-450a, miR-450b-5p and miR-99a showed higher expression levels in responders.
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The effect of miRNAs on paclitaxel resistance in GI cancer
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Dysregulation of miR-34c-5p was one of critical factors in the chemoresistance of GC to paclitaxel [53]. The expression of miR-34c-5p was downregulated in paclitaxel-resistant GC samples. Cells derived from GC tissues with low miR-34c5p expression tended to have increased chemoresistance to paclitaxel in vitro. Overexpression of miR-34c-5p could significantly increase the chemosensitivity of paclitaxel-resistant GC cells by downregulating MAPT expression. Ji et al. have demonstrated that restoration of functional miR-34 could induce chemosensitization and apoptosis in p53-deficient human GC cells by direct modulation of downstream targets Bcl-2, Notch and HMGA2 [54]. miR-125a/b could regulate the activation of cancer stem cells in paclitaxel-resistant HT29-taxol colon cancer cells through upregulating ALDH1A3 and Mcl1 expression [55]. Overexpression of miR-125a/b could significantly reduce the cell survival and tumor growth in HT29-taxol cells and xenograft HT29-taxol mouse model. Upregulation of miR-22 could reverse paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells [56]. miR-22 could increase PTEN expression, which negatively regulated Akt phosphorylation and MTDH expression, and subsequently increased Bax and active caspase-3 levels. miR-203 could reverse chemoresistance of paclitaxel in p53-mutated colon cancer cells through downregulation of Akt2 expression [57]. miR-203 could decrease antiapoptotic gene Bcl-xL expression, increase apoptotic proteins Bax and active caspase-3 levels.
The effect of miRNAs on other drug-induced resistance in GI cancer
7.
miR-497, miR-15b and miR-16 were downregulated in SGC7901/VCR cells [58,59]. Over-expression of them sensitized SGC7901/VCR to VCR and CDDP by targeting Bcl-2. miR-19a/b was upregulated in multidrug-resistant human GC cells [60]. Upregulation of miR-19a/b could decrease the sensitivity of GC cells to ADR by regulating P-gp, PTEN, Bcl-2 and Bax. miR-222 could regulate drug resistance of CRC HCT-8/VCR cells by reducing ADAM-17 expression [61]. Qu et al. have found that miR-195 could chemosensitize colon cancer cells to doxorubicin (Dox) by targeting the first binding site of Bcl-2-L2 mRNA [62]. The results of miRNA array and real-time PCR showed that miR-127, miR-195, miR-22, miR-137 were significantly downregulated, while miR-21, miR-592 were upregulated in both HT29/DOX and LOVO/DOX colon cancer cell lines. Downregulation of miR-195 in HT29 and LOVO cells caused a marked inhibition of Dox-induced cytotoxicity, while over-expression of miR-195 sensitized resistant cells to DOX and enhanced cell apoptosis activity.
miR-451 was involved in the self-renewal, tumorigenicity and chemoresistance of CRC stem cells [63]. miR-451 could cause a decrease in self-renewal, tumorigenicity and chemoresistance to irinotecan of colonspheres by indirectly targeting COX-2. Furthermore, miR-451 restoration could induce irinotecan sensitization by decreasing the expression of the ATP-binding cassette drug transporter ABCB1. miR-224 expression was decreased in methotrexate-resistant human colon cancer cells [64]. Downregulation of miR-224 could induce methotrexate resistance in HT29 colon cancer cells by regulation of CDS2 and HSPC159. Hodzic et al. have found that exposure to gemcitabine could influence miR-330 levels in colon cancer cell lines [65]. miR-1915 could increase drug sensitivity of CRC cells by inhibiting Bcl-2 [66]. In the hydroxycamptothecin (HCPT)-resistant GC cells, the levels of 25 miRNAs were deregulated, including miR-196a, miR-200 family, miR-338, miR-126, miR-31, miR-98, let-7g, miR-7, etc. [67]. Upregulation of miR-506 in established HCPT-resistant colon cancer cell line could confer resistance to HCPT by inhibiting PPARa expression [68]. LynamLennon et al. have found that miR-31 could modulate tumor sensitivity to chemoradiation therapy in esophageal adenocarcinoma [69]. miR-31 expression was significantly reduced in patients demonstrating poor histomorphologic response to neoadjuvant chemoradiation therapy. Upregulation of miR31 could significantly re-sensitize radioresistant cells to radiation. Wang et al. have developed a dual reporter gene imaging system for noninvasively monitoring the kinetic expression of miR-16 during chemoresistance in GC [70]. 8.
Conclusion
Although significant advances have been made in the chemotherapy, drug resistance remains a major obstacle to successful clinical treatment. Drug resistance is a multicellular and multiphase process, which results from deregulation of many genes and miRNAs. Emerging evidence has demonstrated that miRNAs are crucial regulators involved in the initiation and progression of drug resistance (Figure 1). As Table 2 shown, the miRNA expression may serve as biomolecular targets for drug resistance elimination in GI cancer. In different tumor cells, one miRNA can target diverse genes and cause various phenotypes. An increasing body of evidence has proved the important use of specific miRNAs to sensitize tumor cells to chemotherapy, especially their mRNA targets are encoded by oncogenes or tumor suppressor genes. These miRNAs operate by repressing the expression of resistance-related genes and/or signaling pathways. The advantage of miRNAs is their ability of affecting multiple targets with a single hit, and the power of targeting a single miRNA far exceeds that of targeting a single gene. The miRNA mimetics and antagomiRs may serve as potential therapeutic approaches for reversing drug resistance. Although the importance of miRNAs for reversing drug resistance is believable, so far there is no clinical evidence
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miRNAs functions will promote the novel usage of these molecules. Loss-of-function studies are required for better understanding of miRNA functions in vivo.
miR-141, 148a, 200b/429, 106a, 27a, 181b, 497, 15b, 16, 19, 21, 22, 34a, 140, 20a, 125, 143, 192, 195, 215, 222, 155, 451, 224, 203, 1915, 506
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Gastrointestinal cells
Regulation of drug resistance
miR-145, 135b, 296, 483, 200c, 214, 143, Let-7
Gastrointestinal patients
Potential biomarker
Figure 1. The drug resistance-related microRNAs in gastrointestinal cancer.
that miRNAs can make a real difference in terms of therapeutic management in GI cancer patients. When translating the research advances into clinical practice, the efficiency and safety of miRNAs/anti-miRNAs delivery in vivo are the major obstacles to overcome. There seems a tough way from discovery to clinical use. Many questions remain to be answered: How many miRNAs are involved in the drug resistance of GI cancer? How can we treat resistant cancer cells using miRNAs? How to deliver antagomiRs of target miRNAs to the desired tissues without causing unwanted normal tissue toxicity? As continuous scientific and technological methods become more improved, and the preclinical and translational research become more mature, the next few years should see significant progress for miRNA research. 9.
Expert opinion
Despite a lot of progress has been made in the research of drug resistance-related miRNAs, there is a significant gap between basic research and clinical application. In our opinion, more research work should be performed along the following avenues that are likely to lead to successful therapeutic application of miRNAs in the future. Finding more drug resistance-related miRNAs The number of known miRNAs involved in drug resistance of GI cancer remains small. It is necessary to screen and identify novel drug resistance-related miRNAs so as to facilitate the development of cancer-specific targets. The comparative genomics and computational methods will lead to a major breakthrough for screening drug resistance-related miRNAs. Correlating expression profiling of miRNAs from tumor, blood and serum samples with different drug resistance phenotypes will allow the identification of candidate miRNAs. The critical issue for one antidrug resistance miRNA or protein is well defined and specific. The identification of 9.1
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Investigating the mechanisms of miRNA-mediated drug resistance
9.2
A fuller dissection of the cellular and molecular pathways controlled by miRNAs will undoubtedly push insight into the mechanisms of drug resistance. The mechanisms of miRNA-mediated drug resistance are very complex because an individual miRNA regulates different signaling pathways in different cancer types. The effect of miRNAs on drug resistance may vary under different circumstances [71]. miRNAs exert pleiotropic effects on drug resistance by regulating numerous mRNAs. Conversely, a single gene may be regulated by many miRNAs. Although the whole biological pathways seem too complex to clearly understand, it is reasonable for us to experimentally verify the direct targets of drug resistance-related miRNAs. miRNAs are selectively expressed in cancer tissues, and their targets are selectively expressed. Further work to elucidate the roles of miRNA target genes in drug resistance will improve our understanding of their mechanism action and in turn improve our ability to utilize them as clinical biomarkers or therapeutic targets. Developing effective miRNA-delivery strategy Therapeutic application of the miRNAs and their targets depends on developing nontoxic miRNA-delivery strategy in a targeted, safe and effective manner. Several tools are available for selectively targeting miRNA pathways, including mimetics, antagomiRs, anti-miRNA oligonucleotides, miRNA masking, miRNA sponges and small molecule inhibitors. The successful delivery of these tools to the desired cells or tissues of the body remains an exciting goal in clinical practice. Despite the fact that the molecules are very small, the nucleic acids do not easily cross the cell membrane. The liposomes, short-interfering RNA and short heteroduplex RNA delivery systems may be applied to miRNAs and their targets. The adeno-associated virus has been used to deliver therapeutic miRNA in a mouse model [15]. The property of miRNAs and their targets may be a double-edged sword, causing unwanted normal tissue toxicity. The mice models, including knockouts and mutant mice models, should be used to evaluate whether the delivery of miRNA/anti-miRNA to the target organs is effective and safe. 9.3
Performing more miRNA-based clinical trials Since miRNA expression is dysregulated in drug-resistant cancer cells, specific miRNAs may be considered as useful biomarkers that predict the likely response of a patient to chemotherapy, thus guiding individualized therapy. More prospective, randomized clinical trials and evidence-based evaluation should be performed to detect the outcome of patients after chemotherapy with different expression of miRNAs. The downstream genes of miRNAs can be used as 9.4
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MicroRNAs in gastrointestinal cancer
therapeutic targets by reversing drug resistance of cancer cells. The artificial miRNAs can be designed to regulate drug resistance-related genes, thus contributing to cancer therapy. Further clinical studies, coupled with improvements in drug delivery technology, will enable miRNA-based therapy to open a new era in cancer care. Further research is also needed to evaluate the synergistic benefits of combining ant-miRNA technology with frontline chemotherapy.
Acknowledgment
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This study was supported in part by grants from the National Natural Scientific Foundation of China (81100714, 81171923), the Foundation of Shaanxi Province Science and Technology research (2012KJXX-20), and the Top PhD Foundation of China (201075). The authors have no other 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 apart from those disclosed.
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Affiliation Liu Hong1 MD PhD, Yu Han2 MD PhD, Jianjun Yang1 MD PhD, Hongwei Zhang1 MD PhD, Qingchuan Zhao1 MD PhD, Kaichun Wu1 MD PhD & Daiming Fan†1 MD PhD † Author for correspondence 1 Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Xi’an, 710032, Shaanxi Province, China Tel: +86 29 84773974; Fax: +86 29 82539041; E-mail: [email protected] 2 Fourth Military Medical University, Xijing Hospital, Department of Otolaryngology, Xi’an, 710032, Shaanxi Province, China
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Gastrointestinal cancer and drug resistance
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MicroRNA and drug resistance
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The effect of miRNAs on CDDP and 5-flu resistance in
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esophageal cancer 4.
The effect of miRNAs on CDDP and 5-flu resistance in gastric cancer
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The effect of miRNAs on CDDP and 5-flu resistance in colorectal cancer
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The effect of miRNAs on paclitaxel resistance in GI cancer
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The effect of miRNAs on other drug-induced resistance in GI cancer
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Conclusion
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Expert opinion
MicroRNAs in gastrointestinal cancer: prognostic significance and potential role in chemoresistance Liu Hong, Yu Han, Jianjun Yang, Hongwei Zhang, Qingchuan Zhao, Kaichun Wu & Daiming Fan† †
Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Xi’an, China
Introduction: Although chemotherapy is an important therapeutic strategy for gastrointestinal cancer, its clinical effect remains unsatisfied due to drug resistance. Drug resistance is a complex multistep process resulting from deregulated expression of many molecules, including tumor suppressor genes, oncogenes and microRNAs (miRNAs). A better understanding of drug resistance-related miRNAs may eventually lead to optimized therapeutic strategies for cancer patients. Areas covered: This review summarizes the recent advances of drug resistance-related miRNAs in esophageal, gastric and colorectal cancer. Furthermore, this study envisages future developments toward the clinical applications of these miRNAs to cancer therapy. Expert opinion: Drug resistance-related miRNAs may be potentially predicting biomarkers that help guide individualized chemotherapy. Specific miRNAs and their target genes can be used as therapeutic targets by reversing drug resistance. More investigations should be performed to promote the translational bridging of the latest research into clinical application. Keywords: colon cancer, drug resistance, esophageal cancer, gastric cancer, microRNA, rectal cancer Expert Opin. Biol. Ther. (2014) 14(8):1103-1111
1.
Gastrointestinal cancer and drug resistance
Current therapeutic approaches for gastrointestinal (GI) cancer rely primarily upon surgery, chemotherapy and radiotherapy [1]. Surgery is the primary treatment for the early stage of GI cancer, but most patients are diagnosed in an advanced stage. For these patients, chemotherapy is the first-line treatment. The most commonly used chemotherapeutic regimens in GI cancer are 5-fluorouracil (5-flu) and cisplatin (CDDP). Chemotherapy is proved effective for improving survival and life quality of GI cancer patients. However, although many novel chemotherapeutic drugs are increasingly invented, chemotherapy fails to kill all cancer cells because of intrinsic or acquired drug resistance [2]. Acquired resistance accounts for > 90% of unsuccessful treatments in advanced cancer patients. Drug resistance is often mediated by drug efflux transporters, such as P-glycoprotein (P-gp) and multidrug resistance-associated protein [3]. Molecular investigations have discovered many mechanisms underlying drug resistance, including redistribution of intracellular accumulation of drugs, enhanced DNA repair activity, defective DNA damage response, the inactivation of apoptosis pathways, stem cell development, etc [4-6]. 10.1517/14712598.2014.907787 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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Drug resistance is one of clinical obstacles to the successful treatment of gastrointestinal (GI) cancer. MicroRNAs (miRNAs) play important roles in drug resistance by regulating many signal pathways. Drug resistance-related miRNAs and their targets may be used as predicting biomarkers and therapeutic targets for GI cancer. Continued basic studies are needed to investigate the mechanisms of miRNA-mediated drug resistance. More clinical studies should be performed to promote the clinical use of drug resistance-related miRNAs and their targets in the management of GI cancer.
This box summarizes key points contained in the article.
So far, the precise mechanisms of drug resistance remain largely unclear. Therefore, there is a dire need for totally understanding the molecular mechanisms involved in drug resistance of GI cancer. 2.
MicroRNA and drug resistance
MicroRNAs (miRNAs) are an evolutionarily conserved group of small RNAs that function as negative gene regulators at the posttranscriptional level [7]. A mature functional miRNA can negatively regulate the expression of specific protein-coding genes by silencing the translation of messenger RNAs [8]. Since their initial discovery in 1993, emerging reports have shown that alterations of miRNAs are correlated with the pathogenesis of many types of human cancers, suggesting their potential to become diagnostic, prognostic and therapeutic targets [9-11]. An miRNA exhibits altered expression levels in different cancer tissues, affecting fundamental biological processes, such as cell apoptosis, proliferation, migration and differentiation [12-14]. Some miRNAs can act as tumor suppressors by preventing the development of the tumor state [15]. Some miRNAs are called oncomiRs that generally modulate the expression of tumor suppressor genes and contribute to tumor development [11,15]. miRNAs are involved in drug resistance by targeting hundreds of tumor-related gene transcripts, including drug resistance-related genes [8]. Regulating the level of one individual miRNA can eventually affect many complex molecular pathways at the same time [16]. Thus, the mechanisms of miRNA-mediated drug resistance are produced in a complicated series of biological, physiological and pathological processes. A number of investigators have reported the important roles of miRNAs in the establishment of drug resistance (Table 1). Some drug resistance-related miRNAs may have the value of predicting the prognosis of GI cancer (Table 2). The effort to elucidate the functions of drug resistance-related miRNAs may lead to improved clinical strategies for cancer therapy. 1104
The effect of miRNAs on CDDP and 5-flu resistance in esophageal cancer
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Article highlights.
Esophageal cancer (EC) is the eighth most common cancer worldwide, and its incidence is increasingly higher in the Western countries [17]. EC consists of two predominant histological subtypes, squamous cell carcinoma and adenocarcinoma [18]. The prognosis of EC is poor due to lack of effective chemotherapy. Ko et al. have detected the miRNA expression profiling of EC before and after induction chemoradiotherapy [19]. The pretreatment and posttreatment specimens from 25 patients who underwent trimodal therapy using concurrent irinotecan/ CDDP and radiotherapy were collected. After induction therapy, patients with high levels of miR-145 or miR-135b in the posttreatment biopsy specimens had significantly shorter median disease-free survival than those with low levels. Imanaka et al. have found that miR-141 could confer resistance of esophageal squamous cell carcinoma (ESCC) cells to CDDP-induced apoptosis by targeting YAP1 [20]. They detected the miRNA profiles of the CDDP-sensitive and resistant ESCC cell lines by miRNA microarray analysis. miR-141, the most highly expressed miRNA in the CDDP-resistant cell lines, showed increased cell viability after CDDP treatment. Wu et al. have found that an miR-200b/200c/429-binding site polymorphism in the 3¢ untranslated region of the AP-2a gene was associated with CDDP resistance of EC [21]. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3¢ UTR of AP-2a, which upregulated AP-2a protein expression and increased CDDP sensitivity. Upregulation of miR-200c could induce chemoresistance in EC through activation of the Akt signaling pathway [22]. The expression of miR-200c was significantly increased in CDDP-resistant cells as compared with their parent cells. Downregulation of miR-200c could increase chemosensitivity of ESCC cells to CDDP by targeting PPP2R1B. High expression of miR-200c was associated with shortened progressionfree survival of EC patients [23]. Downregulation of miR-27a could increase sensitivity of EC cells to both CDDP and 5-flu, and could promote Adriamycin (ADR)-induced apoptosis [24]. miR-148a could sensitize chemotherapy-sensitive EC cells to CDDP and 5-flu, and could attenuate resistance in chemotherapy-resistant variants [25]. Some drug resistance-related miRNAs, such as Let-7c, miR-296, miR-483 and miR-214, have the value of predicting prognosis of EC patients. Sugimura et al. have found that Let7c was involved in drug resistance of ESCC through regulation of IL-6/STAT3 pathway [26]. Low expression of Let-7c in before-treatment biopsies from 74 patients was significantly correlated with poor response to chemotherapy and poor prognosis. Upregulation of Let-7c in ESCC cells could restore sensitivity to CDDP and increase apoptosis rate after exposure to CDDP. The expression of miR-296 was increasingly upregulated in esophagitis tissues, esophageal carcinoma in situ
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Table 1. Summary of selected drug resistance-related microRNAs in gastroenteric cancer. MicroRNA
Tumor type
Effect on drug resistance
Let-7c miR-141 miR-200c miR-148a
ESCC ESCC EC GC EC
miR-27a miR-296
EC, GC ESCC
Upregulation of let-7c restores sensitivity to cisplatin (CDDP) Upregulation of miR-141 confers drug resistance Upregulation of miR-200c induces chemoresistance Upregulation of miR-200c inhibits chemoresistance Upregulation of miR-148a restores sensitivity to CDDP and 5-fluorouracil Downregulation of miR-27a reverses drug resistance Downregulation of miR-296 confers drug sensitivity of cells
miR-200bc/429 miR-21 miR-106a miR-181b miR-497 miR-15b/16 miR-19a/b miR-34
EC GC, CRC GC GC GC GC GC GC
Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation Upregulation
miR-34a miR-140 miR-20a miR-143
CRC CC CC CC
Upregulation of miR-34 reverses drug resistance Downregulation of miR-140 reverses drug resistance Downregulation of miR-20a reverses drug resistance Upregulation of miR-143 reverses drug resistance
miR-222 miR-195 miR-125a/b miR-22 miR-451 miR-224 miR-203
CRC CC CC CC CC CC CC
Upregulation of miR-222 reverses drug resistance Upregulation of miR-195 reverses drug resistance Upregulation of miR-125a/b inhibits chemoresistance Upregulation of miR-22 reverses drug resistance miR-451 restoration reverses drug resistance Downregulation of miR-224 induces drug resistance Upregulation of miR-203 reverses drug resistance
miR-1915 miR-506
CRC CC
Upregulation of miR-1915 reverses drug resistance Upregulation of miR-506 confers drug resistance
of of of of of of of of
miR-200bc/429 reverses drug resistance miR-21 induces chemoresistance miR-106a promotes chemoresistance miR-181b reverses drug resistance miR-497 reverses drug resistance miR-15b/16 reverses drug resistance miR-19a/b promotes chemoresistance miR-34 reverses drug resistance
Target
Ref.
IL-6/STAT3 YAP1 PPP2R1B E-cadherin NA
[26] [20] [22] [34] [25]
MDR1, p21 P-glycoprotein (P-gp), Bcl-2, cyclin D1, Bax, p27 Bcl-2, XIAP PTEN, hMSH2 PTEN, RUNX3 Bcl-2 Bcl-2 Bcl-2 P-gp, PTEN, Bcl-2, Bax MAPT, Bcl-2, Notch, HMGA2 Sirt1, E2F3 HDAC4 BNIP2 Bcl-2, caspase -3,8, 9 NF-kB ADAM-17 Bcl-2-L2 ALDH1A3, Mcl1 PTEN COX-2, ABCB1 CDS2, HSPC159 Akt2, Bcl-xL, Bax, caspase-3 Bcl-2 PPARa
[24,38] [27]
[21] [35,36,46] [31,32] [33] [58] [59] [60] [54] [42] [43] [44] [50,51] [61] [62] [55] [56] [63] [64] [57] [66] [68]
CC: Colon cancer; CRC: Colorectal cancer; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer; NA: Not applicable.
Table 2. Effect of drug resistance-related microRNAs on prognosis of gastroenteric cancer. MicroRNA
Tumor type
miR-145 miR-135b miR-200c miR-296 Let-7 miR-483 miR-214 miR-143
EC EC EC ESCC ESCC, GC ESCC ESCC CC
Effect on prognosis
Ref.
High miR-145 expression predicts poor survival High miR-135b expression predicts poor survival High miR-200c expression predicts poor survival Low miR-296 expression predicts better survival Low Let-7c, 7i expression predicts poor prognosis High miR-483 expression predicts poor survival High miR-214 expression predicts poor survival Low miR-143 expression predicts poor survival
[19] [19] [23] [27] [26,49] [28] [28] [49]
CC: Colon cancer; EC: Esophageal cancer; ESCC: Esophageal squamous cell carcinoma; GC: Gastric cancer.
and ESCC tissues [27]. Low expression of miR-296 predicted better survival. Downregulation of miR-296 could confer sensitivity of vincristine (VCR), ADR, CDDP and 5-flu on EC cells by decreasing the expression of P-gp, Bcl-2, cyclin D1 as well as upregulating the expression of Bax and p27. Zhou et al. have investigated the expression of miR-483 and miR-214 in 104 cases of EC tissues and matched adjacent
benign esophageal tissues [28]. The expression of miR-483 and miR-214 was found significantly upregulated in ESCC tissues, and high expression of them might predict poor survival. The expression levels of miR-483 and miR-214 showed an inverse correlation with chemotherapy effect. Downregulation of miR-483 and miR-214 could confer sensitivity of ADR, 5-flu and CDDP to EC cells.
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The effect of miRNAs on CDDP and 5-flu resistance in gastric cancer
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4.
Gastric cancer (GC) is the second most common cause of death from cancer in the world [29]. Wang et al. have detected the miRNA expression profiles associated with drug resistance in the 5-flu-induced GC cell line SGC7901 [30]. The expression of nine miRNAs, including miR-10b, -22, -31, -133b, -190, -501, -615, -501-5p and -615-5p, was found upregulated, while the expression of 18 additional miRNAs (miR-32, -197, -210, -766, -1229, -1238, -3131, -3149, -1224-3p, -3162-3p, -532, -877, -4701-5p, -5096, -4728-3p, -1273d, -486-3p and4763-3p) was downregulated in the SGC-7901/5-flu cell line compared with its parental cell line. miR-106a could confer CDDP resistance by regulating PTEN/Akt pathway and RUNX3 in GC cells [31,32]. miR106a was overexpressed in GC, and its expression was upregulated in the SGC7901/CDDP cells compared with its parental line SGC7901. miR-106a could promote CDDP resistance in SGC7901, while suppression of miR-106a in the CDDP resistant GC cell line SGC7901/CDDP led to enhanced CDDP-induced apoptosis. miR-181b could modulate multidrug resistance of GC by targeting Bcl-2 [33]. Overexpression of miR-181b might sensitize SGC7901/VCR cells to VCR and CDDP. miR-200c could inhibit chemotherapy resistance and cell proliferation of the SGC7901/CDDP cells by regulating E-cadherin [34]. Recent studies have provided supporting evidence for miR-21 as an oncogene [35]. Yang et al. have found that miR-21 could confer CDDP resistance in GC cells by regulating PTEN and activation of Akt pathway [36]. The expression of miR-21 was upregulated in the SGC7901/CDDP cells compared to its parental line. Upregulation of miR-21 could significantly decrease CDDP-induced apoptosis, while knockdown of miR-21 could dramatically increase antiproliferative effects and CDDP-induced apoptosis. Inhibition of Akt using PI3K inhibitor LY 294002 could abrogate miR-21-induced cell survival. Liu et al. have found that miR-27a inhibitors alone or in combination with perifosine could suppress the growth of GC cells [37]. miR-27a expression was significantly upregulated in GC tissues, compared with their nontumor adjacent tissues. High expression levels of miR-27a were associated with poor tumor histological grade. Downregulation of miR-27a might reverse drug resistance of GC cells toward CDDP and 5-flu by decreasing the expression of P-gp, and upregulating the expression of p21 [38]. Kim et al. have identified miRNA signature associated with outcome of GC patients following chemotherapy [39]. Biopsy samples were collected prior to chemotherapy from 90 GC patients treated with CDDP/5-flu and from 34 healthy volunteers. Several apoptosis-related miRNAs, including let7g, miR-342, miR-16, miR-181, miR-1 and miR-34, were associated with time to progression. Liu et al. have detected 1106
the expression of Let-7i in 86 cases of GC patients who underwent preoperative chemotherapy (FOLFOX 4) and radical resection [40]. Let-7i was significantly downregulated in most GC tissues, and low levels of let-7i were significantly correlated with local invasion, lymphatic metastasis and poor pathologic tumor response. Low Let-7i expression was an unfavorable prognostic factor of survival, indicating that Let-7i might be a potential tissue marker for the prediction of chemotherapeutic sensitivity in GC patients.
The effect of miRNAs on CDDP and 5-flu resistance in colorectal cancer
5.
Colorectal cancer (CRC) is the third leading cause of cancer in males and the fourth leading cause of cancer in females worldwide [41]. miR-34a could negatively regulate the resistance to 5-flu in human CRC DLD-1 cells by targeting the Sirt1 and E2F3 genes [42]. miR-34a was downregulated in 5-flu-resistant DLD-1 cells compared with the parental cells. The ectopic expression of miR-34a in the 5-flu-resistant cells could attenuate the resistance to 5-flu. The expression of miR-140 was significantly elevated in colon cancer stem-like cells that exhibit chemoresistance [43]. Blocking endogenous miR-140 could partially sensitize resistant colon cancer stem-like cells to 5-flu treatment through suppression of HDAC4. Knockdown of miR-20a could sensitize CRC cells SW620 and SW480 to 5-flu, oxaliplatin and teniposide by targeting BNIP2 [44]. miR-192/miR-215 might influence 5-flu resistance through cell cycle-mediated mechanisms complementary to its posttranscriptional thymidylate synthase regulation [45]. miR-21 induced resistance of CRC to 5-flu by downregulating human DNA MutS homolog 2 [46]. CRC cells overproducing miR-21 exhibited significantly reduced 5-flu-induced G2/M damage arrest and apoptosis. miR-21 could induce stemness by downregulating TGFbR2 and PDCD4 in colon cancer cells [47]. miR-143 might function as one anti-oncomir [48]. Downregulation of miR-143 predicted poor prognosis in Kirsten rat sarcoma viral oncogene homolog wild-type CRC patients [49]. Borralho et al. have found that miR-143 reduced viability and increased sensitivity to 5-flu in HCT116 CRC cells through extracellular-regulated protein kinase 5/ NF-kB-regulated pathways [50]. miR-143 could increase caspase -3, -8 and -9 activities, and decrease the expression of NF-kB and Bcl-2. Adrenaline could increase chemoresistance toward CDDP in colon cancer cells HT29 through induction of miR-155 [51]. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to CDDP-induced apoptosis. Svoboda et al. have evaluated the miRNA expression profile associated with response to neoadjuvant chemoradiotherapy (capecitabine or 5-flu) in 20 cases of locally advanced rectal cancer patients [52]. miR-215, miR-190b and miR-29b2 were found overexpressed in nonresponders, and Let-7e, miR-196b, miR-450a, miR-450b-5p and miR-99a showed higher expression levels in responders.
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The effect of miRNAs on paclitaxel resistance in GI cancer
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Dysregulation of miR-34c-5p was one of critical factors in the chemoresistance of GC to paclitaxel [53]. The expression of miR-34c-5p was downregulated in paclitaxel-resistant GC samples. Cells derived from GC tissues with low miR-34c5p expression tended to have increased chemoresistance to paclitaxel in vitro. Overexpression of miR-34c-5p could significantly increase the chemosensitivity of paclitaxel-resistant GC cells by downregulating MAPT expression. Ji et al. have demonstrated that restoration of functional miR-34 could induce chemosensitization and apoptosis in p53-deficient human GC cells by direct modulation of downstream targets Bcl-2, Notch and HMGA2 [54]. miR-125a/b could regulate the activation of cancer stem cells in paclitaxel-resistant HT29-taxol colon cancer cells through upregulating ALDH1A3 and Mcl1 expression [55]. Overexpression of miR-125a/b could significantly reduce the cell survival and tumor growth in HT29-taxol cells and xenograft HT29-taxol mouse model. Upregulation of miR-22 could reverse paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells [56]. miR-22 could increase PTEN expression, which negatively regulated Akt phosphorylation and MTDH expression, and subsequently increased Bax and active caspase-3 levels. miR-203 could reverse chemoresistance of paclitaxel in p53-mutated colon cancer cells through downregulation of Akt2 expression [57]. miR-203 could decrease antiapoptotic gene Bcl-xL expression, increase apoptotic proteins Bax and active caspase-3 levels.
The effect of miRNAs on other drug-induced resistance in GI cancer
7.
miR-497, miR-15b and miR-16 were downregulated in SGC7901/VCR cells [58,59]. Over-expression of them sensitized SGC7901/VCR to VCR and CDDP by targeting Bcl-2. miR-19a/b was upregulated in multidrug-resistant human GC cells [60]. Upregulation of miR-19a/b could decrease the sensitivity of GC cells to ADR by regulating P-gp, PTEN, Bcl-2 and Bax. miR-222 could regulate drug resistance of CRC HCT-8/VCR cells by reducing ADAM-17 expression [61]. Qu et al. have found that miR-195 could chemosensitize colon cancer cells to doxorubicin (Dox) by targeting the first binding site of Bcl-2-L2 mRNA [62]. The results of miRNA array and real-time PCR showed that miR-127, miR-195, miR-22, miR-137 were significantly downregulated, while miR-21, miR-592 were upregulated in both HT29/DOX and LOVO/DOX colon cancer cell lines. Downregulation of miR-195 in HT29 and LOVO cells caused a marked inhibition of Dox-induced cytotoxicity, while over-expression of miR-195 sensitized resistant cells to DOX and enhanced cell apoptosis activity.
miR-451 was involved in the self-renewal, tumorigenicity and chemoresistance of CRC stem cells [63]. miR-451 could cause a decrease in self-renewal, tumorigenicity and chemoresistance to irinotecan of colonspheres by indirectly targeting COX-2. Furthermore, miR-451 restoration could induce irinotecan sensitization by decreasing the expression of the ATP-binding cassette drug transporter ABCB1. miR-224 expression was decreased in methotrexate-resistant human colon cancer cells [64]. Downregulation of miR-224 could induce methotrexate resistance in HT29 colon cancer cells by regulation of CDS2 and HSPC159. Hodzic et al. have found that exposure to gemcitabine could influence miR-330 levels in colon cancer cell lines [65]. miR-1915 could increase drug sensitivity of CRC cells by inhibiting Bcl-2 [66]. In the hydroxycamptothecin (HCPT)-resistant GC cells, the levels of 25 miRNAs were deregulated, including miR-196a, miR-200 family, miR-338, miR-126, miR-31, miR-98, let-7g, miR-7, etc. [67]. Upregulation of miR-506 in established HCPT-resistant colon cancer cell line could confer resistance to HCPT by inhibiting PPARa expression [68]. LynamLennon et al. have found that miR-31 could modulate tumor sensitivity to chemoradiation therapy in esophageal adenocarcinoma [69]. miR-31 expression was significantly reduced in patients demonstrating poor histomorphologic response to neoadjuvant chemoradiation therapy. Upregulation of miR31 could significantly re-sensitize radioresistant cells to radiation. Wang et al. have developed a dual reporter gene imaging system for noninvasively monitoring the kinetic expression of miR-16 during chemoresistance in GC [70]. 8.
Conclusion
Although significant advances have been made in the chemotherapy, drug resistance remains a major obstacle to successful clinical treatment. Drug resistance is a multicellular and multiphase process, which results from deregulation of many genes and miRNAs. Emerging evidence has demonstrated that miRNAs are crucial regulators involved in the initiation and progression of drug resistance (Figure 1). As Table 2 shown, the miRNA expression may serve as biomolecular targets for drug resistance elimination in GI cancer. In different tumor cells, one miRNA can target diverse genes and cause various phenotypes. An increasing body of evidence has proved the important use of specific miRNAs to sensitize tumor cells to chemotherapy, especially their mRNA targets are encoded by oncogenes or tumor suppressor genes. These miRNAs operate by repressing the expression of resistance-related genes and/or signaling pathways. The advantage of miRNAs is their ability of affecting multiple targets with a single hit, and the power of targeting a single miRNA far exceeds that of targeting a single gene. The miRNA mimetics and antagomiRs may serve as potential therapeutic approaches for reversing drug resistance. Although the importance of miRNAs for reversing drug resistance is believable, so far there is no clinical evidence
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miRNAs functions will promote the novel usage of these molecules. Loss-of-function studies are required for better understanding of miRNA functions in vivo.
miR-141, 148a, 200b/429, 106a, 27a, 181b, 497, 15b, 16, 19, 21, 22, 34a, 140, 20a, 125, 143, 192, 195, 215, 222, 155, 451, 224, 203, 1915, 506
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Gastrointestinal cells
Regulation of drug resistance
miR-145, 135b, 296, 483, 200c, 214, 143, Let-7
Gastrointestinal patients
Potential biomarker
Figure 1. The drug resistance-related microRNAs in gastrointestinal cancer.
that miRNAs can make a real difference in terms of therapeutic management in GI cancer patients. When translating the research advances into clinical practice, the efficiency and safety of miRNAs/anti-miRNAs delivery in vivo are the major obstacles to overcome. There seems a tough way from discovery to clinical use. Many questions remain to be answered: How many miRNAs are involved in the drug resistance of GI cancer? How can we treat resistant cancer cells using miRNAs? How to deliver antagomiRs of target miRNAs to the desired tissues without causing unwanted normal tissue toxicity? As continuous scientific and technological methods become more improved, and the preclinical and translational research become more mature, the next few years should see significant progress for miRNA research. 9.
Expert opinion
Despite a lot of progress has been made in the research of drug resistance-related miRNAs, there is a significant gap between basic research and clinical application. In our opinion, more research work should be performed along the following avenues that are likely to lead to successful therapeutic application of miRNAs in the future. Finding more drug resistance-related miRNAs The number of known miRNAs involved in drug resistance of GI cancer remains small. It is necessary to screen and identify novel drug resistance-related miRNAs so as to facilitate the development of cancer-specific targets. The comparative genomics and computational methods will lead to a major breakthrough for screening drug resistance-related miRNAs. Correlating expression profiling of miRNAs from tumor, blood and serum samples with different drug resistance phenotypes will allow the identification of candidate miRNAs. The critical issue for one antidrug resistance miRNA or protein is well defined and specific. The identification of 9.1
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Investigating the mechanisms of miRNA-mediated drug resistance
9.2
A fuller dissection of the cellular and molecular pathways controlled by miRNAs will undoubtedly push insight into the mechanisms of drug resistance. The mechanisms of miRNA-mediated drug resistance are very complex because an individual miRNA regulates different signaling pathways in different cancer types. The effect of miRNAs on drug resistance may vary under different circumstances [71]. miRNAs exert pleiotropic effects on drug resistance by regulating numerous mRNAs. Conversely, a single gene may be regulated by many miRNAs. Although the whole biological pathways seem too complex to clearly understand, it is reasonable for us to experimentally verify the direct targets of drug resistance-related miRNAs. miRNAs are selectively expressed in cancer tissues, and their targets are selectively expressed. Further work to elucidate the roles of miRNA target genes in drug resistance will improve our understanding of their mechanism action and in turn improve our ability to utilize them as clinical biomarkers or therapeutic targets. Developing effective miRNA-delivery strategy Therapeutic application of the miRNAs and their targets depends on developing nontoxic miRNA-delivery strategy in a targeted, safe and effective manner. Several tools are available for selectively targeting miRNA pathways, including mimetics, antagomiRs, anti-miRNA oligonucleotides, miRNA masking, miRNA sponges and small molecule inhibitors. The successful delivery of these tools to the desired cells or tissues of the body remains an exciting goal in clinical practice. Despite the fact that the molecules are very small, the nucleic acids do not easily cross the cell membrane. The liposomes, short-interfering RNA and short heteroduplex RNA delivery systems may be applied to miRNAs and their targets. The adeno-associated virus has been used to deliver therapeutic miRNA in a mouse model [15]. The property of miRNAs and their targets may be a double-edged sword, causing unwanted normal tissue toxicity. The mice models, including knockouts and mutant mice models, should be used to evaluate whether the delivery of miRNA/anti-miRNA to the target organs is effective and safe. 9.3
Performing more miRNA-based clinical trials Since miRNA expression is dysregulated in drug-resistant cancer cells, specific miRNAs may be considered as useful biomarkers that predict the likely response of a patient to chemotherapy, thus guiding individualized therapy. More prospective, randomized clinical trials and evidence-based evaluation should be performed to detect the outcome of patients after chemotherapy with different expression of miRNAs. The downstream genes of miRNAs can be used as 9.4
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therapeutic targets by reversing drug resistance of cancer cells. The artificial miRNAs can be designed to regulate drug resistance-related genes, thus contributing to cancer therapy. Further clinical studies, coupled with improvements in drug delivery technology, will enable miRNA-based therapy to open a new era in cancer care. Further research is also needed to evaluate the synergistic benefits of combining ant-miRNA technology with frontline chemotherapy.
Acknowledgment
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L Hong, Y Han and J Yang contributed equally to this work. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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This study was supported in part by grants from the National Natural Scientific Foundation of China (81100714, 81171923), the Foundation of Shaanxi Province Science and Technology research (2012KJXX-20), and the Top PhD Foundation of China (201075). The authors have no other 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 apart from those disclosed.
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Affiliation Liu Hong1 MD PhD, Yu Han2 MD PhD, Jianjun Yang1 MD PhD, Hongwei Zhang1 MD PhD, Qingchuan Zhao1 MD PhD, Kaichun Wu1 MD PhD & Daiming Fan†1 MD PhD † Author for correspondence 1 Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Xi’an, 710032, Shaanxi Province, China Tel: +86 29 84773974; Fax: +86 29 82539041; E-mail: [email protected] 2 Fourth Military Medical University, Xijing Hospital, Department of Otolaryngology, Xi’an, 710032, Shaanxi Province, China
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