REVIEW ARTICLE
Functions and Mechanisms of Long Noncoding RNAs in Ovarian Cancer Chengcheng Ren, MMed,* Xiaobo Li, PhD,* Tianzhen Wang, PhD,* Guangyu Wang, PhD,þ Ci Zhao, PhD,þ Tian Liang, PhD,* Yuanyuan Zhu, MMed,* Minghui Li, MMed,§ Chao Yang, MMed,* Yunlong Zhao, MMed,* and Guang-mei Zhang, PhDÞ
Abstract: Long noncoding RNAs (lncRNAs) are longer than 200-nucleotide, noncoding transcripts in length, have a variety of biological functions, and are closely associated with tumor development. Ovarian cancer, as 1 of the 3 common gynecological malignancies, is the leading cause of death in women with gynecological malignant tumor. In this study, a review of the literature found that lncRNAs H19, LSINCT5, and XIST have a close relationship to the development of ovarian cancer occurrence, growth, invasion, and metastasis, and they can promote ovarian cancer cell proliferation. Hence, in this article, the progress of above-mentioned 3 kinds of lncRNAs in ovarian cancer was reviewed and designed to help in the diagnosis, treatment, and prognosis of ovarian cancer. Key Words: LncRNA, Ovarian cancer, Gene expression, Gene regulation Received November 4, 2014, and in revised form January 13, 2015. Accepted for publication January 21, 2015. (Int J Gynecol Cancer 2015;25: 566Y569)
noncoding RNAs (lncRNAs) are longer than 200L ong nucleotide, noncoding transcripts in length, which wide-
ly exist in the nucleus and cytoplasm of eukaryotic cells. However, because of a lack of significant open reading frames, they cannot encode proteins.1 With the continuous improvement of research methods, many lncRNA biological functions have been identified; for example, lncRNAs are involved in epigenetic modification through interaction with chromatin or methylation and ubiquitination, as well as through direct binding of transcription factors or heterologous DNA to form multimeric transcription
*Harbin Medical University, Harbin, China; †The First Affiliated Hospital of Harbin Medical University, Harbin, China; ‡The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China; and §Inner Mongolia Medical College, Hohhot, China. Address correspondence and reprint requests to Guang-mei Zhang, PhD, The First Affiliated Hospital of Harbin Medical University, Heilongjiang 150001, China. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000413
566
regulation complexes. Long nonconding RNAs may also regulate the posttranscription processing, splicing, transport, translation, and degradation processes of messenger RNA.2Y4 According to a large number of experimental studies, lncRNAs are closely associated with tumor development; for example, lncRNAYhigh expression in hepatocellular carcinoma (HEIH) promotes liver cancer by combining with E2H2, leading to the down-regulation of P21 and other cell cycle regulators, promoting cell-cycle G0 into S phase and inducing hepatocellular carcinoma. The down-regulation of lncRNA-HEIH significantly inhibited the growth of liver cancer cells.5 Therefore, it may become a new target for the treatment of liver cancer. In contrast, lncRNAYmaternally expressed gene 3 (MEG3) expression is obviously decreased in gastric cancer, and high expression of MEG3 can inhibit gastric cancer cell proliferation and promote apoptosis of gastric carcinoma cells.6 Therefore, lncRNAs’ specific expression in certain types of cancer can be diagnosed as tumor markers and also be used as therapeutic targets to overcome cancer (Table 1). Ovarian cancer, as 1 of the 3 common gynecological malignant tumors, ranks third in incidence rate. Because of insidious onset and a lack of effective methods for early diagnosis, more than 70% of patients are at an advanced stage
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
lncRNAs in Ovarian Cancer
TABLE 1. Disease-associated lncRNAs LncRNA
Size
Cytoband
Functions
Reference
HAR1A BCYRN1 HOTAIR MALAT1 HEIH MEG3 H19 LSINCT5 XIST
4 kb 260 bp 2158 bp 7.5 kb 2.2 kb 1.6 kb 2.3 kb 2.6 kb 17 kb
20q13.33 2p21 12q13.13 11q13.1 5p35.3 14q32.2 11p15.5 5p15.33 X
Participate in the human brain development Associated with Alzheimer disease Associated with breast cancer Associated with lung liver colon cancer Associated with liver cancer Associated with gastric cancer Associated with ovary lung breast liver cancer Associated with ovary cancer Associated with ovary cancer
7
when it is discovered.17 Currently, there are 3 major therapeutic areas of ovarian cancer, which include surgery, chemotherapy, and radiotherapy, but most patients relapse after surgery or develop resistance to chemotherapy drugs. Only approximately 30% of patients have a 5-year survival rate.18 Early detection, early diagnosis, and early treatment of ovarian cancer should greatly reduce mortality in patients with great significance on prognosis of patients. Researchers at home and abroad have been committed to looking for effective early ovarian cancer diagnostic markers to improve patient survival rate and have found that, in some cases, the development of ovarian cancer is closely related to the presence of the lncRNAs, such as H19, long stress-induced noncoding transcript 5 (LSINCT5), and X-inactive specific transcript (XIST), providing a new approach for early diagnosis and treatment of ovarian cancer. Therefore, in this article, H19, LSINCT5, and XIST functions and mechanisms in ovarian cancer were reviewed.14,19,20
Functions of lncRNAs in Ovarian Cancer H19 Promotes the Development of Ovarian Cancer H19 is the first discovered lncRNA associated with cancer, with a length of 2.3 kb. H19 differentially expresses in various cancers, and it has a dual role: tumor promoter or tumor suppressor.11 Mizrahi et al12 reported that, using H19RNA probe technique for situ hybridization in cells of ascites from ovarian cancer, H19 can be detected in 90% of patients with ovarian cancer ascites. In ectopic subcutaneous tumors injected with DTA-H19 in female mice, it is found that H19 downgraded expression and 40% of tumor growth inhibition. This suggests that H19 promotes tumorigenesis in ovarian cancer and interference with H19 expression can inhibit the growth of ovarian tumors.
LSINCT5 Promotes the Growth of Ovarian Cancer LSINCT5 is located in the nucleus, with a length of 2.6 kb. It is a stress-induced long noncoding transcript that is polyadenylated and transcribed by RNA polymerase III. LSINCT5 is highly expressed in ovarian cancer cell lines and tissue. Knockout LSINCT5 can decrease cell proliferation, but also
8 9 10 5 6 11Y13 14 15,16
with some changes in gene expression, including nuclear paraspeckle assembly transcript 1 (NEAT-1) and the proteincoding gene paraspeckle component 1 (PSPC1), whose expressions were significantly decreased.14 Therefore, LSINCT5 plays an important role in the proliferation and development of ovarian cancer.
XIST Promotes the Proliferation and Differentiation of Ovarian Cancer XIST gene is located on chromosome X inactivation center transcribed from chromosome X inactivation (Xi) and, in female cells, plays an important role in the start time of X chromosome inactivation.15 XIST is usually expressed in all female cells, but was not expressed in breast cancer, ovarian cancer, and cervical cancer cells. Kawakami et al,16 in the analysis of several XAS alleles, found 3 lost modes of Xi: Xi was lost without an increase in Xa, Xi was lost with an increase in Xa, and a small number of Xis were resurrected. The exact molecular mechanism of XIST in the initiation of X chromosome inactivation is still being investigated, but there is considerable evidence that XIST plays an important role in the proliferation, differentiation, and maintenance of genomic stability in human cells.
Mechanisms of lncRNAs in Ovarian Cancer H19 Imprint Mechanism Genomic imprinting is a genetic mechanism for the expression of genes in a group structure of 2 alleles in which maternal and paternal differences can directly affect replication, recombination, translocation, and destruction replication. Therefore, genomic imprinting is a basic biological phenomenon having a role in normal embryonic development and tumor development.21 H19/IGFII (insulin-like growth factor II) is a group of imprinted genes with maternal/paternal expression patterns. Although it is a relative marker, it is important in regulating gene expression.22 The H19/IGF2 gene imprinting control mechanism is very complex, and recent studies have found a competition for its common enhancer and allelic differences in methylation, chromatin conformation, and transcription cycle, but the formation of a unified regulatory mechanisms has not yet been identified.23 The H19 gene is transcribed into a multipolyadenylated RNA,
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
567
Ren et al
International Journal of Gynecological Cancer
which has no contact with the ribosome. It suggests that the function of H19 is at the RNA level and may be as a ribonucleoprotein in RNA component.24 H19 is significantly expressed in embryonic ovary matrix, whereas it is rarely expressed in the body cavity epithelial tissue. In adults, there is a rare expression of H19 in ovarian tissue, which may be related to steroid metabolism.25 Tanos et al19 have shown that H19 was expressed in 67% of epithelial ovarian benign tumors, in 75% of low potential of malignant ovarian tumors, and in 65% of malignant ovarian tumors. Therefore, it might be a potential tumor marker.
LSINCT5 and NNK Stress in Ovarian Cancer LSINCT5 is one of LSINCT family members, both of which are expressed during stress-induced cell formation and also participated in the development of cancers. They are found in the extracts of normal human bronchial epithelial cells exposed to 4-methylsulfinyl ammonium-1 (3-pyridyl)-1butanone (NNK).26 NNK is the strongest tobacco carcinogen, which leads to the metabolic activation by cytochrome P450 enzymes (mainly, CYPZA6 and CYPZA13) of a methylated intermediate resulting in the formation of DNA complexes and DNA single-strand breaks.27 NNK stress affects cell survival, proliferation, and motility as well as the cell cycle and expression of various genes.28 The LSINCT5 molecular mechanisms have not yet been found, which researchers need to continue to explore.
XIST and Chemotherapy Resistance Benoit et al,29 who explored X chromosome gene expression and Barr body staining in ovarian cancer cell lines, found that XIST was undetectable and no Barr body staining was observed in more than half of ovarian cancer cell lines compared with normal ovarian cancer cell lines. Other researchers found that XIST expression decreased and its sensitivity to paclitaxel treatment was reduced in ovarian cancer cell lines, suggesting that XIST gene expression in ovarian cancer cells can be used as a chemical marker of prognosis after treatment. This could be adjusted by the XIST toxic effects of paclitaxel and may also be linked via the reactivation of the X-‘‘specific resistance gene,’’ increasing the expression of genes on the X chromosome. Another possibility is that in cancer cells, XIST loss is a result of a genetic instability and has received chemotherapy resistance.30
Prospect Because lncRNAs showed high expression in liver, ovary, and lung cancers, with multiple regulatory roles in the development of tumors, their potential applications in the clinical diagnosis and treatment of cancer have broad prospects. Compared with microRNAs, researches of lncRNAs are still in there infancy, and most of lncRNA functions remain unclear. In addition, few lncRNAs were closely associated with ovarian cancer, and the mechanisms of action of ovarian cancer are not clear. Therefore, further studies on ovarian cancer occurrence and development of pathological process are needed, to help in the early detection and treatment of ovarian cancer. Long noncoding RNAs are expected as tumor markers to have high specificity and sensitivity
568
& Volume 25, Number 4, May 2015
to help indicate prognosis and directly target therapy to inhibit tumor growth or metastasis. These aspects of lncRNAs could help to achieve a more effective antitumor therapeutic approach so that lncRNA-based methods are expected to fundamentally improve the treatment and prognosis of ovarian cancer. Consequently, exploring the relationship between lncRNAs and ovarian cancer is a difficult task. There is a great need to invest more energy into this type of research. With advances in life sciences and technology leading to a more profound understanding of lncRNAs, the mechanism of lncRNAs in ovarian cancer will also become increasingly clear. Certain lncRNAs may act as ovarian cancerYspecific molecular markers and drug targets, providing new ideas and strategies for ovarian cancer diagnosis and treatment. Not only investigating the role of lncRNAs in ovarian cancer can enrich the content of noncoding RNAs research, but it may also be very important in the future for providing the theoretical basis and potential application in human ovarian cancer diagnosis and treatment in the field. Therefore, lncRNA research in ovarian cancer has farreaching significance.
REFERENCES 1. Spizzo R, Almeida MI, Colombatti A, et al. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31:4577Y4587. 2. Zhang H, Zeitz MJ, Wang H, et al. Long noncoding RNAYmediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 2014;204:61Y75. 3. Wang X, Arai S, Song X, et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature. 2008;454:126Y130. 4. Yang L, Lin C, Liu W, et al. lncRNA- and Pc2 methylationYdependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147:773Y788. 5. Yang F, Zhang L, Huo XS, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54:1679Y1689. 6. Sun M, Xia R, Jin F, et al. Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol. 2013;35:1065Y1073. 7. Pollard KS, Salanma SR, Lambert N, et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006;443:167Y172. 8. Mus E, Hof PR, Tiedge H. Dendritie BC200 RNA in aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2007;104:10679Y10684. 9. Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071Y1076. 10. Lin R, Maeda S, Liu C, et al. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. 2007;26:851Y858. 11. Hibi K, Nakamura H, Hirai A, et al. Loss of H19 imprinting in esophageal cancer. Cancer Res. 1996;56:480Y482. 12. Mizrahi A, Czerniak A, Levy T, et al. Development of targeted therapy for ovarian cancer mediated by a plasmid expressing * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
13. 14.
15.
16.
17. 18.
19.
20. 21.
22.
& Volume 25, Number 4, May 2015
diphtheria toxin under the control of H19 regulatory sequences. J Transl Med. 2009;7:1479Y5876. Hao Y, Crenshaw T, Moulton T, et al. Tumor-suppressor activity of H19 RNA. Nature. 1993;365:764Y767. Silva JM, Boczek NJ, Berres MW, et al. LSINCT5 is overexpressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol. 2011;8:496Y505. Weakley SM, Wang H, Yao Q, et al. Expression and function of a large non-coding RNA gene XIST in human cancer. World J Surg. 2011;35:1751Y1756. Kawakami T, Zhang C, Taniguchi T, et al. Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived cancer cells. Oncogene. 2004;23:6163Y6169. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10Y29. Brinkhuis M, Izquierdo MA, Baak JP, et al. Expression of multidrug resistance-associated markers, their relation to quantitative pathologic tumour characteristics and prognosis in advanced ovarian cancer. Anal Cell Pathol. 2002;24:17Y23. Tanos V, Prus D, Ayesh S, et al. Expression of the imprinted H19 oncofetal RNA in epithelial ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 1999;85:7Y11. Lyon MF. Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet. 1962;14:135Y148. Ohana P, Bibi O, Matouk I, et al. Use of H19 regulatory sequences for targeted gene therapy in cancer. Int J Cancer. 2001;98:645Y650. Ayesh S, Matouk I, Schneider T, et al. Possible physiological role of H19 RNA. Mol Carcinog. 2002;35:63Y74.
lncRNAs in Ovarian Cancer
23. Cui H, Onyango P, Brandenburg S, et al. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002;62:6442Y6446. 24. Erdmann VA, Barciszewska MZ, Szymanski M, et al. The non-coding RNAs as riboregulators. Nucleic Acids Res. 2001;29:189Y193. 25. Ariel I, Weinstein D, Voutilainen R, et al. Genomic imprinting and the endometrial cycle. The expression of the imprinted gene H19 in the human female reproductive organs. Diagn Mol Pathol. 1997;6:17Y25. 26. Hecht SS, Hatsukami DK, Bonilla LE, et al. Quantitation of 4-oxo-4-(3-pyridyl) butanoic acid and enantiomers of 4-hydroxy-4-(3-pyridyl)butanoic acid in human urine: a substantial pathway of nicotine. Chem Res Toxicol. 1999;12:172Y179. 27. Hecht SS. DNA adduct formation from tobacco-specific N-nitrosamines. Mutat Res. 1999;424:127Y142. 28. Modesto JL, Hull A, Angstadt AY, et al. NNK reduction pathway gene polymorphisms and risk of lung cancer. Mol Carcinog. 2014;29:22187. 29. Benoit MH, Hudson TJ, Maire G, et al. Global analysis of chromosome X gene expression in primary cultures of normal ovarian surface epithelial cells and epithelial ovarian cancer cell lines. Int J Oncol. 2007; 30:5Y17. 30. Huang KC, Rao PH, Lau CC, et al. Relationship of XIST expression and responses of ovarian cancer to chemotherapy. Mol Cancer Ther. 2002;1:769Y776.
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
569
Functions and Mechanisms of Long Noncoding RNAs in Ovarian Cancer Chengcheng Ren, MMed,* Xiaobo Li, PhD,* Tianzhen Wang, PhD,* Guangyu Wang, PhD,þ Ci Zhao, PhD,þ Tian Liang, PhD,* Yuanyuan Zhu, MMed,* Minghui Li, MMed,§ Chao Yang, MMed,* Yunlong Zhao, MMed,* and Guang-mei Zhang, PhDÞ
Abstract: Long noncoding RNAs (lncRNAs) are longer than 200-nucleotide, noncoding transcripts in length, have a variety of biological functions, and are closely associated with tumor development. Ovarian cancer, as 1 of the 3 common gynecological malignancies, is the leading cause of death in women with gynecological malignant tumor. In this study, a review of the literature found that lncRNAs H19, LSINCT5, and XIST have a close relationship to the development of ovarian cancer occurrence, growth, invasion, and metastasis, and they can promote ovarian cancer cell proliferation. Hence, in this article, the progress of above-mentioned 3 kinds of lncRNAs in ovarian cancer was reviewed and designed to help in the diagnosis, treatment, and prognosis of ovarian cancer. Key Words: LncRNA, Ovarian cancer, Gene expression, Gene regulation Received November 4, 2014, and in revised form January 13, 2015. Accepted for publication January 21, 2015. (Int J Gynecol Cancer 2015;25: 566Y569)
noncoding RNAs (lncRNAs) are longer than 200L ong nucleotide, noncoding transcripts in length, which wide-
ly exist in the nucleus and cytoplasm of eukaryotic cells. However, because of a lack of significant open reading frames, they cannot encode proteins.1 With the continuous improvement of research methods, many lncRNA biological functions have been identified; for example, lncRNAs are involved in epigenetic modification through interaction with chromatin or methylation and ubiquitination, as well as through direct binding of transcription factors or heterologous DNA to form multimeric transcription
*Harbin Medical University, Harbin, China; †The First Affiliated Hospital of Harbin Medical University, Harbin, China; ‡The Affiliated Tumor Hospital of Harbin Medical University, Harbin, China; and §Inner Mongolia Medical College, Hohhot, China. Address correspondence and reprint requests to Guang-mei Zhang, PhD, The First Affiliated Hospital of Harbin Medical University, Heilongjiang 150001, China. E-mail: [email protected]. The authors declare no conflicts of interest. Copyright * 2015 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000413
566
regulation complexes. Long nonconding RNAs may also regulate the posttranscription processing, splicing, transport, translation, and degradation processes of messenger RNA.2Y4 According to a large number of experimental studies, lncRNAs are closely associated with tumor development; for example, lncRNAYhigh expression in hepatocellular carcinoma (HEIH) promotes liver cancer by combining with E2H2, leading to the down-regulation of P21 and other cell cycle regulators, promoting cell-cycle G0 into S phase and inducing hepatocellular carcinoma. The down-regulation of lncRNA-HEIH significantly inhibited the growth of liver cancer cells.5 Therefore, it may become a new target for the treatment of liver cancer. In contrast, lncRNAYmaternally expressed gene 3 (MEG3) expression is obviously decreased in gastric cancer, and high expression of MEG3 can inhibit gastric cancer cell proliferation and promote apoptosis of gastric carcinoma cells.6 Therefore, lncRNAs’ specific expression in certain types of cancer can be diagnosed as tumor markers and also be used as therapeutic targets to overcome cancer (Table 1). Ovarian cancer, as 1 of the 3 common gynecological malignant tumors, ranks third in incidence rate. Because of insidious onset and a lack of effective methods for early diagnosis, more than 70% of patients are at an advanced stage
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
& Volume 25, Number 4, May 2015
lncRNAs in Ovarian Cancer
TABLE 1. Disease-associated lncRNAs LncRNA
Size
Cytoband
Functions
Reference
HAR1A BCYRN1 HOTAIR MALAT1 HEIH MEG3 H19 LSINCT5 XIST
4 kb 260 bp 2158 bp 7.5 kb 2.2 kb 1.6 kb 2.3 kb 2.6 kb 17 kb
20q13.33 2p21 12q13.13 11q13.1 5p35.3 14q32.2 11p15.5 5p15.33 X
Participate in the human brain development Associated with Alzheimer disease Associated with breast cancer Associated with lung liver colon cancer Associated with liver cancer Associated with gastric cancer Associated with ovary lung breast liver cancer Associated with ovary cancer Associated with ovary cancer
7
when it is discovered.17 Currently, there are 3 major therapeutic areas of ovarian cancer, which include surgery, chemotherapy, and radiotherapy, but most patients relapse after surgery or develop resistance to chemotherapy drugs. Only approximately 30% of patients have a 5-year survival rate.18 Early detection, early diagnosis, and early treatment of ovarian cancer should greatly reduce mortality in patients with great significance on prognosis of patients. Researchers at home and abroad have been committed to looking for effective early ovarian cancer diagnostic markers to improve patient survival rate and have found that, in some cases, the development of ovarian cancer is closely related to the presence of the lncRNAs, such as H19, long stress-induced noncoding transcript 5 (LSINCT5), and X-inactive specific transcript (XIST), providing a new approach for early diagnosis and treatment of ovarian cancer. Therefore, in this article, H19, LSINCT5, and XIST functions and mechanisms in ovarian cancer were reviewed.14,19,20
Functions of lncRNAs in Ovarian Cancer H19 Promotes the Development of Ovarian Cancer H19 is the first discovered lncRNA associated with cancer, with a length of 2.3 kb. H19 differentially expresses in various cancers, and it has a dual role: tumor promoter or tumor suppressor.11 Mizrahi et al12 reported that, using H19RNA probe technique for situ hybridization in cells of ascites from ovarian cancer, H19 can be detected in 90% of patients with ovarian cancer ascites. In ectopic subcutaneous tumors injected with DTA-H19 in female mice, it is found that H19 downgraded expression and 40% of tumor growth inhibition. This suggests that H19 promotes tumorigenesis in ovarian cancer and interference with H19 expression can inhibit the growth of ovarian tumors.
LSINCT5 Promotes the Growth of Ovarian Cancer LSINCT5 is located in the nucleus, with a length of 2.6 kb. It is a stress-induced long noncoding transcript that is polyadenylated and transcribed by RNA polymerase III. LSINCT5 is highly expressed in ovarian cancer cell lines and tissue. Knockout LSINCT5 can decrease cell proliferation, but also
8 9 10 5 6 11Y13 14 15,16
with some changes in gene expression, including nuclear paraspeckle assembly transcript 1 (NEAT-1) and the proteincoding gene paraspeckle component 1 (PSPC1), whose expressions were significantly decreased.14 Therefore, LSINCT5 plays an important role in the proliferation and development of ovarian cancer.
XIST Promotes the Proliferation and Differentiation of Ovarian Cancer XIST gene is located on chromosome X inactivation center transcribed from chromosome X inactivation (Xi) and, in female cells, plays an important role in the start time of X chromosome inactivation.15 XIST is usually expressed in all female cells, but was not expressed in breast cancer, ovarian cancer, and cervical cancer cells. Kawakami et al,16 in the analysis of several XAS alleles, found 3 lost modes of Xi: Xi was lost without an increase in Xa, Xi was lost with an increase in Xa, and a small number of Xis were resurrected. The exact molecular mechanism of XIST in the initiation of X chromosome inactivation is still being investigated, but there is considerable evidence that XIST plays an important role in the proliferation, differentiation, and maintenance of genomic stability in human cells.
Mechanisms of lncRNAs in Ovarian Cancer H19 Imprint Mechanism Genomic imprinting is a genetic mechanism for the expression of genes in a group structure of 2 alleles in which maternal and paternal differences can directly affect replication, recombination, translocation, and destruction replication. Therefore, genomic imprinting is a basic biological phenomenon having a role in normal embryonic development and tumor development.21 H19/IGFII (insulin-like growth factor II) is a group of imprinted genes with maternal/paternal expression patterns. Although it is a relative marker, it is important in regulating gene expression.22 The H19/IGF2 gene imprinting control mechanism is very complex, and recent studies have found a competition for its common enhancer and allelic differences in methylation, chromatin conformation, and transcription cycle, but the formation of a unified regulatory mechanisms has not yet been identified.23 The H19 gene is transcribed into a multipolyadenylated RNA,
* 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
567
Ren et al
International Journal of Gynecological Cancer
which has no contact with the ribosome. It suggests that the function of H19 is at the RNA level and may be as a ribonucleoprotein in RNA component.24 H19 is significantly expressed in embryonic ovary matrix, whereas it is rarely expressed in the body cavity epithelial tissue. In adults, there is a rare expression of H19 in ovarian tissue, which may be related to steroid metabolism.25 Tanos et al19 have shown that H19 was expressed in 67% of epithelial ovarian benign tumors, in 75% of low potential of malignant ovarian tumors, and in 65% of malignant ovarian tumors. Therefore, it might be a potential tumor marker.
LSINCT5 and NNK Stress in Ovarian Cancer LSINCT5 is one of LSINCT family members, both of which are expressed during stress-induced cell formation and also participated in the development of cancers. They are found in the extracts of normal human bronchial epithelial cells exposed to 4-methylsulfinyl ammonium-1 (3-pyridyl)-1butanone (NNK).26 NNK is the strongest tobacco carcinogen, which leads to the metabolic activation by cytochrome P450 enzymes (mainly, CYPZA6 and CYPZA13) of a methylated intermediate resulting in the formation of DNA complexes and DNA single-strand breaks.27 NNK stress affects cell survival, proliferation, and motility as well as the cell cycle and expression of various genes.28 The LSINCT5 molecular mechanisms have not yet been found, which researchers need to continue to explore.
XIST and Chemotherapy Resistance Benoit et al,29 who explored X chromosome gene expression and Barr body staining in ovarian cancer cell lines, found that XIST was undetectable and no Barr body staining was observed in more than half of ovarian cancer cell lines compared with normal ovarian cancer cell lines. Other researchers found that XIST expression decreased and its sensitivity to paclitaxel treatment was reduced in ovarian cancer cell lines, suggesting that XIST gene expression in ovarian cancer cells can be used as a chemical marker of prognosis after treatment. This could be adjusted by the XIST toxic effects of paclitaxel and may also be linked via the reactivation of the X-‘‘specific resistance gene,’’ increasing the expression of genes on the X chromosome. Another possibility is that in cancer cells, XIST loss is a result of a genetic instability and has received chemotherapy resistance.30
Prospect Because lncRNAs showed high expression in liver, ovary, and lung cancers, with multiple regulatory roles in the development of tumors, their potential applications in the clinical diagnosis and treatment of cancer have broad prospects. Compared with microRNAs, researches of lncRNAs are still in there infancy, and most of lncRNA functions remain unclear. In addition, few lncRNAs were closely associated with ovarian cancer, and the mechanisms of action of ovarian cancer are not clear. Therefore, further studies on ovarian cancer occurrence and development of pathological process are needed, to help in the early detection and treatment of ovarian cancer. Long noncoding RNAs are expected as tumor markers to have high specificity and sensitivity
568
& Volume 25, Number 4, May 2015
to help indicate prognosis and directly target therapy to inhibit tumor growth or metastasis. These aspects of lncRNAs could help to achieve a more effective antitumor therapeutic approach so that lncRNA-based methods are expected to fundamentally improve the treatment and prognosis of ovarian cancer. Consequently, exploring the relationship between lncRNAs and ovarian cancer is a difficult task. There is a great need to invest more energy into this type of research. With advances in life sciences and technology leading to a more profound understanding of lncRNAs, the mechanism of lncRNAs in ovarian cancer will also become increasingly clear. Certain lncRNAs may act as ovarian cancerYspecific molecular markers and drug targets, providing new ideas and strategies for ovarian cancer diagnosis and treatment. Not only investigating the role of lncRNAs in ovarian cancer can enrich the content of noncoding RNAs research, but it may also be very important in the future for providing the theoretical basis and potential application in human ovarian cancer diagnosis and treatment in the field. Therefore, lncRNA research in ovarian cancer has farreaching significance.
REFERENCES 1. Spizzo R, Almeida MI, Colombatti A, et al. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31:4577Y4587. 2. Zhang H, Zeitz MJ, Wang H, et al. Long noncoding RNAYmediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol. 2014;204:61Y75. 3. Wang X, Arai S, Song X, et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature. 2008;454:126Y130. 4. Yang L, Lin C, Liu W, et al. lncRNA- and Pc2 methylationYdependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147:773Y788. 5. Yang F, Zhang L, Huo XS, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54:1679Y1689. 6. Sun M, Xia R, Jin F, et al. Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol. 2013;35:1065Y1073. 7. Pollard KS, Salanma SR, Lambert N, et al. An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006;443:167Y172. 8. Mus E, Hof PR, Tiedge H. Dendritie BC200 RNA in aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2007;104:10679Y10684. 9. Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071Y1076. 10. Lin R, Maeda S, Liu C, et al. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene. 2007;26:851Y858. 11. Hibi K, Nakamura H, Hirai A, et al. Loss of H19 imprinting in esophageal cancer. Cancer Res. 1996;56:480Y482. 12. Mizrahi A, Czerniak A, Levy T, et al. Development of targeted therapy for ovarian cancer mediated by a plasmid expressing * 2015 IGCS and ESGO
Copyright © 2015 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer
13. 14.
15.
16.
17. 18.
19.
20. 21.
22.
& Volume 25, Number 4, May 2015
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lncRNAs in Ovarian Cancer
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