Skip to main content
Top
Published in: Molecular Cancer 1/2018

Open Access 01-12-2018 | Research

Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 Kip1 axis

Authors: Hui Liu, Yuan Liu, Zhaolian Bian, Jing Zhang, Rui Zhang, Xiaoyu Chen, Yanxia Huang, Yang Wang, Jinshui Zhu

Published in: Molecular Cancer | Issue 1/2018

Login to get access

Abstract

Background

Circular RNAs (circRNAs) are a new type of non-coding RNAs and their functions in gastric cancer (GC) remain unclear. Recent studies have revealed that circRNAs play an important role in cancer development and certain types of pathological responses, acting as microRNA (miRNA) sponges to regulate gene expression.

Methods

CircNet was used to screen potential circRNAs and validated circYAP1 expression levels in 17 GC tissues by quantitative real-time PCR (qRT-PCR) and another 80 paired GC tissues by FISH. CircYAP1 overexpression and knockdown experiments were conducted to assess the effects of circYAP1 in vitro and in vivo, and its molecular mechanism was demonstrated by RNA in vivo precipitation assays, western blotting, luciferase assay and rescue experiments.

Results

CircYAP1 expression level was significantly lower in GC tissues than the adjacent normal tissues, and GC patients with circYAP1 low expression had shorter survival times as compared with those with circYAP1 high expression. Functionally, circYAP1 overexpression inhibited cell growth and invasion in vitro and in vivo, but its knockdown reversed these effects. Further analysis showed that circYAP1 sponged miR-367-5p to inhibit p27 Kip1 expression and GC progression.

Conclusion

Our findings demonstrate that circYAP1 functions as a tumor suppressor in GC cells by targeting the miR-367-5p/p27 Kip1 axis and may provide a prognostic indicator of survival in GC patients.
Appendix
Available only for authorised users
Literature
1.
go back to reference Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.CrossRef
2.
go back to reference Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385:977–1010.CrossRef Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385:977–1010.CrossRef
3.
go back to reference Wang J, Song Y-X, Wang Z-N. Non-coding RNAs in gastric cancer. Gene. 2015;560:1–8.CrossRef Wang J, Song Y-X, Wang Z-N. Non-coding RNAs in gastric cancer. Gene. 2015;560:1–8.CrossRef
4.
go back to reference Song JH, Meltzer SJ. MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology. 2012;143:35–47 e32.CrossRef Song JH, Meltzer SJ. MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology. 2012;143:35–47 e32.CrossRef
5.
go back to reference Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, Wu M. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.CrossRef Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, Wu M. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.CrossRef
6.
go back to reference Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9:e1003777.CrossRef Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9:e1003777.CrossRef
7.
go back to reference Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.CrossRef Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.CrossRef
8.
go back to reference Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.CrossRef Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.CrossRef
10.
go back to reference Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential functions. Development. 2016;143:1838–47.CrossRef Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential functions. Development. 2016;143:1838–47.CrossRef
11.
go back to reference Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.CrossRef Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.CrossRef
12.
go back to reference Chen Y, Li C, Tan C, Liu X. Circular RNAs: a new frontier in the study of human diseases. J Med Genet. 2016;53:359–65.CrossRef Chen Y, Li C, Tan C, Liu X. Circular RNAs: a new frontier in the study of human diseases. J Med Genet. 2016;53:359–65.CrossRef
13.
go back to reference Han D, Li J, Wang H, Su X, Hou J, Gu Y, Qian C, Lin Y, Liu X, Huang M, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.CrossRef Han D, Li J, Wang H, Su X, Hou J, Gu Y, Qian C, Lin Y, Liu X, Huang M, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.CrossRef
14.
go back to reference Hsiao KY, Lin YC, Gupta SK, Chang N, Yen L, Sun HS, Tsai SJ. Non-coding effects of circular RNA CCDC66 promote colon cancer growth and metastasis. Cancer Res. 2017;77:2339-50.CrossRef Hsiao KY, Lin YC, Gupta SK, Chang N, Yen L, Sun HS, Tsai SJ. Non-coding effects of circular RNA CCDC66 promote colon cancer growth and metastasis. Cancer Res. 2017;77:2339-50.CrossRef
15.
go back to reference Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, Ge S. circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551-61.CrossRef Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, Ge S. circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551-61.CrossRef
16.
go back to reference Zhong Z, Huang M, Lv M, He Y, Duan C, Zhang L, Chen J. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Lett. 2017;403:305–17.CrossRef Zhong Z, Huang M, Lv M, He Y, Duan C, Zhang L, Chen J. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Lett. 2017;403:305–17.CrossRef
17.
go back to reference Li F, Zhang L, Li W, Deng J, Zheng J, An M, Lu J, Zhou Y. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget. 2015;6:6001–13.PubMedPubMedCentral Li F, Zhang L, Li W, Deng J, Zheng J, An M, Lu J, Zhou Y. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget. 2015;6:6001–13.PubMedPubMedCentral
18.
go back to reference Su X, Wang H, Ge W, Yang M, Hou J, Chen T, Li N, Cao X. An in vivo method to identify microRNA targets not predicted by computation algorithms: p21 targeting by miR-92a in Cancer. Cancer Res. 2015;75:2875–85.CrossRef Su X, Wang H, Ge W, Yang M, Hou J, Chen T, Li N, Cao X. An in vivo method to identify microRNA targets not predicted by computation algorithms: p21 targeting by miR-92a in Cancer. Cancer Res. 2015;75:2875–85.CrossRef
19.
go back to reference Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, Hur K, Yoo MW, Lee HJ, Yang HK, Kim VN. Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009;37:1672–81.CrossRef Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, Hur K, Yoo MW, Lee HJ, Yang HK, Kim VN. Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009;37:1672–81.CrossRef
20.
go back to reference Sun M, Liu XH, Li JH, Yang JS, Zhang EB, Yin DD, Liu ZL, Zhou J, Ding Y, Li SQ, et al. MiR-196a is upregulated in gastric cancer and promotes cell proliferation by downregulating p27(kip1). Mol Cancer Ther. 2012;11:842–52.CrossRef Sun M, Liu XH, Li JH, Yang JS, Zhang EB, Yin DD, Liu ZL, Zhou J, Ding Y, Li SQ, et al. MiR-196a is upregulated in gastric cancer and promotes cell proliferation by downregulating p27(kip1). Mol Cancer Ther. 2012;11:842–52.CrossRef
21.
go back to reference Yan K, Tian J, Shi W, Xia H, Zhu Y. LncRNA SNHG6 is associated with poor prognosis of gastric Cancer and promotes cell proliferation and EMT through epigenetically silencing p27 and sponging miR-101-3p. Cell Physiol Biochem. 2017;42:999–1012.CrossRef Yan K, Tian J, Shi W, Xia H, Zhu Y. LncRNA SNHG6 is associated with poor prognosis of gastric Cancer and promotes cell proliferation and EMT through epigenetically silencing p27 and sponging miR-101-3p. Cell Physiol Biochem. 2017;42:999–1012.CrossRef
22.
go back to reference Zhang Q, Hou D, Luo Z, Chen P, Lv B, Wu L, Ma Y, Chu Y, Liu H, Liu F, et al. The novel protective role of P27 in MLN4924-treated gastric cancer cells. Cell Death Dis. 2015;6:e1867.CrossRef Zhang Q, Hou D, Luo Z, Chen P, Lv B, Wu L, Ma Y, Chu Y, Liu H, Liu F, et al. The novel protective role of P27 in MLN4924-treated gastric cancer cells. Cell Death Dis. 2015;6:e1867.CrossRef
23.
go back to reference He J, Xie Q, Xu H, Li J, Li Y. Circular RNAs and cancer. Cancer Lett. 2017;396:138–44.CrossRef He J, Xie Q, Xu H, Li J, Li Y. Circular RNAs and cancer. Cancer Lett. 2017;396:138–44.CrossRef
24.
go back to reference Kristensen LS, Hansen TB, Veno MT, Kjems J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene. 2017;37:555-65.CrossRef Kristensen LS, Hansen TB, Veno MT, Kjems J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene. 2017;37:555-65.CrossRef
25.
go back to reference Wang K, Sun Y, Tao W, Fei X, Chang C. Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer Lett. 2017;394:1–12.CrossRef Wang K, Sun Y, Tao W, Fei X, Chang C. Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals. Cancer Lett. 2017;394:1–12.CrossRef
26.
go back to reference Yao Z, Luo J, Hu K, Lin J, Huang H, Wang Q, Zhang P, Xiong Z, He C, Huang Z, et al. ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways. Mol Oncol. 2017;11:422–37.CrossRef Yao Z, Luo J, Hu K, Lin J, Huang H, Wang Q, Zhang P, Xiong Z, He C, Huang Z, et al. ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways. Mol Oncol. 2017;11:422–37.CrossRef
27.
go back to reference Zhang J, Liu H, Hou L, Wang G, Zhang R, Huang Y, Chen X, Zhu J. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. Mol Cancer. 2017;16:151.CrossRef Zhang J, Liu H, Hou L, Wang G, Zhang R, Huang Y, Chen X, Zhu J. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. Mol Cancer. 2017;16:151.CrossRef
28.
go back to reference Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 2015;58:870–85.CrossRef Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 2015;58:870–85.CrossRef
29.
go back to reference Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17:2130–9.CrossRef Kang W, Tong JH, Chan AW, Lee TL, Lung RW, Leung PP, So KK, Wu K, Fan D, Yu J, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17:2130–9.CrossRef
30.
go back to reference Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JC, et al. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 2015;14:52.CrossRef Kang W, Tong JH, Lung RW, Dong Y, Zhao J, Liang Q, Zhang L, Pan Y, Yang W, Pang JC, et al. Targeting of YAP1 by microRNA-15a and microRNA-16-1 exerts tumor suppressor function in gastric adenocarcinoma. Mol Cancer. 2015;14:52.CrossRef
31.
go back to reference Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44:2846–58.CrossRef Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44:2846–58.CrossRef
32.
go back to reference Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.CrossRef Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.CrossRef
33.
go back to reference Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Res. 2013;73:5609–12.CrossRef Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Res. 2013;73:5609–12.CrossRef
34.
go back to reference Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 2016;13:34–42.CrossRef Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M. CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 2016;13:34–42.CrossRef
35.
go back to reference Piwecka M, Glazar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F, Cerda Jara CA, Fenske P, et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 2017. 357. Piwecka M, Glazar P, Hernandez-Miranda LR, Memczak S, Wolf SA, Rybak-Wolf A, Filipchyk A, Klironomos F, Cerda Jara CA, Fenske P, et al. Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science 2017. 357.
36.
go back to reference Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in Cancer cells and the tumor microenvironment. Cancer Discov. 2016;6:235–46.CrossRef Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK. miRNA deregulation in Cancer cells and the tumor microenvironment. Cancer Discov. 2016;6:235–46.CrossRef
37.
go back to reference Ling JW, Lu PR, Zhang YB, Jiang S, Zhang ZC. miR-367 promotes uveal melanoma cell proliferation and migration by regulating PTEN. Genet Mol Res. 2017;16. Ling JW, Lu PR, Zhang YB, Jiang S, Zhang ZC. miR-367 promotes uveal melanoma cell proliferation and migration by regulating PTEN. Genet Mol Res. 2017;16.
38.
go back to reference Cai W, Jiang H, Yu Y, Xu Y, Zuo W, Wang S, Su Z. miR-367 regulation of DOC-2/DAB2 interactive protein promotes proliferation, migration and invasion of osteosarcoma cells. Biomed Pharmacother. 2017;95:120–8.CrossRef Cai W, Jiang H, Yu Y, Xu Y, Zuo W, Wang S, Su Z. miR-367 regulation of DOC-2/DAB2 interactive protein promotes proliferation, migration and invasion of osteosarcoma cells. Biomed Pharmacother. 2017;95:120–8.CrossRef
39.
go back to reference Kaid C, Silva PB, Cortez BA, Rodini CO, Semedo-Kuriki P, Okamoto OK. miR-367 promotes proliferation and stem-like traits in medulloblastoma cells. Cancer Sci. 2015;106:1188–95.CrossRef Kaid C, Silva PB, Cortez BA, Rodini CO, Semedo-Kuriki P, Okamoto OK. miR-367 promotes proliferation and stem-like traits in medulloblastoma cells. Cancer Sci. 2015;106:1188–95.CrossRef
40.
go back to reference Campayo M, Navarro A, Vinolas N, Diaz T, Tejero R, Gimferrer JM, Molins L, Cabanas ML, Ramirez J, Monzo M, Marrades R. Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer. Eur Respir J. 2013;41:1172–8.CrossRef Campayo M, Navarro A, Vinolas N, Diaz T, Tejero R, Gimferrer JM, Molins L, Cabanas ML, Ramirez J, Monzo M, Marrades R. Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer. Eur Respir J. 2013;41:1172–8.CrossRef
41.
go back to reference Xiao G, Zhang B, Meng J, Wang J, Xu C, Tang SC, Li X, Zhang J, Liang R, Ren H, Sun X. miR-367 stimulates Wnt cascade activation through degrading FBXW7 in NSCLC stem cells. Cell Cycle. 2017;16:2374–85.CrossRef Xiao G, Zhang B, Meng J, Wang J, Xu C, Tang SC, Li X, Zhang J, Liang R, Ren H, Sun X. miR-367 stimulates Wnt cascade activation through degrading FBXW7 in NSCLC stem cells. Cell Cycle. 2017;16:2374–85.CrossRef
42.
go back to reference Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8:253–67.CrossRef Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8:253–67.CrossRef
43.
go back to reference Mori M, Mimori K, Shiraishi T, Tanaka S, Ueo H, Sugimachi K, Akiyoshi T. p27 expression and gastric carcinoma. Nat Med. 1997;3:593.CrossRef Mori M, Mimori K, Shiraishi T, Tanaka S, Ueo H, Sugimachi K, Akiyoshi T. p27 expression and gastric carcinoma. Nat Med. 1997;3:593.CrossRef
Metadata
Title
Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 Kip1 axis
Authors
Hui Liu
Yuan Liu
Zhaolian Bian
Jing Zhang
Rui Zhang
Xiaoyu Chen
Yanxia Huang
Yang Wang
Jinshui Zhu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2018
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-018-0902-1

Other articles of this Issue 1/2018

Molecular Cancer 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine