Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cellular Oncology
Published in: Cellular Oncology 2/2017

01-04-2017 | Original Paper

microRNA-145 modulates epithelial-mesenchymal transition and suppresses proliferation, migration and invasion by targeting SIP1 in human cervical cancer cells

Authors: Anusha Sathyanarayanan, Karthik Subramanian Chandrasekaran, Devarajan Karunagaran

Published in: Cellular Oncology | Issue 2/2017

Login to get access

Abstract

Purpose

Previously, it has been reported that microRNA-145 (miR-145) is lowly expressed in human cervical cancers and that its putative tumour suppressive role may be attributed to epithelial-mesenchymal transition (EMT) regulation. Here, we aimed to assess whether miR-145 may affect EMT-associated markers/genes and suppress cervical cancer growth and motility, and to provide a mechanistic basis for these phenomena.

Methods

The identification of the SMAD-interacting protein 1 (SIP1) mRNA as putative miR-145 target was investigated using a 3’ untranslated region (3’UTR) luciferase assay and Western blotting, respectively. The functional effects of exogenous miR-145 expression, miR-145 suppression or siRNA-mediated SIP1 expression down-regulation in cervical cancer-derived C33A and SiHa cells were analysed using Western blotting, BrdU incorporation (proliferation), transwell migration and invasion assays. In addition, the expression levels of miR-145 and SIP1 were determined in primary human cervical cancer and non-cancer tissue samples using qRT-PCR.

Results

We found that miR-145 binds to the wild-type 3’UTR of SIP1, but not to its mutant counterpart, and that, through this binding, miR-145 can effectively down-regulate SIP1 expression. In addition, we found that exogenous miR-145 expression or siRNA-mediated down-regulation of SIP1 expression attenuates the proliferation, migration and invasion of C33A and SiHa cells and alters the expression of the EMT-associated markers CDH1, VIM and SNAI1, whereas inhibition of endogenous miR-145 expression elicited the opposite effects. The expression of miR-145 in cervical cancer tissue samples was found to be low, while that of SIP1 was found to be high compared to non-cancerous cervical tissues. An inverse expression correlation between the two was substantiated through the anlaysis of data deposited in the TCGA database.

Conclusion

Our data indicate that low miR-145 expression levels in conjunction with elevated SIP1 expression levels may contribute to cervical cancer development. MiR-145-mediated regulation of SIP1 provides a novel mechanistic basis for its tumour suppressive mode of action in human cervical cancer cells.
Literature
1.
J. Ferlay, I.I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo, D.M. Parkin, D.D. Forman, F. Bray, Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2014)CrossRefPubMed
2.
C.D. Capo-Chichi, B. Aguida, N.W. Chabi, Q.K. Cai, G. Offrin, V.K. Agossou, A. Sanni, X.-X. Xu, Lamin A/C deficiency is an independent risk factor for cervical cancer. Cell. Oncol. 39, 59–68 (2016)CrossRef
3.
S.B. Prasad, S.S. Yadav, M. Das, A. Modi, S. Kumari, L.K. Pandey, S. Singh, S. Pradhan, G. Narayan, PI3K/AKT pathway-mediated regulation of p27Kip1 is associated with cell cycle arrest and apoptosis in cervical cancer. Cell. Oncol. 38, 215–225 (2015)CrossRef
4.
W.-O. Lui, N. Pourmand, B.K. Patterson, A. Fire, Patterns of known and novel small RNAs in human cervical cancer. Cancer Res. 67, 6031–6043 (2007)CrossRefPubMed
5.
M. Schiffman, N. Wentzensen, Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol. Biomarkers Prev. 22, 553–560 (2013)CrossRefPubMedPubMedCentral
6.
J.M.M. Walboomers, M.V. Jacobs, M.M. Manos, F.X. Bosch, J.A. Kummer, K.V. Shah, P.J.F. Snijders, J. Peto, C.J.L.M. Meijer, N. Muoz, Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189, 12–19 (1999)CrossRefPubMed
7.
X. Wang, S. Tang, S.-Y. Le, R. Lu, J.S. Rader, C. Meyers, Z.-M. Zheng, Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS ONE 3, e2557 (2008)CrossRefPubMedPubMedCentral
8.
9.
10.
11.
S. Sassen, E.A. Miska, C. Caldas, MicroRNA: implications for cancer. Virchows Arch. 452, 1–10 (2008)CrossRefPubMed
12.
A. Esquela-Kerscher, F.J. Slack, Oncomirs - microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006)CrossRefPubMed
13.
S. Volinia, G.A. Calin, C.-G. Liu, S. Ambs, A. Cimmino, F. Petrocca, R. Visone, M. Iorio, C. Roldo, M. Ferracin, R.L. Prueitt, N. Yanaihara, G. Lanza, A. Scarpa, A. Vecchione, M. Negrini, C.C. Harris, C.M. Croce, A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. U. S. A. 103, 2257–2261 (2006)CrossRefPubMedPubMedCentral
14.
M. Pichler, G.A. Calin, MicroRNAs in cancer: from developmental genes in worms to their clinical application in patients. Br. J. Cancer 113, 569–573 (2015)CrossRefPubMedPubMedCentral
15.
X. Wang, H.-K. Wang, J.P. McCoy, N.S. Banerjee, J.S. Rader, T.R. Broker, C. Meyers, L.T. Chow, Z.-M. Zheng, Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 15, 637–647 (2009)CrossRefPubMedPubMedCentral
16.
M. Melar-New, L.A. Laimins, Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins. J. Virol. 84, 5212–5521 (2010)CrossRefPubMedPubMedCentral
17.
T. Hou, J. Ou, X. Zhao, X. Huang, Y. Huang, Y. Zhang, MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. Br. J. Cancer 110, 1260–1268 (2014)CrossRefPubMedPubMedCentral
18.
T. Tang, H.K. Wong, W. Gu, M.Y. Yu, K.-F.F. To, C.C. Wang, Y.F. Wong, T.H. Cheung, T.K.H. Chung, K.W. Choy, MicroRNA-182 plays an onco-miRNA role in cervical cancer. Gynecol. Oncol. 129, 199–208 (2013)CrossRefPubMed
19.
M. Shi, L. Du, D. Liu, L. Qian, M. Hu, M. Yu, Z. Yang, M. Zhao, C. Chen, L. Guo, L. Wang, L. Song, Y. Ma, N. Guo, Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. J. Pathol. 228, 148–157 (2012)CrossRefPubMed
20.
21.
M.-Y. Lee, C.-Y. Chou, M.-J. Tang, M.-R. Shen, Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin. Cancer Res. 14, 4743–4750 (2008)CrossRefPubMed
22.
K. Shibata, H. Kajiyama, K. Ino, M. Terauchi, E. Yamamoto, A. Nawa, S. Nomura, F. Kikkawa, Twist expression in patients with cervical cancer is associated with poor disease outcome. Ann. Oncol. 19, 81–85 (2008)CrossRefPubMed
23.
J. Comijn, G. Berx, P. Vermassen, K. Verschueren, L. van Grunsven, E. Bruyneel, M. Mareel, D. Huylebroeck, F. van Roy, The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001)CrossRefPubMed
24.
C. Vandewalle, J. Comijn, B. De Craene, P. Vermassen, E. Bruyneel, H. Andersen, E. Tulchinsky, F. Van Roy, G. Berx, SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 33, 6566–6578 (2005)CrossRefPubMedPubMedCentral
25.
M. Korpal, E.S. Lee, G. Hu, Y. Kang, The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910–14914 (2008)CrossRefPubMedPubMedCentral
26.
Y. Hou, J. Zhen, X. Xu, K. Zhen, B. Zhu, R. Pan, C. Zhao, miR‑215 functions as a tumor suppressor and directly targets ZEB2 in human non‑small cell lung cancer. Oncol. Lett. 10, 1985–1992 (2015)PubMedPubMedCentral
27.
D.-K. Sun, J.-M. Wang, P. Zhang, Y.-Q. Wang, MicroRNA-138 regulates metastatic potential of bladder cancer through ZEB2. Cell. Physiol. Biochem. 37, 2366–2374 (2015)CrossRefPubMed
28.
K. Saito, T. Oku, N. Ata, H. Miyashiro, M. Hattori, I. Saiki, A modified and convenient method for assessing tumor cell invasion and migration and its application to screening for inhibitors. Biol. Pharm. Bull. 20, 345–348 (1997)CrossRefPubMed
29.
A.V. Das, R.M. Pillai, Implications of miR cluster 143/145 as universal anti-oncomiRs and their dysregulation during tumorigenesis. Cancer Cell Int. 15, 92 (2015)CrossRefPubMedPubMedCentral
30.
M. Garg, Epithelial-mesenchymal transition - activating transcription factors - multifunctional regulators in cancer. World J. Stem Cells 5, 188–195 (2013)CrossRefPubMedPubMedCentral
31.
V. Taucher, H. Mangge, J. Haybaeck, Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application. Cell. Oncol. 39, 295–318 (2016)CrossRef
32.
A. Ferraro, Altered primary chromatin structures and their implications in cancer development. Cell. Oncol. 39, 195–210 (2016)CrossRef
33.
M. Vitiello, A. Tuccoli, L. Poliseno, Long non-coding RNAs in cancer: implications for personalized therapy. Cell. Oncol. 38, 17–28 (2015)CrossRef
34.
35.
L. Huang, J.-X. Lin, Y.-H. Yu, M.-Y. Zhang, H.-Y. Wang, M. Zheng, Downregulation of six microRNAs is associated with advanced stage, lymph node metastasis and poor prognosis in small cell carcinoma of the cervix. PLoS ONE 7, e33762 (2012)CrossRefPubMedPubMedCentral
36.
D. Geng, X. Song, F. Ning, Q. Song, H. Yin, MiR-34a inhibits viability and invasion of human papillomavirus-positive cervical cancer cells by targeting 2F3 and regulating survivin. Int. J. Gynecol. Cancer 25, 707–713 (2015)CrossRefPubMed
37.
J. Li, Z. Ping, H. Ning, MiR-218 impairs tumor growth and increases chemo-sensitivity to cisplatin in cervical cancer. Int. J. Mol. Sci. 13, 16053–16064 (2012)CrossRefPubMedPubMedCentral
38.
C. Lin, F. Huang, G. Shen, A. Yiming, MicroRNA-101 regulates the viability and invasion of cervical cancer cells. Int. J. Clin. Exp. Pathol. 8, 10148–10155 (2015)PubMedPubMedCentral
39.
L. Liu, X. Yu, X. Guo, Z. Tian, M. Su, Y. Long, C. Huang, F. Zhou, M. Liu, X. Wu, X. Wang, miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol. Med. Rep. 5, 753–760 (2012)PubMed
40.
K. Doberstein, N. Steinmeyer, A.-K. Hartmetz, W. Eberhardt, M. Mittelbronn, P.N. Harter, E. Juengel, R. Blaheta, J. Pfeilschifter, P. Gutwein, MicroRNA-145 targets the metalloprotease ADAM17 and is suppressed in renal cell carcinoma patients. Neoplasia 15, 218–230 (2013)CrossRefPubMedPubMedCentral
41.
Y. Feng, J. Zhu, C. Ou, Z. Deng, M. Chen, W. Huang, L. Li, MicroRNA-145 inhibits tumour growth and metastasis in colorectal cancer by targeting fascin-1. Br. J. Cancer 110, 2300–2309 (2014)CrossRefPubMedPubMedCentral
42.
R. Liu, J. Liao, M. Yang, J. Sheng, H. Yang, Y. Wang, E. Pan, W. Guo, Y. Pu, S.J. Kim, L. Yin, The cluster of miR-143 and miR-145 affects the risk for esophageal squamous cell carcinoma through co-regulating fascin homolog 1. PLoS ONE 7, e33987 (2012)CrossRefPubMedPubMedCentral
43.
J. Qin, F. Wang, H. Jiang, J. Xu, Y. Jiang, Z. Wang, MicroRNA-145 suppresses cell migration and invasion by targeting paxillin in human colorectal cancer cells. Int. J. Clin. Exp. Pathol. 8, 1328–1340 (2015)PubMedPubMedCentral
44.
D. Ren, M. Wang, W. Guo, S. Huang, Z. Wang, X. Zhao, H. Du, L. Song, X. Peng, Double-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells. Cell Tissue Res. 358, 763–778 (2014)CrossRefPubMed
45.
M. Sachdeva, Y.-Y. Mo, MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res. 70, 378–387 (2010)CrossRefPubMed
46.
J. Zhang, H. Guo, H. Zhang, H. Wang, G. Qian, X. Fan, A.R. Hoffman, J.-F. Hu, S. Ge, Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene Friend leukemia virus integration 1 gene. Cancer 117, 86–95 (2011)CrossRefPubMed
47.
D. Dan Zhou, X. Wang, Y. Wang, X.J. Xiang, Z.C. Liang, Y. Zhou, A. Xu, C.H. Bi, L. Zhang, MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway. Mol. Immunol. 75, 151–160 (2016)CrossRef
48.
Z. Jiang, Q. Song, R. Zeng, H. Werner, J. Li, X. Lin, X. Chen, J. Zhang, Y. Zheng, Z. Jiang, Q. Song, R. Zeng, MicroRNA-218 inhibits EMT, migration and invasion by targeting SFMBT1 and DCUN1D1 in cervical cancer. Oncotarget 7, 45622–45636 (2016)PubMedPubMedCentral
49.
Y. Cheng, G. Chen, C. Chen, Q. Zhang, F. Pan, M. Hu, B. Li, MicroRNA-200b inhibits epithelial-mesenchymal transition and migration of cervical cancer cells by directly targeting RhoE. Mol. Med. Rep. 13, 3139–3146 (2016)PubMed
50.
H. Xia, S.S. Ng, S. Jiang, W.K.C. Cheung, J. Sze, X.W. Bian, H. Fu Kung, M.C. Lin, miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem. Biophys. Res. Commun. 391, 535–541 (2010)CrossRefPubMed
51.
J. You, Y. Li, N. Fang, B. Liu, L. Zu, R. Chang, X. Li, Q. Zhou, MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. PLoS ONE 9, e91827 (2014)CrossRefPubMedPubMedCentral
52.
E.V. Usova, M.R. Kopantseva, M.B. Kostina, A.N. Van’kovich, V.I. Egorov, E.P. Kopantsev, Expression of the ZEB2 gene in pancreatic stromal cells in pancreatic ductal adenocarcinoma, pancreatitis, and normal state. Dokl. Biol. Sci. 448, 61–64 (2013)CrossRefPubMed
53.
S. Qi, Y. Song, Y. Peng, H. Wang, H. Long, X. Yu, Z. Li, L. Fang, A. Wu, W. Luo, Y. Zhen, Y. Zhou, Y. Chen, C. Mai, Z. Liu, W. Fang, ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PLoS ONE 7, e38842 (2012)CrossRefPubMedPubMedCentral
54.
N. Cong, P. Du, A. Zhang, F. Shen, J. Su, P. Pu, T. Wang, J. Zjang, C. Kang, Q. Zhang, Downregulated microRNA-200a promotes EMT and tumor growth through the wnt/β-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma. Oncol. Rep. 29, 1579–1587 (2013)PubMed
55.
M.-Y. Cai, R.-Z. Luo, J.-W. Chen, X.-Q. Pei, J.-B. Lu, J.-H. Hou, J.-P. Yun, Overexpression of ZEB2 in peritumoral liver tissue correlates with favorable survival after curative resection of hepatocellular carcinoma. PLoS ONE 7, e32838 (2012)CrossRefPubMedPubMedCentral
56.
R. Yoshida, M. Morita, F. Shoji, Y. Nakashima, N. Miura, K. Yoshinaga, T. Koga, E. Tokunaga, H. Saeki, E. Oki, Y. Oda, Y. Maehara, Clinical significance of SIP1 and E-cadherin in patients with esophageal squamous cell carcinoma. Ann. Surg. Oncol. 22, 2608–2614 (2015)CrossRefPubMed
57.
Y.H. Kong, S.N. Syed Zanaruddin, S.H. Lau, A. Ramanathan, T.G. Kallarakkal, V.K. Vincent-Chong, W.M. Wan Mustafa, M.T. Abraham, Z.A. Abdul Rahman, R.B. Zain, S.C. Cheong, Co-expression of TWIST1 and ZEB2 in oral squamous cell carcinoma is associated with poor survival. PLoS ONE 10, e0134045 (2015)CrossRefPubMedPubMedCentral
58.
S. Elloul, M.B. Elstrand, J.M. Nesland, C.G. Tropé, G. Kvalheim, I. Goldberg, R. Reich, B. Davidson, Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103, 1631–1643 (2005)CrossRefPubMed
Metadata
Title
microRNA-145 modulates epithelial-mesenchymal transition and suppresses proliferation, migration and invasion by targeting SIP1 in human cervical cancer cells
Authors
Anusha Sathyanarayanan
Karthik Subramanian Chandrasekaran
Devarajan Karunagaran
Publication date
01-04-2017
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 2/2017
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-016-0307-3

Other articles of this Issue 2/2017

Cellular Oncology 2/2017 Go to the issue

Original Paper

Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis

Original Paper

CDKN2A-p53 mediated antitumor effect of Lupeol in head and neck cancer

Original Paper

HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation

Original Paper

microRNA-761 induces aggressive phenotypes in triple-negative breast cancer cells by repressing TRIM29 expression

Report

ELMO3 expression indicates a poor prognosis in head and neck squamous cell carcinoma - a short report

Review

Emerging diagnostic, prognostic and therapeutic biomarkers for ovarian cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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
Image Credits