Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy. Current standard practices for treatment of HCC are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting CSCs, or cancer cells with CSCs-like properties, is a new approach for HCC treatment. As we reported previously, microRNA-491 (miR-491) is lower expressed in poorly differentiated HCC tissues relative to well-differentiated HCC tissues. Here, we further evaluate the effects of miR-491 on the CSCs-like properties by using HCC cell lines and HCC tissue samples. Our data showed that miR-491 had a negative relationship with CSCs-like properties both in cell lines and tissue samples of HCC. Further, miR-491 levels of non-recurrence HCC tissues were higher than those of recurrence HCC tissues. In HCC cell lines, nuclear factor kappa B (NF-κB)/snail pathway was involved in the epithelial to mesenchymal transition and the maintenance of CSCs-like properties. Overexpression of miR-491 targeted G-protein-coupled receptor kinase-interacting protein 1 (GIT-1), which blocked the activation of NF-κB by the inhibition of extracellular signal-regulated kinases (ERKs). Such process attenuated the CSCs-like properties in HCC cells. Our results point to a previously undefined mechanism by which miR-491 decreases CSCs-like properties and help to identify potential targets for the therapy of HCCs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Tsochatzis EA, Meyer T, Burroughs AK. Hepatocellular carcinoma. N Engl J Med. 2012;366:92–3.
Thomas MB, Jaffe D, Choti MM, Belghiti J, Curley S, Fong Y, et al. Hepatocellular carcinoma: consensus recommendations of the national cancer institute clinical trials planning meeting. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:3994–4005.
Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.
Uchino K, Tateishi R, Shiina S, Kanda M, Masuzaki R, Kondo Y, et al. Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer. 2011;117:4475–83.
Zhou Y, Li Y, Ye J, Jiang R, Yan H, Yang X, et al. Microrna-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. Liver Int Off J Int Assoc Study Liver. 2013;33:1271–80.
Garcion E, Naveilhan P, Berger F, Wion D. Cancer stem cells: beyond Koch's postulates. Cancer Lett. 2009;278:3–8.
Xin YH, Bian BS, Yang XJ, Cui W, Cui HJ, Cui YH, et al. Pou5f1 enhances the invasiveness of cancer stem-like cells in lung adenocarcinoma by upregulation of mmp-2 expression. PLoS One. 2013;8, e83373.
Avivar-Valderas A, Wen HC, Aguirre-Ghiso JA: Stress signaling and the shaping of the mammary tissue in development and cancer. Oncogene. 2014
Jun HJ, Bronson RT, Charest A. Inhibition of egfr induces a c-met-driven stem cell population in glioblastoma. Stem Cells. 2014;32:338–48.
Hirsch D, Barker N, McNeil N, Hu Y, Camps J, McKinnon K, et al. Lgr5 positivity defines stem-like cells in colorectal cancer. Carcinogenesis. 2014;35:849–58.
Kim HM, Haraguchi N, Ishii H, Ohkuma M, Okano M, Mimori K, et al. Increased cd13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann Surg Oncol. 2012;19 Suppl 3:S539–548.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Ding SJ, Li Y, Shao XX, Zhou H, Zeng R, Tang ZY, et al. Proteome analysis of hepatocellular carcinoma cell strains, mhcc97-h and mhcc97-l, with different metastasis potentials. Proteomics. 2004;4:982–94.
Li Y, Ling M, Xu Y, Wang S, Li Z, Zhou J, et al. The repressive effect of nf- b on p53 by mot-2 is involved in human keratinocyte transformation induced by low levels of arsenite. Toxicol Sci. 2010;116:174–82.
Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, et al. Discrete nature of epcam + and cd90+ cancer stem cells in human hepatocellular carcinoma. Hepatology. 2013;57:1484–97.
Jiang R, Li Y, Xu Y, Zhou Y, Pang Y, Shen L, et al. Emt and csc-like properties mediated by the ikkbeta/ikappabalpha/rela signal pathway via the transcriptional regulator, snail, are involved in the arsenite-induced neoplastic transformation of human keratinocytes. Arch Toxicol. 2013;87:991–1000.
Huang WC, Chan SH, Jang TH, Chang JW, Ko YC, Yen TC, et al. Mirna-491-5p and git1 serve as modulators and biomarkers for oral squamous cell carcinoma invasion and metastasis. Cancer Res. 2014;74:751–64.
Yin G, Haendeler J, Yan C, Berk BC. Git1 functions as a scaffold for mek1-extracellular signal-regulated kinase 1 and 2 activation by angiotensin ii and epidermal growth factor. Mol Cell Biol. 2003;24:875–85.
Zhang N, Cai W, Yin G, Nagel DJ, Berk BC. Git1 is a novel mek1-erk1/2 scaffold that localizes to focal adhesions. Cell Biol Int. 2010;34:41–7.
Peng H, Dara L, Li TW, Zheng Y, Yang H, Tomasi ML, et al. Mat2b-git1 interplay activates mek1/erk 1 and 2 to induce growth in human liver and colon cancer. Hepatology. 2013;57:2299–313.
Yan H, Dong X, Zhong X, Ye J, Zhou Y, Yang X, Shen J, Zhang J. Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in mir-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog. 2013
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.
Zhang K, Zhaos J, Liu X, Yan B, Chen D, Gao Y, et al. Activation of nf-b upregulates snail and consequent repression of e-cadherin in cholangiocarcinoma cell invasion. Hepatogastroenterology. 2011;58:1–7.
Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12:5369–76.
Zhu LF, Hu Y, Yang CC, Xu XH, Ning TY, Wang ZL, et al. Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in scc9 cells. Laboratory investigation. J Tech Methods Pathol. 2012;92:744–52.
Li Y, Jiang R, Zhao Y, Xu Y, Ling M, Pang Y, et al. Opposed arsenite-mediated regulation of p53-survivin is involved in neoplastic transformation, DNA damage, or apoptosis in human keratinocytes. Toxicology. 2012;300:121–31.
Kim JH, Na HK, Pak YK, Lee YS, Lee SJ, Moon A, et al. Roles of erk and p38 mitogen-activated protein kinases in phorbol ester-induced nf-kappab activation and cox-2 expression in human breast epithelial cells. Chem Biol Interact. 2008;171:133–41.
Kavitha K, Kowshik J, Kishore TK, Baba AB, Nagini S. Astaxanthin inhibits nf-kappab and wnt/beta-catenin signaling pathways via inactivation of erk/mapk and pi3k/akt to induce intrinsic apoptosis in a hamster model of oral cancer. Biochim Biophys. 1830;2013:4433–44.
Acknowledgments
The authors wish to thank Donald L. Hill (University of Alabama at Birmingham, USA) for editing. This work was supported by the Natural Science Foundations of China (81272713, 81100253, and 81273114).
Conflicts of interest
The authors declare they have no competing financial interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xiaojun Yang, Jing Ye, and Han Yan contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 375 kb)
Rights and permissions
About this article
Cite this article
Yang, X., Ye, J., Yan, H. et al. MiR-491 attenuates cancer stem cells-like properties of hepatocellular carcinoma by inhibition of GIT-1/NF-κB-mediated EMT. Tumor Biol. 37, 201–209 (2016). https://doi.org/10.1007/s13277-015-3687-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3687-5