Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Accumulating studies have revealed that microRNAs (miRNAs) play a critical role in the development and progression of HCC. Through microarray-based gene expression profiling of HCC, miR-370, and BEX2 were identified in HCC. Hence, this study aimed to evaluate their abilities on the cellular processes in HCC. It was determined that BEX2 was highly expressed and miR-370 was poorly expressed in HCC cell lines and tissues. Then, the cell line presenting with the highest BEX2 expression and the lowest miR-370 expression was selected for subsequent gain- and loss-of-function experimentation. The antitumor effect of miR-370 on HCC cell proliferation, invasion, migration, and apoptosis, as well as the MAPK/JNK signaling pathway was examined. Meanwhile, the interaction among miR-370, BEX2, and MAPK/JNK signaling pathway was identified. BEX2 is verified to be a target of miR-370. Moreover, miR-370 exerted antitumor effect on HCC development through suppression of the MAPK/JNK signaling pathway by targeting BEX2. Later, it was further verified by in vivo experiment that overexpression of miR-370 inhibited tumor growth. Above results provide evidence that miR-370 could downregulate BEX2 gene and inhibit activation of MAPK/JNK signaling pathway, thus inhibiting the development of HCC. It provides a worth-trying novel therapeutic target for HCC treatment.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. Cancer J Clin. 2015;65:5–29.
Lv J, Kong Y, Gao Z, Liu Y, Zhu P, Yu Z. LncRNA TUG1 interacting with miR-144 contributes to proliferation, migration and tumorigenesis through activating the JAK2/STAT3 pathway in hepatocellular carcinoma. Int J Biochem Cell Biol. 2018;101:19–28.
Zhang J, Zhang D, Zhao Q, Qi J, Li X, Qin C. A distinctively expressed long noncoding RNA, RP11-466I1.1, may serve as a prognostic biomarker in hepatocellular carcinoma. Cancer Med. 2018. https://doi.org/10.1002/cam4.1565
Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007;43:1529–44.
Han G, Zhang L, Ni X, Chen Z, Pan X, Zhu Q, et al. MicroRNA-873 promotes cell proliferation, migration, and invasion by directly targeting TSLC1 in hepatocellular carcinoma. Cell Physiol Biochem. 2018;46:2261–70.
Lv J, Xia K, Xu P, Sun E, Ma J, Gao S, et al. miRNA expression patterns in chemoresistant breast cancer tissues. Biomed Pharmacother. 2014;68:935–42.
Shen X, Zuo X, Zhang W, Bai Y, Qin X, Hou N. MiR-370 promotes apoptosis in colon cancer by directly targeting MDM4. Oncol Lett. 2018;15:1673–9.
Lu M, Wang Y, Zhou S, Xu J, Li J, Tao R, et al. MicroRNA-370 suppresses the progression and proliferation of human astrocytoma and glioblastoma by negatively regulating beta-catenin and causing activation of FOXO3a. Exp Ther Med. 2018;15:1093–8.
Huang F, Cai P, Wang Y, Zhou X, Chen H, Liao W, et al. Up-regulation of brain-expressed X-linked 2 is critical for hepatitis B virus X protein-induced hepatocellular carcinoma development. Oncotarget. 2017;8:65789–99.
Zhou X, Meng Q, Xu X, Zhi T, Shi Q, Wang Y, et al. Bex2 regulates cell proliferation and apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway. Biochem Biophys Res Commun. 2012;427:574–80.
Papa S, Bubici C. Feeding the Hedgehog: a new meaning for JNK signalling in liver regeneration. J Hepatol. 2018;69:572–4.
Chen Z, Zuo X, Zhang Y, Han G, Zhang L, Wu J, et al. MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1alpha-mediated Warburg effect. Cell Death Dis. 2018;9:549.
Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002;94:1760–9.
Hu Y, Xiao Q, Chen H, He J, Tan Y, Liu Y, et al. BEX2 promotes tumor proliferation in colorectal cancer. Int J Biol Sci. 2017;13:286–94.
Naderi A, Liu J, Hughes-Davies L. BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer. Mol Cancer. 2010;9:111.
Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol 2018;2:6.
Pan XP, Wang HX, Tong DM, Li Y, Huang LH, Wang C. miRNA-370 acts as a tumor suppressor via the downregulation of PIM1 in hepatocellular carcinoma. Eur Rev Med Pharmacol Sci. 2017;21:1254–63.
Zhou X, Xu X, Meng Q, Hu J, Zhi T, Shi Q, et al. Bex2 is critical for migration and invasion in malignant glioma cells. J Mol Neurosci. 2013;50:78–87.
Zeng Y, Fu M, Wu GW, Zhang AZ, Chen JP, Lin HY, et al. Upregulation of microRNA-370 promotes cell apoptosis and inhibits proliferation by targeting PTEN in human gastric cancer. Int J Oncol. 2016;49:1589–99.
Chen T, Gao F, Feng S, Yang T, Chen M. MicroRNA-370 inhibits the progression of non-small cell lung cancer by downregulating oncogene TRAF4. Oncol Rep. 2015;34:461–8.
Naderi A, Liu J, Bennett IC. BEX2 regulates mitochondrial apoptosis and G1 cell cycle in breast cancer. Int J Cancer. 2010;126:1596–610.
Meng Q, Zhi T, Chao Y, Nie E, Xu X, Shi Q, et al. Bex2 controls proliferation of human glioblastoma cells through NF-kappaB signaling pathway. J Mol Neurosci. 2014;53:262–70.
Russell N, Grossmann M. Plasma miRNA expression profile in the diagnosis of late-onset hypogonadism. Asian J Androl. 2016;18:713–5.
Meng X, Wu J, Pan C, Wang H, Ying X, Zhou Y, et al. Genetic and epigenetic down-regulation of microRNA-212 promotes colorectal tumor metastasis via dysregulation of MnSOD. Gastroenterology. 2013;145:426–36, e1–6.
Wang JL, Yang MY, Xiao S, Sun B, Li YM, Yang LY. Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling. J Exp Clin Cancer Res. 2018;37:45.
Chen Y, Yamaguchi Y, Suzuki T, Doi M, Okamura H. Effect of daily light on c-Fos expression in the suprachiasmatic nucleus under jet lag conditions. Acta Histochem Cytochem. 2018;51:73–80.
Fan Q, He M, Deng X, Wu WK, Zhao L, Tang J, et al. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma. Cell Biochem Funct. 2013;31:319–24.
Xu WP, Yi M, Li QQ, Zhou WP, Cong WM, Yang Y, et al. Perturbation of MicroRNA-370/Lin-28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma. Hepatology. 2013;58:1977–91.
Liu Z, Ma M, Yan L, Chen S, Li S, Yang D, et al. miR-370 regulates ISG15 expression and influences IFN-alpha sensitivity in hepatocellular carcinoma cells. Cancer Biomark. 2018;22:453–66.
Acknowledgements
We would also like to thank all participants enrolled in the present study.
Funding
This study was supported by the Hubei Chen Xiaoping Science and Technology Development Foundation—Henrui Research Foundation of Malignant Tumors of Liver, Gallbladder and Pancreas (CXPJJH11800001–2018320), Medical and Health Science and Technology Development Plan Project of Shandong Province (2016WS0272), and Project “Clinical Medicine + X” of Medical Department of Qingdao University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics statement
All experimental procedures were approved by the Ethics Committee, as well as the Animal Care and Use Committee of the Affiliated Hospital of Qingdao University. Signed informed consents were obtained from all patients, or their parents and guardians. All efforts were made to minimize the suffering of the included animals.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, X., Zhu, W., Xu, C. et al. MicroRNA-370 functions as a tumor suppressor in hepatocellular carcinoma via inhibition of the MAPK/JNK signaling pathway by targeting BEX2. J Hum Genet 64, 1203–1217 (2019). https://doi.org/10.1038/s10038-019-0653-x
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s10038-019-0653-x
This article is cited by
-
MicroRNA let-7b inhibits cell proliferation via upregulation of p21 in hepatocellular carcinoma
Cell & Bioscience (2020)
