Identification of microRNA-96-5p as a postoperative, prognostic microRNA predictor in nonviral hepatocellular carcinoma.
HCC recurrence
hepatocellular carcinoma (HCC)
miR-96-5p
microRNA
Journal
Hepatology research : the official journal of the Japan Society of Hepatology
ISSN: 1386-6346
Titre abrégé: Hepatol Res
Pays: Netherlands
ID NLM: 9711801
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
revised:
04
05
2021
received:
20
03
2021
accepted:
13
05
2021
pubmed:
27
5
2021
medline:
27
5
2021
entrez:
26
5
2021
Statut:
ppublish
Résumé
The microRNA (miR) clusters miR-183/96/182 and miR-217/216a/216b are significantly upregulated in nonviral hepatocellular carcinoma (NBNC-HCC). Here, we investigate the impact of each member of these clusters on the clinical outcome of NBNC-HCC and analyze the antitumor effects of miR-96-5p. The association between recurrence-free survival of 111 NBNC-HCC patients and the levels of miR-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, miR-216a-5p, and miR-216b-5p in tumor and adjacent tissues was investigated. The impact of miR-96-5p on apoptosis and invasion of a hepatoma cell line, HepG2, was investigated by cell counting, Transwell assay, and flow cytometry, respectively. MicroRNA-183-5p, miR-96-5p, miR-182-5p, miR-217-5p, and miR-216b-5p were significantly upregulated in tumor tissues compared to the adjacent tissues (p = 0.0005, p = 0.0030, p = 0.0002, p = 0.0011, and p = 0.0288, respectively). By multivariate Cox regression analysis, high tumor/adjacent ratios of miR-182-5p (p = 0.007) and miR-217-5p (p = 0.008) were associated with poor recurrence-free survival. In contrast, a low tumor/adjacent ratio of miR-96-5p (p < 0.001) was associated with poor recurrence-free survival. It suggested that further upregulation of miR-96-5p in tumors might have an inhibitory effect on recurrence. Transfection of miR-96-5p mimic significantly induced apoptosis of HepG2 cells, in association with downregulation of Nucleophosmin 1 (NPM1) and a decrease of phosphorylated AKT protein. Interestingly, simultaneous knockdown of the NPM1 and AKT genes induced apoptosis. MicroRNA-96-5p also suppressed proliferation and invasion, which inhibited epithelial-to-mesenchymal transition of HCC cells. MicroRNA-96-5p as a tumor suppressor would be valuable to stratify NBNC-HCC patients at high risk of recurrence.
Types de publication
Journal Article
Langues
eng
Pagination
93-104Subventions
Organisme : Thailand Research Fund
ID : RTA6280004
Organisme : Japan Agency for Medical Research and Development
ID : JP19fk0210048
Organisme : Japan Agency for Medical Research and Development
ID : JP20fk0210048
Informations de copyright
© 2021 The Japan Society of Hepatology.
Références
Ferlay JSI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, et al. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v1.0. 2012. https://publications.iarc.fr/Databases/Iarc-Cancerbases/GLOBOCAN-2012-Estimated-Cancer-Incidence-Mortality-And-Prevalence-Worldwide-In-2012-V1.0-2012. Accessed May 2019.
Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134-40.
Hashimoto E, Yatsuji S, Tobari M, Taniai M, Torii N, Tokushige K, et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol. 2009;44:89-95.
Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972-8.
Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428-33.
Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D. Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog. 2013;52:297-303.
Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28:3526-36.
Zheng Z, Wen Y, Nie K, Tang S, Chen X, Lan S, et al. Construction of a 13-microRNA-based signature and prognostic nomogram for predicting overall survival in patients with hepatocellular carcinoma. Hepatol Res. 2020;50:1151-63.
Nojima M, Matsui T, Tamori A, Kubo S, Shirabe K, Kimura K, et al. Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma. Mol Canc. 2016;15:31.
Guttilla IK, White BA. Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem. 2009;284:23204-16.
Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, et al. Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Canc Res. 2010;70:367-77.
Bandres E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, et al. Identification by real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Canc. 2006;5:29.
Lin H, Dai T, Xiong H, Zhao X, Chen X, Yu C, et al. Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One. 2010;5:e15797.
Liu X, Liu D, Qian D, Dai J, An Y, Jiang S, et al. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J Biol Chem. 2012;287:19599-609.
Qin FX, Shao HY, Chen XC, Tan S, Zhang HJ, Miao ZY, et al. Knockdown of NPM1 by RNA interference inhibits cells proliferation and induces apoptosis in leukemic cell line. Int J Med Sci. 2011;8:287-94.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857-68.
Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156-72.
Leung WK, He M, Chan AW, Law PT, Wong N. Wnt/beta-catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion. Canc Lett. 2015;362:97-105.
Zhao Q, Li T, Qi J, Liu J, Qin C. The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. PLoS One. 2014;9:e109782.
Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58:629-41.
Yang H, Lan P, Hou Z, Guan Y, Zhang J, Xu W, et al. Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma. Br J Canc. 2015;112:112-21.
Huang Y, Zhang J, Li H, Peng H, Gu M, Wang H. miR-96 regulates liver tumor-initiating cells expansion by targeting TP53INP1 and predicts sorafenib resistance. J Canc. 2020;11:6545-55.
Iwai N, Yasui K, Tomie A, Gen Y, Terasaki K, Kitaichi T, et al. Oncogenic miR-96-5p inhibits apoptosis by targeting the caspase-9 gene in hepatocellular carcinoma. Int J Oncol. 2018;53:237-45.
Wang TH, Yeh CT, Ho JY, Ng KF, Chen TC. OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma. Mol Carcinog. 2016;55:366-75.
Yang N, Zhou J, Li Q, Han F, Yu Z. miR-96 exerts carcinogenic effect by activating AKT/GSK-3beta/beta-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma. Canc Cell Int. 2019;19:38.
Holmberg Olausson K, Elsir T, Moazemi Goudarzi K, Nister M, Lindstrom MS. NPM1 histone chaperone is upregulated in glioblastoma to promote cell survival and maintain nucleolar shape. Sci Rep. 2015;5:16495.
Wong JC, Hasan MR, Rahman M, Yu AC, Chan SK, Schaeffer DF, et al. Nucleophosmin 1, upregulated in adenomas and cancers of the colon, inhibits p53-mediated cellular senescence. Int J Canc. 2013;133:1567-77.
Liu Y, Zhang F, Zhang XF, Qi LS, Yang L, Guo H, et al. Expression of nucleophosmin/NPM1 correlates with migration and invasiveness of colon cancer cells. J Biomed Sci. 2012;19:53.
Kalra RS, Bapat SA. Enhanced levels of double-strand DNA break repair proteins protect ovarian cancer cells against genotoxic stress-induced apoptosis. J Ovarian Res. 2013;6:66.
Lee SB, Xuan Nguyen TL, Choi JW, Lee KH, Cho SW, Liu Z, et al. Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival. Proc Natl Acad Sci USA. 2008;105:16584-9.
Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Canc Res. 2016;76:3666-70.
Zhang J, Kong X, Li J, Luo Q, Li X, Shen L, et al. miR-96 promotes tumor proliferation and invasion by targeting RECK in breast cancer. Oncol Rep. 2014;31:1357-63.
Gao F, Wang W. MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a. Mol Med Rep. 2015;11:1200-6.
Rapti SM, Kontos CK, Papadopoulos IN, Scorilas A. High miR-96 levels in colorectal adenocarcinoma predict poor prognosis, particularly in patients without distant metastasis at the time of initial diagnosis. Tumour Biol. 2016;37:11815-24.
Lang C, Xu M, Zhao Z, Chen J, Zhang L. MicroRNA-96 expression induced by low-dose cisplatin or doxorubicin regulates chemosensitivity, cell death and proliferation in gastric cancer SGC7901 cells by targeting FOXO1. Oncol Lett. 2018;16:4020-6.
Guo H, Li Q, Li W, Zheng T, Zhao S, Liu Z. MiR-96 downregulates RECK to promote growth and motility of non-small cell lung cancer cells. Mol Cell Biochem. 2014;390:155-60.
Li J, Li P, Chen T, Gao G, Chen X, Du Y, et al. Expression of microRNA-96 and its potential functions by targeting FOXO3 in non-small cell lung cancer. Tumour Biol. 2015;36:685-92.
Xu D, He X, Chang Y, Xu C, Jiang X, Sun S, et al. Inhibition of miR-96 expression reduces cell proliferation and clonogenicity of HepG2 hepatoma cells. Oncol Rep. 2013;29:653-61.
Li C, Du X, Tai S, Zhong X, Wang Z, Hu Z, et al. GPC1 regulated by miR-96-5p, rather than miR-182-5p, in inhibition of pancreatic carcinoma cell proliferation. Int J Mol Sci. 2014;15:6314-27.
Feng J, Yu J, Pan X, Li Z, Chen Z, Zhang W, et al. HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96. Oncotarget. 2014;5:5832-44.
Huang X, Lv W, Zhang JH, Lu DL. miR96 functions as a tumor suppressor gene by targeting NUAK1 in pancreatic cancer. Int J Mol Med. 2014;34:1599-605.
Zhou Y, Chen Y, Ding W, Hua Z, Wang L, Zhu Y, et al. LncRNA UCA1 impacts cell proliferation, invasion, and migration of pancreatic cancer through regulating miR-96/FOXO3. IUBMB Life. 2018;70:276-90.