MiR-449a Is Related to Short-Term Recurrence of Hepatocellular Carcinoma and Inhibits Migration and Invasion by Targeting Notch1

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2019 Dec 20

PMID 31853185

Citations 7

Authors

Bing Han

Jiawei Huang

Zhenjie Yang

Jiaqi Zhang

Xiaomin Wang

Ning Xu

Haining Meng

Junyu Wu

Qiao Huang

Xi Yang

Ruowu Shen

Chuandong Sun

Affiliations

Soon will be listed here.

Abstract

Purpose: To explore the effect of miR-449a inhibits migration and invasion by targeting Notch1 and regulating epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and further study on the molecular mechanism.

Patients And Methods: The expression of miR-449a and Notch1 in HCC cells and tissues was detected by qRT-PCR. The HCC cell line HCCLM3 and SMMC-7721 were transfected with miR-449a. The invasion and migration of HCC cell lines were detected by transwell assay and wound healing assay. The Notch pathway and EMT related protein were detected with Western Blotting. The specific binding site of mir-449a on notch1 gene was detected by luciferase assay.

Results: We found the expression of miR-449a was related to short-term recurrence of hepatocellular carcinoma after hepatectomy and acted as independent risk factors of DFS and OS. The expression of miR-449a decreased in tumor tissues and HCC cell lines, but the expression of Notch1 increased. The overexpressed miR-449a promoted the invasiveness in vitro by regulating EMT via Notch pathway. Mechanically, miR-449a inhibited the translation of Notch1 protein by binding to 3' UTR of its mRNA directly.

Conclusion: miR-449a is short-term recurrence-related miRNA and inhibits the invasion and metastasis ability of HCC cells by regulating EMT via Notch pathway. miR-449a may be a new effective therapeutic target for HCC.

Citing Articles

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References

Chen S, Liu B, Xu J, Pei X, Liao Y, Yuan F . MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC Cancer. 2015; 15:706. PMC: 4608176. DOI: 10.1186/s12885-015-1738-3. View

Mazzola A, Costantino A, Petta S, Bartolotta T, Raineri M, Sacco R . Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol. 2015; 11(21):2923-36. DOI: 10.2217/fon.15.239. View

Joyce B, Zheng Y, Zhang Z, Liu L, Kocherginsky M, Murphy R . miRNA-Processing Gene Methylation and Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2018; 27(5):550-557. PMC: 5932226. DOI: 10.1158/1055-9965.EPI-17-0849. View

Hwang H, Mendell J . MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2007; 96 Suppl:R40-4. View

Zhang Y, Xu Z, Zhang T, Wang Y . Circulating microRNAs as diagnostic and prognostic tools for hepatocellular carcinoma. World J Gastroenterol. 2015; 21(34):9853-62. PMC: 4566380. DOI: 10.3748/wjg.v21.i34.9853. View

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View

Wan X, Cheng C, Shao Q, Lin Z, Lu S, Chen Y . CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment. Tumour Biol. 2015; 37(5):6073-84. DOI: 10.1007/s13277-015-4442-7. View

Liu L, Li D, Xu H, Zheng S, Zhang X . Role of microRNAs in hepatocellular carcinoma. Front Biosci (Landmark Ed). 2015; 20(7):1056-67. DOI: 10.2741/4358. View

You J, Zhang Y, Li Y, Fang N, Liu B, Zu L . MiR-449a suppresses cell invasion by inhibiting MAP2K1 in non-small cell lung cancer. Am J Cancer Res. 2015; 5(9):2730-44. PMC: 4633902. View

10.

Noonan E, Place R, Pookot D, Basak S, Whitson J, Hirata H . miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene. 2009; 28(14):1714-24. DOI: 10.1038/onc.2009.19. View

11.

Liu S, Liu K, Zhang W, Wang Y, Jin Z, Jia B . miR-449a inhibits proliferation and invasion by regulating ADAM10 in hepatocellular carcinoma. Am J Transl Res. 2016; 8(6):2609-19. PMC: 4931155. View

12.

Chen H, Lin Y, Mao Y, Wu J, Liu Y, Zheng X . MicroRNA-449a acts as a tumor suppressor in human bladder cancer through the regulation of pocket proteins. Cancer Lett. 2012; 320(1):40-7. DOI: 10.1016/j.canlet.2012.01.027. View

13.

Liu W, Zhang J, Gan X, Shen F, Yang X, Du N . LGR5 promotes epithelial ovarian cancer proliferation, metastasis, and epithelial-mesenchymal transition through the Notch1 signaling pathway. Cancer Med. 2018; 7(7):3132-3142. PMC: 6051213. DOI: 10.1002/cam4.1485. View

14.

Sandbothe M, Buurman R, Reich N, Greiwe L, Vajen B, Gurlevik E . The microRNA-449 family inhibits TGF-β-mediated liver cancer cell migration by targeting SOX4. J Hepatol. 2017; 66(5):1012-1021. DOI: 10.1016/j.jhep.2017.01.004. View

15.

Kumar P, Sharad S, Petrovics G, Mohamed A, Dobi A, Sreenath T . Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1. Oncotarget. 2016; 7(16):22791-806. PMC: 5008401. DOI: 10.18632/oncotarget.8061. View

16.

Lize M, Pilarski S, Dobbelstein M . E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis. Cell Death Differ. 2009; 17(3):452-8. DOI: 10.1038/cdd.2009.188. View

17.

Li Q, Peng J, Li X, Leng A, Liu T . miR-449a targets Flot2 and inhibits gastric cancer invasion by inhibiting TGF-β-mediated EMT. Diagn Pathol. 2015; 10:202. PMC: 4650491. DOI: 10.1186/s13000-015-0435-5. View

18.

OBrien-Ball C, Biddle A . Reprogramming to developmental plasticity in cancer stem cells. Dev Biol. 2017; 430(2):266-274. DOI: 10.1016/j.ydbio.2017.07.025. View

19.

Liu Y, Wang Y, Sun X, Mei C, Wang L, Li Z . miR-449a promotes liver cancer cell apoptosis by downregulation of Calpain 6 and POU2F1. Oncotarget. 2015; 7(12):13491-501. PMC: 4924656. DOI: 10.18632/oncotarget.4821. View

20.

Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C . miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Mol Cancer. 2011; 10:29. PMC: 3070685. DOI: 10.1186/1476-4598-10-29. View