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LncRNA HEIH Confers Cell Sorafenib Resistance in Hepatocellular Carcinoma by Regulating miR-98-5p/PI3K/AKT Pathway

Authors Shen Q, Jiang S, Wu M, Zhang L, Su X, Zhao D

Received 6 December 2019

Accepted for publication 10 May 2020

Published 29 July 2020 Volume 2020:12 Pages 6585—6595


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Sanjeev Srivastava

Qian Shen,1 Shenhua Jiang,2 Mingyun Wu,2 Lei Zhang,3 Xue Su,1 Ding Zhao4

1Department of Nephrology, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People’s Republic of China; 2Department of Pediatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, People’s Republic of China; 3School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People’s Republic of China; 4Department of Oncology, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng, Jiangsu, 224000, People’s Republic of China

Correspondence: Ding Zhao
Department of Oncology, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, No. 53 North Renmin Road, Yancheng, Jiangsu 224000, People’s Republic of China
Tel +86-15951612124

Background: The hepatocellular carcinoma up-regulated EZH2-associated long non-coding RNA (HEIH) has been identified to act as an oncogene to promote cell tumorigenesis in hepatocellular carcinoma (HCC); however, the roles of HEIH in sorafenib resistance in HCC cells remain elusive.
Materials and Methods: The expression of HEIH and microRNA (miR)-98-5p was detected using quantitative real-time polymerase chain reaction. Cell viability, apoptosis, migration and invasion were analyzed using cell counting kit-8 assay, flow cytometry and transwell assay. Western blot was used to measure the levels of apoptosis-related protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related protein. The interaction between HEIH and miR-98-5p was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were performed using murine xenograft models.
Results: HEIH was up-regulated in sorafenib-resistant HCC tissues and cell lines, and HEIH silence weakened sorafenib resistance by suppressing cell viability, invasion and migration, decreasing the IC50 values to sorafenib, and increasing apoptosis in sorafenib-resistant HCC cells in vitro and reinforced the anti-tumor effects of sorafenib in vivo. HEIH was a sponge of miR-98-5p, and miR-98-5p inhibition reversed the sorafenib sensitivity induced by HEIH deletion in sorafenib-resistant HCC cells. MiR-98-5p inhibition could activate PI3K/AKT pathway, and enhanced sorafenib resistance by regulating the activation of PI3K/AKT pathway in sorafenib-resistant HCC cells. Besides, HEIH also activated PI3K/AKT pathway through regulating miR-98-5p in sorafenib-resistant HCC cells.
Conclusion: HEIH conferred an advantage to sorafenib resistance in HCC by the activation of PI3K/AKT pathway through miR-98-5p, indicating a potential therapeutic strategy for HCC chemotherapy.

Keywords: HEIH, miR-98-5p, PI3K/AKT, HCC, chemoresistance

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