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MiR-145 Regulates the Chemoresistance of Hepatic Carcinoma Cells Against 5-Fluorouracil by Targeting Toll-Like Receptor 4

Authors Zheng RP, Ma DK, Li Z, Zhang HF

Received 9 April 2020

Accepted for publication 19 June 2020

Published 22 July 2020 Volume 2020:12 Pages 6165—6175

DOI https://doi.org/10.2147/CMAR.S257598

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Lu-Zhe Sun


Rui-Peng Zheng,1 Dong-Kai Ma,2 Zhuo Li,3 Hai-Feng Zhang1

1Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China; 2Department of Gastroenterology and Hepatology, Qian Wei Hospital of Jilin Province, Changchun, Jilin Province 130012, People’s Republic of China; 3Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China

Correspondence: Hai-Feng Zhang
Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China
Tel +86 13756696677
Email HaifengZhang159@outlook.com

Background: 5-fluorouracil (5-FU) is a common drug for hepatic carcinoma (HCC), but the drug resistance of clinical chemotherapy restricts its use. Studies have demonstrated that miRNA molecules can act as a chemoresistance regulator in drug resistance of tumors, whereas the role of miR-145 in the 5-FU-resistant HCC remains unclear.
Objective: To explore the prognostic value of miR-145 in HCC and its molecular mechanism in 5-FU-resistant HCC cells.
Methods: A qRT-PCR assay was conducted to quantify miR-145 in HCC tissues and 5-FU-resistant HCC cells. The Cell Counting Kit-8 (CCK-8) and flow cytometry were adopted to analyze the proliferation and apoptosis of 5-FU-resistant HCC cells. The Western blot was adopted to quantify toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and apoptosis-related proteins. Moreover, an in vivo tumor xenotransplantation of nude mice was conducted to determine the effect of miR-145 on 5-FU-resistant HCC cells.
Results: MiR-145 was expressed lowly in HCC tissues and cells, and linked to high TNM staging and lymph node metastasis of HCC patients. Down-regulation of miR-145 indicated a poorer prognosis and it promoted drug resistance of HCC cells and inhibited cell apoptosis. In contrast, miR-145 overexpression improved the sensitivity of HCC cells to 5-FU and enhanced the inhibition of 5-FU on tumor growth. The luciferase reporter gene assay showed that TLR4 was the direct target of miR-145, and the Western blot assay revealed that overexpression of TLR4 reversed the inhibitory effect of miR-145 overexpression on TLR4 and MyD88 protein and the effects of it on apoptosis-related proteins.
Conclusion: MiR-145 is an inhibiting factor in HCC and can target TLR4 to mediate the chemoresistance of HCC, which may provide novel ideas for treating HCC.

Keywords: hepatic carcinoma, miR-145, toll-like receptor 4, TLR4, 5-fluorouracil, drug resistance

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