Back to Journals » OncoTargets and Therapy » Volume 9

Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression

Authors Xue F, Liu YH, Zhang HW, Wen Y, Yan L, Tang Q, Xiao EH, Zhang DY

Received 30 June 2016

Accepted for publication 23 September 2016

Published 28 November 2016 Volume 2016:9 Pages 7253—7261

DOI https://doi.org/10.2147/OTT.S116127

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Manfred Beleut

Peer reviewer comments 3

Editor who approved publication: Dr Ingrid Espinoza


Fei Xue,1 Yanhui Liu,2 Hongwei Zhang,1 Yu Wen,1 Lei Yan,1 Qiang Tang,1 Erhui Xiao,1 Dongyi Zhang1

1Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Hematology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, People’s Republic of China

Background: Let-7 miRNAs are reported to play an inhibitory role in carcinogenesis, tumor progression, recurrence, and pluripotency of cancer. However, few studies have reported the relationship between let-7 and drug sensitivity, especially for let-7a (a subtype of let-7). This study aimed to investigate the function of let-7a in regulating the sensitivity of hepatocellular carcinoma (HCC) cell lines to cetuximab.
Methods: The cytotoxicity of cetuximab on HCC cell lines (Huh7, Hep3B, HepG2, SNU449, and SNU387) was evaluated using a cell viability assay (the Cell Counting Kit-8 assay) and a cell proliferation assay (the Click-iT EdU Imaging Kit) in the presence of a control, a let-7a mimic, and a let-7a inhibitor. Small interfering RNA to knockdown the expression of signal transducer and activator of transcription 3 (STAT3) were employed. Protein and mRNA expression levels were determined using quantitative polymerase chain reaction and Western blot analysis.
Results: It was found that let-7a enhances the sensitivity of HCC cells with an epithelial phenotype (Huh7, Hep3B, and HepG2) to cetuximab, but has no effect on cells with the mesenchymal phenotype (SNU449 and SNU387). It was determined that STAT3 was a target mRNA of let-7a using TargetScan. Expression of STAT3 and let-7a mRNA were negatively correlated in HCC cell lines. Moreover, let-7a altered the protein and mRNA expression of STAT3. Furthermore, STAT3 knockdown enhanced the function of cetuximab on HCC cell lines with epithelial phenotypes, but not on HCC cell lines with mesenchymal phenotypes. Finally, a rescue experiment confirmed that let-7a affected the sensitivity of HCC cell lines to cetuximab by interacting with STAT3.
Conclusions: There is a functional link between let-7a and STAT3 in enhancing the sensitivity of HCC cells with an epithelial phenotype to cetuximab. Our results provide novel insight into new methodologies for combating HCC drug resistance.

Keywords: hepatocellular carcinoma, microRNA, STAT3, let-7a

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]  View Full Text [HTML][Machine readable]