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Connexin 32 downregulation is critical for chemoresistance in oxaliplatin-resistant HCC cells associated with EMT

Authors Yang Y, Yao JH, Du QY, Zhou YC, Yao TJ, Wu Q, Liu J, Ou YR

Received 31 January 2019

Accepted for publication 16 April 2019

Published 31 May 2019 Volume 2019:11 Pages 5133—5146

DOI https://doi.org/10.2147/CMAR.S203656

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Chien-Feng Li


Yan Yang,1 Jing-Hao Yao,1 Qian-Yu Du,1 Yong-Chun Zhou,2 Ting-Jing Yao,3 Qiong Wu,4 Jing Liu,1 Yu-Rong Ou4

1Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, People’s Republic of China; 3Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, People’s Republic of China; 4Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, People’s Republic of China

Background: Oxaliplatin (OXA)-based chemotherapy is critical in the management of advanced hepatocellular carcinoma (HCC); however, acquired drug resistance has largely restricted its clinical efficacy. This study aims to explore the key mechanisms and regulatory factors determining chemosensitivity in HCC.
Methods: We developed OXA-resistant (OR) HCC cells and used multiple methods, including real-time RT-PCR, Western blot, immunofluorescence, transwell invasion assay, wound-healing assay, MTT assay, gene transfection, and immunohistochemistry to achieve our goals.
Results: We found that OR HCC cells showed a typical epithelial–mesenchymal transition (EMT) phenotype. Meanwhile, the expression of Cx32, a major member of the liver connexin (Cx) family, was lowly expressed in OR HCC cells. Downregulation of Cx32 in parental HCC cells led to EMT induction and thereby reduced OXA cytotoxicity, while Cx32 upregulation in OR HCC cells could reverse the EMT phenotype and partially restore chemosensitivity to OXA. Finally, in human HCC tissue samples, Cx32 was positively correlated with the expression of the EMT marker E-cadherin and negatively correlated with the expression of Vimentin.
Conclusion: Our findings demonstrated that downregulation of Cx32 may be an important determinant for HCC cells to acquire EMT-related acquired drug resistance to OXA, and targeting Cx32 could be a novel strategy to overcome OXA resistance in HCC.

Keywords: hepatocellular carcinoma, oxaliplatin chemoresistance, connexin32, epithelial-mesenchymal transition


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