Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma - 18/09/19

Doi : 10.1016/j.biopha.2019.109270

Chengzhi Xie ^a,^c,^{^{1
These authors contributed equally to this work.}} , Guoxing Liu ^a,^{^{1
These authors contributed equally to this work.}} , Min Li ^b,^{^{1
These authors contributed equally to this work.}} , Yu Fang ^a , Ke Qian ^a , Yu Tang ^b , Xiaolong Wu ^a , Xiaohua Lei ^a , Xiaocheng Li ^a , Qiang Liu ^a , Gao Liu ^a , Jiefeng Liu ^a , Yueming Zhang ^a , Zhao Huang ^a , Zecheng Hu ^a , Zhenyu Cao ^a , Jixiong Hu ^a , Shengfu Huang ^a , Dewu Zhong ^a , Jiangsheng Huang ^a , Fangxiang Wu ^b,^d , Jun Wang ^e , Masaki Mori ^a,^f , Hirofumi Yamamoto ^a,^f , Jianxin Wang ^b,^⁎ , Xundi Xu ^a,^⁎
^a Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China
^b Department of computer science and technology, School of Information Science and Engineering, Central South University, Changsha, Hunan Province, 410083, China
^c Department of General Surgery, The Second Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan Province, 410005, China
^d Division of Biomedical Engineering, Department of Mechanical Engineering, College of Engineering, University of Saskatchewan, 57 Campus Dr., Saskatoon, SK Canada, Canada
^e Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
^f Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, 565-0871, Japan

^⁎Corresponding author at: Department of computer science and technology, School of Information Science and Engineering, Central South University, Lushan South Road 293, Changsha, Hunan Province, 410083, China.Department of computer science and technologySchool of Information Science and EngineeringCentral South UniversityLushan South Road 293ChangshaHunan Province410083China^⁎⁎Corresponding author at: Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2nd Xiangya Hospital, Central South University, Renmin Zhong Road 139, Changsha, Hunan Province, 410011, China.Hunan Provincial Key Laboratory of Hepatobiliary Disease ResearchDivision of Hepato-Biliary-Pancreatic SurgeryDepartment of SurgeryThe 2nd Xiangya HospitalCentral South UniversityRenmin Zhong Road 139ChangshaHunan Province410011China

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Highlights

•	TRPV1 shows targeting potential in hepatocellular carcinoma.
•	TRPV1 gives rise to phenotypic plasticity in hepatocarcinogenesis.
•	Tumor initiating cells and biliary cells were cellular origins in TRPV1 induced HCC.
•	TRPV 1 exert its role via transcription factors Ovol 2 and Zeb 1 mediated by SOX 10.

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Abstract

The landscape of cellular plasticity and sources with relevant niche signals in hepatocellular carcinoma is still obscure. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is involved in a variety of malignancies and overexpressed in hepatocellular carcinoma (HCC). We have investigated the role of TRPV1 in HCC from different angles by various experimental techniques, such as in vivo and in vitro experiments, and by bioinformatics analysis of data from genetic models induced by diethylnitrosamine (DEN), mice samples and human HCC samples. We find that TRPV1 knockout promotes to hepatocarcinogenesis and deconstructs the portal triad adjacent to tumor border that is contributed by originations of tumor initiating cells and biliary cells. Epithelial to mesenchymal transition (EMT) is involved and transcription factors Ovol2 and Zeb1 coordinated with Sox 10 drive gene expression in the event which is also confirmed by the expression of these proteins in human HCC samples. Treatment with TRPV1 agonist Capsaicin inhibits the growth of HCC cells in xenograft models. Our findings demonstrate that TRPV1 is a potential therapeutic target in human HCC and exerts effects on cellular plasticity with modulation of Ovol2, Zeb1 and Sox10.

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Abbreviations : TRPV1, HCC, DEN, EMT, MET, Zeb, DMEM, STR, H&E, hrEGF, ChIP, RSAT, KO, WT, AFP, ALT, AST, TBA, TBIL, DBI, CHOL

Keywords : HCC, TRPV1, Hepatocarcinogenesis, EMT, Zeb1, Ovol2

Plan

Introduction

Material and methods

Cell culture and reagents

Tissue specimens of patients

Animal care and ethics statement

Diethylnitrosamine-induced HCC

Histopathological examination

Immunohistochemistry (IHC)

Western blotting analysis and antibodies

Transmission and scanning electron microscopy

Flow cytometry

Cell viability assay

Colony formation in soft agar assays

Spheroid formation assay

In vivo tumorigenicity assay

Chromatin immunoprecipitation (ChIP) sequencing

ChIP-sequencing data analysis

Trpv1 knockout (KO) promotes hepatocarcinogenesis and causes cellular plasticity initiated by diethylnitrosamine (DEN)

Capsaicin inhibits the growth of HCC cells in a xenograft model

TRPV1 can be targeted in HCC tumor-initiating cells

Biliary cells respond to TRPV1 knockout during hepatocarcinogenesis

EMT/MET transcription factors Ovol2 and Zeb1, as well as Sox10 were dysregulated in TRPV 1 induced hepatocarcinogenesis

TRPV 1 induced EMT with the regulation of Ovol2 and Zeb1

Discussion

Conclusion

Funding

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Vol 118

Article 109270- octobre 2019 Retour au numéro

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Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma - 18/09/19

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