HMGB2 upregulation promotes the progression of hepatocellular carcinoma cells through the activation of ZEB1/vimentin axis

Kai Lu; Teng Zhao; Lixue Yang; Yang Liu; Xiang Ruan; Longjiu Cui; Yongjie Zhang

doi:10.21037/jgo-23-447

HMGB2 upregulation promotes the progression of hepatocellular carcinoma cells through the activation of ZEB1/vimentin axis

J Gastrointest Oncol. 2023 Oct 31;14(5):2178-2191. doi: 10.21037/jgo-23-447. Epub 2023 Oct 24.

Authors

Kai Lu^#¹, Teng Zhao^#¹, Lixue Yang^#¹, Yang Liu¹, Xiang Ruan¹, Longjiu Cui¹, Yongjie Zhang¹

Affiliation

¹ Department of Biliary Tract Surgery, The Third Affiliated Hospital of Navy Military Medical University, Shanghai, China.

^# Contributed equally.

Abstract

Background: High mobility group box 2 (HMGB2) is abnormally expressed in human cancers and participated in multiple biological behaviors, such as proliferation, invasion and prognosis. However, its role in hepatocellular carcinoma (HCC) is largely unknown.

Methods: In clinical sample analysis, 62 HCC patients were enrolled in this study. The expression of HMGB2 was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical method, clinical prognosis data were analyzed by Kaplan-Meier analysis. In cellular and molecular biology experiments, HMGB2 expression was analyzed in HCC cells. HMGB2 knockdown model was constructed by small interfering RNA (siRNA). Cell counting kit-8 (CCK-8) and cell migration & invasion assay were used to evaluate cell proliferative potential and motility. Recombinant human vimentin protein was used to partially restore the expression and function of vimentin. Western blot and immunochemical staining were performed to detect HMGB2 protein, zinc finger E-box binding homeobox 1 (ZEB1) and vimentin. Flow cytometry analyses were performed to determine the alteration of cell cycle in different groups.

Results: HMGB2 was abnormally overexpressed in HCC. HMGB2 knockdown reduced malignant behaviors especially the proliferative potential and motility of HCC cells. The inhibition of HCC cells proliferation and mobility could be partially restored via treatment with recombinant vimentin protein. Our findings confirmed abnormal activation of HMGB2-ZEB1 vimentin axis facilitates HCC malignant proliferation and motility. The elevated HMGB2 expression in clinical samples was related to postoperative survival time of HCC patients. It indicated HMGB2 promotes the proliferation and motility potential of HCC via HMGB2-ZEB1-vimentin axis activation.

Conclusions: HMGB2 is up-regulated in HCC and affects the malignant transformation by modulating HMGB2-ZEB1-vimentin signaling pathway, which may provide a research basis for evaluating the disease progression and developing clinical treatment strategies of HCC.

Keywords: High mobility group box 2 (HMGB2); hepatocellular carcinoma (HCC); malignant transformation; vimentin; zinc finger E-box binding homeobox 1 (ZEB1).