FBXO43 increases CCND1 stability to promote hepatocellular carcinoma cell proliferation and migration

Chun-Ming Li; Jie Zhang; Wu Wu; Zhu Zhu; Feng Li; Di Wu; Xiao-Jun Wang; Chuan-Ming Xie; Jian-Ping Gong

doi:10.3389/fonc.2023.1138348

FBXO43 increases CCND1 stability to promote hepatocellular carcinoma cell proliferation and migration

Front Oncol. 2023 Mar 3:13:1138348. doi: 10.3389/fonc.2023.1138348. eCollection 2023.

Authors

Chun-Ming Li¹, Jie Zhang², Wu Wu¹, Zhu Zhu¹, Feng Li³, Di Wu², Xiao-Jun Wang², Chuan-Ming Xie², Jian-Ping Gong¹

Affiliations

¹ Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
³ Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Abstract

Background and aims: Abnormal expression of E3 ubiquitin ligase plays an important role in the development and progression of hepatocellular carcinoma (HCC), although the mechanism has remained elusive. This study aimed to investigate the biological function and potential mechanism of FBXO43 in HCC.

Methods: FBXO43 expression in tissues and cells were detected by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC). The Kaplan-Meier method and Cox regression analysis were used to explore the correlation between the expression level of FBXO43 and the clinical survival. MTT assay, EdU incorporation, colony formation, Transwell, and wound healing assays were performed to evaluate the function of FBXO43 in cell proliferation and migration in vitro. The interaction between FBXO43 and cyclin D1 (CCND1) was assessed by co-immunoprecipitation (Co-IP) assay and in vivo ubiquitination assay.

Results: We found that FBXO43 was upregulated in HCC patient tissues and positively associated with poor clinicopathological features. Meanwhile, HCC patients with high expression of FBXO43 had shorter overall survival (OS) and disease-free survival (DFS). Furthermore, knockdown of FBXO43 inhibited HCC cell proliferation, migration and epithelial-mesenchymal transition (EMT) in HCC cells. Mechanistically, FBXO43 interacted with CCND1 and promoted its stability by polyubiquitination, leading to HCC cell proliferation, migration and EMT. Functional rescue experiments demonstrated that knockdown of CCND1 blocks FBXO43-mediated cell proliferation and metastasis.

Conclusions: FBXO43, as an independent prognostic biomarker, promotes HCC cell proliferation, metastasis and EMT by stability of CCND1, which provides a new potential strategy for HCC treatment by targeting FBXO43-CCND1 axis.

Keywords: CCND1; FBXO43; hepatocellular carcinoma (HCC); migration; proliferation.

Grants and funding

This work was supported by the Introduction of Special Funds for Talents from the Third Military Medical University (Army Medical University) (4174C6) and National Natural Science Foundation of China (NSFC, 32071294) to C-MX.