ACTR10 Overexpression Facilitates the Progression and Tyrosine Kinase Inhibitor Resistance in Hepatocellular Carcinoma

Jie Luo; Kai Qin; Rong Quan He; Jian Di Li; Zhi Guang Huang; Bin Tong Yin; Tong Wu; Yu Zhen Chen; Di Yuan Qin; Jia Yuan Luo; Mei Wu; Bang Teng Chi; Gang Chen; Jian Jun Li; Yu Bin Huang

doi:10.14740/wjon1944

ACTR10 Overexpression Facilitates the Progression and Tyrosine Kinase Inhibitor Resistance in Hepatocellular Carcinoma

World J Oncol. 2024 Dec;15(6):882-901. doi: 10.14740/wjon1944. Epub 2024 Dec 11.

Authors

Jie Luo^{1

2}, Kai Qin^{3

2}, Rong Quan He⁴, Jian Di Li⁵, Zhi Guang Huang⁵, Bin Tong Yin⁴, Tong Wu⁴, Yu Zhen Chen⁴, Di Yuan Qin⁶, Jia Yuan Luo⁵, Mei Wu⁵, Bang Teng Chi⁵, Gang Chen⁵, Jian Jun Li³, Yu Bin Huang³

Affiliations

¹ Department of Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi, China.
² These authors contributed equally to this work.
³ Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi, China.
⁴ Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
⁵ Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
⁶ Department of Computer Science and Technology, School of Computer and Electronic Information, Guangxi University, Nanning 530004, Guangxi, China.

Abstract

Background: In the present day, hepatocellular carcinoma (HCC) remains a formidable threat to human health. Actin-related protein 10 (ACTR10) is related to tyrosine kinase inhibitor (TKI) resistance. A comprehensive analysis of ACTR10 in HCC will further our understanding of the molecular mechanisms underlying this resistance phenomenon, shedding light on potential therapeutic strategies for combating TKI resistance in HCC.

Methods: We conducted an integration of high-throughput datasets across various centers, analyzing ACTR10 expression using the Cancer Cell Line Encyclopedia (CCLE) and assessing its implications through clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen. Pathogenic mechanisms were elucidated through enrichment analysis. Prognostic assessment utilized Kaplan-Meier survival and univariate Cox analyses. An integrated analysis of gene expression profiles related to TKI in HCC was conducted, and TKI resistance mechanisms were explored through enrichment analysis. Potential therapeutic drugs were identified using the Drug Gene Budger database and molecular docking techniques.

Results: The standardized mean difference (SMD) of 0.34 (95% confidence interval (CI): 0.22 - 0.45, P < 0.05) and ACTR10-dependent growth in HCC cells confirm its upregulation in HCC. The area under the summary receiver operating characteristic (sROC) curve was 0.69, indicating moderate discriminative ability of ACTR10 in HCC patients. ACTR10 exerts its pro-cancer effect by influencing RNA splicing, mRNA processing and nucleocytoplasmic transport. A hazard ratio of 2.19 (95% CI: 1.56 - 3.08, P < 0.05) identifies ACTR10 as an independent prognostic risk factor. Additionally, the SMD of 0.88 (95% CI: 0.01 - 0.76, P < 0.05) validates ACTR10 as a TKI-resistance gene, mediating resistance via enhanced exocytosis, autophagy, and apoptosis in HCC patients. Trichostatin A emerges as a prospective targeted agent for HCC.

Conclusion: The upregulation of ACTR10 accelerates HCC progression, promotes TKI resistance, and emerges as a prospective target for the treatment of HCC.

Keywords: Actin-related protein 10; Hepatocellular carcinoma; Prospective therapeutic target; Risk factor; Tyrosine kinase inhibitor resistance.

Grants and funding

Guangxi Zhuang Autonomous Region Health Committee Scientific Research Project, No. Z20201147; China Undergraduate Innovation and Entrepreneurship Training Program, No. 202210598043X, No. S202310598056X; Innovation Project of Guangxi Graduate Education, No. JGY2023068; Guangxi Higher Education Undergraduate Teaching Reform Project, No. 2022JGA146; Guangxi Educational Science Planning Key Project, No. 2022ZJY2791; Guangxi Medical University Undergraduate Education and Teaching Reform Project, No. 2023Z10; China Undergraduate Innovation and Entrepreneurship Training Program (X202410598360); Future Academic Star of Guangxi Medical University (WLXSZX24073).