Downregulated Acetyl-CoA Acyltransferase 2 Promoted the Progression of Hepatocellular Carcinoma and Participated in the Formation of Immunosuppressive Microenvironment

Dehai Wu; Guanqun Liao; Yuanfei Yao; Lining Huang; Bowen Dong; Yong Ma; Guangchao Yang

doi:10.2147/JHC.S418429

Downregulated Acetyl-CoA Acyltransferase 2 Promoted the Progression of Hepatocellular Carcinoma and Participated in the Formation of Immunosuppressive Microenvironment

J Hepatocell Carcinoma. 2023 Aug 9:10:1327-1339. doi: 10.2147/JHC.S418429. eCollection 2023.

Authors

Dehai Wu^#¹, Guanqun Liao^#², Yuanfei Yao^#³, Lining Huang⁴, Bowen Dong⁵, Yong Ma⁶, Guangchao Yang⁶

Affiliations

¹ Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
² Department of Hepatobiliary Surgery, Foshan Hospital Affiliated to Southern Medical University, Foshan, People's Republic of China.
³ Key Laboratory of Tumor Immunology in Heilongjiang, Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
⁴ Department of Hepatobiliary Surgery, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, People's Republic of China.
⁵ Department of Biochemistry & Molecular Biology, Harbin Medical University, Harbin, People's Republic of China.
⁶ Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Minimal Invasive Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.

^# Contributed equally.

Abstract

Background: The aim of this study is to explore the role of acetyl-CoA acyltransferase 2 (ACAA2) in the progression of hepatocellular carcinoma (HCC).

Methods: Bulk RNA data and single-cell RNA data were acquired from The Cancer Genome Atlas and Gene Expression Omnibus. Both in vitro and in vivo studies were used to determine the effect of ACAA2 on the progression of HCC, and RNA sequencing analysis was performed to explore the mechanism.

Results: We found downregulation of ACAA2 was involved in the malignant progression of HCC. The patient with low ACAA2 level had an immunosuppressive microenvironment in the HCC and predicted to have a poor prognosis. Decreased ACAA2 facilitated HCC proliferation and metastasis by activating the nuclear factor-κB (NFκB) signaling pathway. And increased CXCL1 induced by NFκB signaling pathway might be responsible for low level of ACAA2 related immunosuppressive microenvironment. Furthermore, the expression of ACAA2 was also detected in immune cells. The expression of ACAA2 in CD4⁺TCF7⁺T, CD4⁺FOXP3⁺T, CD8⁺GZMK⁺T, and CD8⁺KLRD1⁺T cells was inversely correlated with the composition of CD8⁺PDCD1⁺T cells in HCC. This effect might be due to the CCL5-CCRs and HLA-E-KLRCs ligand-receptor networks.

Conclusion: In a conclusion, downregulated ACAA2 promoted the progression of hepatocellular carcinoma and might be participated in the formation of immunosuppressive microenvironment. ACAA2 could be served as a favorable indicator for the prognosis of HCC and an ideal biomarker for immunotherapy.

Keywords: acetyl-CoA acyltransferase 2; biomarker; hepatocellular carcinoma; immunotherapy; nuclear factor-κB signaling pathway.

Grants and funding

This study was supported by the National Natural Science Foundation of China (81803001), Heilongjiang Province Youth Innovating Talents Training Plan Fund for Regular Undergraduate Colleges (UNPYSCT-2017066), Heilongjiang Province Postdoctoral Science Foundation (LBH-Q21034, 21042220024), Scientific Foundation of the First Affiliated Hospital of Harbin Medical University (HYD2020YQ0011, HYD2020JQ0007), Haiyan Research Fund of Harbin Medical University Cancer Hospital (JJMS2022-01).