ABCC6 Knockdown Fuels Cell Proliferation by Regulating PPARα in Hepatocellular Carcinoma

Zhicong Zhao; Zhenjun Zhao; Jianye Wang; He Zhang; Zhifeng Xi; Qiang Xia

doi:10.3389/fonc.2022.840287

ABCC6 Knockdown Fuels Cell Proliferation by Regulating PPARα in Hepatocellular Carcinoma

Front Oncol. 2022 Feb 24:12:840287. doi: 10.3389/fonc.2022.840287. eCollection 2022.

Authors

Zhicong Zhao^{1

2}, Zhenjun Zhao¹, Jianye Wang^{1

3}, He Zhang^{1

4}, Zhifeng Xi¹, Qiang Xia^{1

5

6}

Affiliations

¹ Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA, United States.
³ Department of Surgery, School of Medicine, Technical University of Munich, Munich, Germany.
⁴ Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
⁵ Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China.
⁶ Shanghai Institute of Transplantation, Shanghai, China.

Abstract

The ATP binding cassette (ABC) transporter family is ubiquitous in eukaryotes, specifically in vertebrates, and plays a crucial role in energy homeostasis, cell signaling, and drug resistance. Accumulating evidence indicates that some ABC transporters contribute to cancer cell proliferation and tumor progression; however, relatively little is known about the behavior of the ABC transporter family in hepatocellular carcinoma (HCC). By analyzing two public transcriptomic databases, we evaluated the effect of genes in the ABC transporter family on HCC prognostic prediction; ABCC6 was selected for further study. Notably, ABCC6 was found to be downregulated in HCC tissues and correlated with favorable outcomes in patients with HCC. Moreover, ABCC6 knockdown not only significantly promoted cell proliferation in vitro and in vivo, but also inhibited cell cycle arrest and cell apoptosis. Transcriptome analysis revealed that ABCC6 depletion enhanced the "mitotic cell cycle" and "DNA replication" pathways, and suppressed the "PPAR signaling pathway". Further investigation demonstrated that PPARα, one of the key regulators in peroxisome metabolism, is located downstream of ABCC6. In summary, our study provides profound insights into the behavior of ABC transporter family genes in various HCC cohorts, identifies ABCC6 as a biomarker for early-stage HCC diagnosis, and offers experimental basis for further investigations of targeting ABCC6 in the treatment of patients with HCC.

Keywords: ABC transporter family; ABCC6; PPARα; biomarker; cell proliferation; hepatocellular carcinoma; peroxisome.