Open Access

ARTICLE

Aldo-keto reductase family member C3 (AKR1C3) promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α

KUO-SHYANG JENG¹, PO-YU CHENG², YUEH-HSIEN LIN², PO-CHUN LIU², PING-HUI TSENG³, YU-CHAO WANG⁴, CHIUNG-FANG CHANG⁵, CHUEN-MIIN LEU^2,*

1 Division of General Surgery, Far Eastern Memorial Hospital, New Taipei City, 22060, Taiwan
2 Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei City, 11221, Taiwan
3 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei City, 11221, Taiwan
4 Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei City, 11221, Taiwan
5 Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, 22060, Taiwan

* Corresponding Author: CHUEN-MIIN LEU. Email:

Oncology Research 2024, 32(1), 163-174. https://doi.org/10.32604/or.2023.030975

Received 09 May 2023; Accepted 18 July 2023; Issue published 15 November 2023

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Current therapies are effective for HCC patients with early disease, but many patients suffer recurrence after surgery and have a poor response to chemotherapy. Therefore, new therapeutic targets are needed. We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different. The analysis showed that AKR1C3 was upregulated in tumors, and high AKR1C3 expression was associated with a poorer prognosis in HCC patients. In vitro, assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines. Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo. To explore the mechanism, we performed pathway enrichment analysis, and the results linked the expression of AKR1C3 with prostaglandin F2 alpha (PGF2α) downstream target genes. Suppression of AKR1C3 activity reduced the production of PGF2α, and supplementation with PGF2α restored the growth of indomethacin-treated Huh7 cells. Knockdown of the PGF receptor (PTGFR) and treatment with a PTGFR inhibitor significantly reduced HCC growth. We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib. In summary, our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α, and suppression of PTGFR limited HCC growth. Therefore, targeting the AKR1C3-PGF2α-PTGFR axis may be a new strategy for the treatment of HCC.

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Supplementary Material

Supplementary Material File

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