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Hepatology
Original research
Blocking hepatocarcinogenesis by a cytochrome P450 family member with female-preferential expression
  1. Fubo Ji1,2,
  2. Jianjuan Zhang1,2,
  3. Niya Liu1,2,
  4. Yuanzhuo Gu1,
  5. Yan Zhang1,2,
  6. Peipei Huang1,2,
  7. Nachuan Zhang1,2,
  8. Shengda Lin1,
  9. Ran Pan3,
  10. Zhuoxian Meng3,
  11. Xin-Hua Feng1,2,4,
  12. Stephanie Roessler5,
  13. Xin Zheng6,
  14. Junfang Ji1,2
  1. 1 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
  2. 2 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
  3. 3 Department of Pathology and Pathophysiology, Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  4. 4 Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China
  5. 5 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
  6. 6 Taoharmony Biotech L.L.C, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Junfang Ji, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang Province, China; junfangji{at}zju.edu.cn

Abstract

Objects The incidence of hepatocellular carcinoma (HCC) shows an obvious male dominance in rodents and humans. We aimed to identify the key autosomal liver-specific sex-related genes and investigate their roles in hepatocarcinogenesis.

Design Two HCC cohorts (n=551) with available transcriptome and metabolome data were used. Class comparisons of omics data and ingenuity pathway analysis were performed to explore sex-related molecules and their associated functions. Functional assays were employed to investigate roles of the key candidates, including cellular assays, molecular assays and multiple orthotopic HCC mouse models.

Results A global comparison of multiple omics data revealed 861 sex-related molecules in non-tumour liver tissues between female and male HCC patients, which denoted a significant suppression of cancer-related diseases and functions in female liver than male. A member of cytochrome P450 family, CYP39A1, was one of the top liver-specific candidates with significantly higher levels in female vs male liver. In HCC tumours, CYP39A1 expression was dramatically reduced in over 90% HCC patients. Exogenous CYP39A1 significantly blocked tumour formation in both female and male mice and partially reduced the sex disparity of hepatocarcinogenesis. The HCC suppressor role of CYP39A1 did not rely on its known P450 enzyme activity but its C-terminal region, by which CYP39A1 impeded the transcriptional activation activity of c-Myc, leading to a significant inhibition of hepatocarcinogenesis.

Conclusions The liver-specific CYP39A1 with female-preferential expression was a strong suppressor of HCC development. Strategies to up-regulate CYP39A1 might be promising methods for HCC treatment in both women and men in future.

  • hepatocellular carcinoma
  • carcinogenesis
  • cytochrome P450

Data availability statement

Data are available in a public, open access repository. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as online supplemental information. The miRNA profiling data of cohort 1 were available at GEO datasets of NCBI (GSE6857, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE6857). The mRNA profiling data of cohort 1 were available at GEO datasets (GSE14520, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE14520). The miRNA and mRNA sequencing data of cohort 2 were available at the Cancer Genome Atlas (TCGA) portal (https://portal.gdc.cancer.gov). The metabolomic profiling data of cohort 1 were obtained from Dr Xin W Wang (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633738/).

https://doi.org/10.1136/gutjnl-2021-326050

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    Data availability statement

    Data are available in a public, open access repository. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as online supplemental information. The miRNA profiling data of cohort 1 were available at GEO datasets of NCBI (GSE6857, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE6857). The mRNA profiling data of cohort 1 were available at GEO datasets (GSE14520, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE14520). The miRNA and mRNA sequencing data of cohort 2 were available at the Cancer Genome Atlas (TCGA) portal (https://portal.gdc.cancer.gov). The metabolomic profiling data of cohort 1 were obtained from Dr Xin W Wang (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633738/).

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    Footnotes

    • Contributors Conception and design: FJ and JJ; Acquisition of data: FJ, JZ, NZ, YG, YZ, PH, NZ and JJ; Analysis and interpretation of data: FJ and JJ; Methodology, resources and materials: FJ, JZ, NL, SL, RP, ZM, X-HF and XZ; Writing and/or revision of the manuscript: FJ, JZ, NL, YG, SR, XZ and JJ; Study supervision and guarantor: JJ.

    • Funding This work was supported by National Natural Science Foundation of China (No. 81874054 and 81672905) (JJ), National Key R&D Program of China (2018YFA0800504) (JJ), Zhejiang Basic Public Welfare Research Programme (LZ20H160003) (JJ), the Fundamental Research Funds for the Central Universities in China (JJ).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.