The CBS-H2S axis promotes liver metastasis of colon cancer by upregulating VEGF through AP-1 activation.

Abstract

BACKGROUND:

The main therapy for colon cancer with liver metastasis is chemotherapy based on 5-fluorouracil combined with targeted drugs. However, acquired drug resistance and severe adverse reactions limit patients' benefit from standard chemotherapy. Here, we investigate the involvement of endogenous hydrogen sulfide (H2S) in liver metastasis of colon cancer and its potential value as a novel therapeutic target.

METHODS:

We used the CRISPR/Cas9 system to knockdown CBS gene expression in colon cancer cell lines. PCR arrays and proteome arrays were applied to detect the transcription and protein expression levels, respectively, of angiogenesis-related genes after knockdown. The molecular mechanism was investigated by western blot analysis, RT-qPCR, immunofluorescence staining, ChIP assays and dual-luciferase reporter assays. A liver metastasis mouse model was adopted to investigate the effect of targeting CBS on tumour metastasis in vivo.

RESULTS:

Knockdown of CBS decreased the metastasis and invasion of colon cancer cells and inhibited angiogenesis both in vivo and in vitro. Tissue microarray analysis showed a positive correlation between CBS and VEGF expression in colon cancer tissues. Further analysis at the molecular level validated a positive feedback loop between the CBS-H2S axis and VEGF.

CONCLUSIONS:

Endogenous H2S promotes angiogenesis and metastasis in colon cancer, and targeting the positive feedback loop between the CBS-H2S axis and VEGF can effectively intervene in liver metastasis of colon cancer.

• Authors: Shihao Guo, Jichang Li, Zhihao Huang, Taohua Yue, Jing Zhu, Xin Wang, Yucun Liu, Pengyuan Wang, Shanwen Chen
• Journal: British journal of cancer (Br J Cancer) Vol. 126 Issue 7 Pg. 1055-1066 (04 2022) ISSN: 1532-1827 [Electronic] England
• PMID: 34952931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Transcription Factor AP-1
• Vascular Endothelial Growth Factor A
• Cystathionine beta-Synthase
• Hydrogen Sulfide

Topics

• Animals
• Cell Proliferation
• Colonic Neoplasms (complications)
• Cystathionine beta-Synthase (genetics)
• Humans
• Hydrogen Sulfide (metabolism)
• Liver Neoplasms (genetics, secondary)
• Mice
• Transcription Factor AP-1 (genetics)
• Vascular Endothelial Growth Factor A (genetics)