Division of General Surgery, Peking University First Hospital, Peking University, 100034, Beijing, People's Republic of China.
Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Br J Cancer. 2022 Apr;126(7):1055-1066. doi: 10.1038/s41416-021-01681-7. Epub 2021 Dec 24.
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 (HS) in liver metastasis of colon cancer and its potential value as a novel therapeutic target.
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.
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-HS axis and VEGF.
Endogenous HS promotes angiogenesis and metastasis in colon cancer, and targeting the positive feedback loop between the CBS-HS axis and VEGF can effectively intervene in liver metastasis of colon cancer.
结直肠癌伴肝转移的主要治疗方法是基于氟尿嘧啶联合靶向药物的化疗。然而，获得性耐药和严重的不良反应限制了标准化疗给患者带来的益处。在这里，我们研究了内源性硫化氢（HS）在结直肠癌肝转移中的作用及其作为一种新的治疗靶点的潜在价值。
我们使用 CRISPR/Cas9 系统敲低结直肠癌细胞系中的 CBS 基因表达。PCR 阵列和蛋白质组阵列分别用于检测敲低后血管生成相关基因的转录和蛋白质表达水平。通过 Western blot 分析、RT-qPCR、免疫荧光染色、ChIP 测定和双荧光素酶报告基因测定来研究分子机制。采用肝转移小鼠模型研究靶向 CBS 对体内肿瘤转移的影响。
敲低 CBS 可降低结直肠癌细胞的转移和侵袭，并在体内和体外抑制血管生成。组织微阵列分析显示 CBS 与结直肠癌组织中 VEGF 的表达呈正相关。进一步的分子水平分析验证了 CBS-HS 轴与 VEGF 之间的正反馈环。
内源性 HS 促进结直肠癌的血管生成和转移，靶向 CBS-HS 轴与 VEGF 的正反馈环可有效干预结直肠癌的肝转移。
