Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong province, China; Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
EBioMedicine. 2019 Dec;50:224-237. doi: 10.1016/j.ebiom.2019.11.011. Epub 2019 Nov 19.
Alcohol intake is a well-known lifestyle risk factor for CRC, and an increasing number of studies have revealed that alcohol intake is also tightly associated with CRC metastasis. However, the effect of alcohol on CRC metastasis and its underlying mechanism remain unclear.
A retrospective cohort study was performed to investigate the characteristics of patients with alcohol-related CRC. The effects of ethanol on the biological behaviours of CRC cells were assessed through in vivo and in vitro assays using the Lieber-DeCarli ethanol liquid diet and ethanol, respectively. The ethanol-mediated signalling pathway and downstream factors were screened through ELISA, western blot, immunofluorescence and co-immunoprecipitation.
Most patients with alcohol-related CRC, particularly those with tumour metastasis, were characterized by a notably higher circulating ethanol level and a lower systemic acetaldehyde level. Moreover, CRC cells accumulated in ethanol, but not acetaldehyde, to notably higher levels compared with adjacent normal cells. Alcohol intake significantly promoted CRC metastasis via the ethanol-mediated TGF-β/Smad/Snail axis, and ethanol induced the cytoplasmic mislocalization of RUNX3 and further promoted the aggressiveness of CRC by targeting Snail. Pirfenidone (PFD) significantly eliminated the effects of ethanol on CRC metastasis by specifically blocking TGF-β signalling.
Alcohol intake plays a vital role in CRC metastasis via the ethanol-mediated TGF-β/RUNX3/Snail axis, and PFD might be a novel therapeutic management strategy for CRC.
饮酒是 CRC 的一种众所周知的生活方式风险因素，越来越多的研究表明，饮酒也与 CRC 转移密切相关。然而，酒精对 CRC 转移的影响及其潜在机制仍不清楚。
进行了一项回顾性队列研究，以调查与酒精相关的 CRC 患者的特征。通过 Lieber-DeCarli 乙醇液体饮食和乙醇分别在体内和体外实验中评估乙醇对 CRC 细胞生物学行为的影响。通过 ELISA、western blot、免疫荧光和共免疫沉淀筛选乙醇介导的信号通路和下游因子。
大多数与酒精相关的 CRC 患者，特别是那些有肿瘤转移的患者，其特征是循环乙醇水平明显升高，而全身乙醛水平明显降低。此外，与相邻正常细胞相比，CRC 细胞在乙醇中积累，但不在乙醛中积累到明显更高的水平。饮酒通过乙醇介导的 TGF-β/Smad/Snail 轴显著促进 CRC 转移，乙醇诱导 RUNX3 的细胞质定位错误，并通过靶向 Snail 进一步促进 CRC 的侵袭性。Pirfenidone (PFD) 通过特异性阻断 TGF-β 信号显著消除了乙醇对 CRC 转移的影响。
饮酒通过乙醇介导的 TGF-β/RUNX3/Snail 轴在 CRC 转移中发挥重要作用，PFD 可能是 CRC 的一种新的治疗管理策略。
