Fay Mary L, Nicol Chris, Orr Christine, Wilson Brooke, Hurlbut David, Feilotter Harriet, Davey Scott
Division of Cancer Biology and Genetics, Sinclair Cancer Research Institute at Queen's University, Kingston, ON K7L 3N6, Canada.
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
Curr Oncol. 2025 Feb 27;32(3):138. doi: 10.3390/curroncol32030138.
Type 2 diabetes is a risk factor for colorectal cancer (CRC) development and progression. However, metformin-treated diabetic CRC patients tend to have better clinical outcomes than those managed by other means. To better characterize the molecular underpinnings of metformin's protective effects, we performed a targeted transcriptomic analysis of primary CRC tissue samples ( = 272). A supervised learning algorithm pinpointed molecular features that discriminate between metformin-treated and diet-controlled diabetic CRC samples, as well as those that discriminated between non-diabetic samples based on their five-year overall survival status. Our results show downregulation of TMEM132 in metformin-treated samples ( = 0.05) and non-diabetics with good clinical outcomes ( = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples ( = 0.04) and non-diabetics with good clinical outcomes ( = 0.01) relative to diet-controlled samples and those with poor clinical outcomes, respectively. We also show that the antiapoptotic protein sFas is downregulated in metformin-treated samples relative to diet-controlled samples ( = 0.005). These findings suggest a role for the unfolded protein response in mediating metformin-related CRC-protective effects by enhancing apoptosis and suggest the investigation of these proteins as targets for novel CRC therapies.
2型糖尿病是结直肠癌（CRC）发生和进展的一个风险因素。然而，接受二甲双胍治疗的糖尿病CRC患者往往比采用其他治疗方式的患者具有更好的临床结局。为了更好地描述二甲双胍保护作用的分子基础，我们对原发性CRC组织样本（n = 272）进行了靶向转录组分析。一种监督学习算法确定了能够区分二甲双胍治疗组和饮食控制组糖尿病CRC样本的分子特征，以及能够根据五年总生存状态区分非糖尿病样本的分子特征。我们的结果显示，相对于饮食控制组和生存较差的非糖尿病患者，二甲双胍治疗组样本（P = 0.05）和临床结局良好的非糖尿病患者（P = 0.05）中TMEM132表达下调。此外，相对于饮食控制组样本和临床结局较差的样本，二甲双胍治疗组样本（P = 0.04）和临床结局良好的非糖尿病患者（P = 0.01）中SCNN1A表达上调。我们还表明，相对于饮食控制组样本，二甲双胍治疗组样本中抗凋亡蛋白sFas表达下调（P = 0.005）。这些发现表明未折叠蛋白反应通过增强细胞凋亡在介导二甲双胍相关的CRC保护作用中发挥作用，并建议将这些蛋白作为新型CRC治疗靶点进行研究。
