Downregulation of the Unfolded Protein Response Links Metformin Treatment to Good Clinical Outcomes in Colorectal Cancer Patients.

IF 3.4 4区医学 Q2 ONCOLOGY Current oncology Pub Date : 2025-02-27 DOI:10.3390/curroncol32030138

Mary L Fay, Chris Nicol, Christine Orr, Brooke Wilson, David Hurlbut, Harriet Feilotter, Scott Davey

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Abstract

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 (n = 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 (p = 0.05) and non-diabetics with good clinical outcomes (p = 0.05) relative to diet-controlled and non-diabetics with poor survival, respectively. Furthermore, upregulation of SCNN1A is observed in metformin-treated samples (p = 0.04) and non-diabetics with good clinical outcomes (p = 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 (p = 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.

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未折叠蛋白反应的下调将二甲双胍治疗与结直肠癌患者的良好临床结果联系起来。

2型糖尿病是结直肠癌（CRC）发生和发展的危险因素。然而，二甲双胍治疗的糖尿病结直肠癌患者往往比其他方法治疗的患者有更好的临床结果。为了更好地表征二甲双胍保护作用的分子基础，我们对原发性结直肠癌组织样本（n = 272）进行了靶向转录组学分析。一种监督学习算法精确地确定了区分二甲双胍治疗和饮食控制的糖尿病结直肠癌样本的分子特征，以及基于其五年总体生存状态区分非糖尿病样本的分子特征。我们的研究结果显示，在二甲双胍治疗的样本（p = 0.05）和临床结果良好的非糖尿病患者（p = 0.05）中，TMEM132分别相对于饮食控制和生存差的非糖尿病患者下调。此外，在二甲双胍治疗的样本（p = 0.04）和临床结果较好的非糖尿病患者（p = 0.01）中，SCNN1A的表达分别相对于饮食控制的样本和临床结果较差的样本上调。我们还发现，相对于饮食控制的样本，二甲双胍处理的样本中抗凋亡蛋白sFas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介导二甲双胍相关的CRC保护作用，并建议研究这些蛋白作为新型CRC治疗的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current oncology ONCOLOGY-

CiteScore

3.30

自引率

7.70%

发文量

664

审稿时长

1 months

期刊介绍： Current Oncology is a peer-reviewed, Canadian-based and internationally respected journal. Current Oncology represents a multidisciplinary medium encompassing health care workers in the field of cancer therapy in Canada to report upon and to review progress in the management of this disease. We encourage submissions from all fields of cancer medicine, including radiation oncology, surgical oncology, medical oncology, pediatric oncology, pathology, and cancer rehabilitation and survivorship. Articles published in the journal typically contain information that is relevant directly to clinical oncology practice, and have clear potential for application to the current or future practice of cancer medicine.