Background: Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. Methods: The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA–target gene pairs. Results: Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA–target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to targetPIK3R3and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly targetSTMN1to inhibit CRC cell proliferation and cell cycle progression. Conclusions: This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
背景：二甲双胍作为2型糖尿病的一线治疗药物，通过干扰细胞代谢发挥作用。尽管二甲双胍与较低的癌症发病率相关，但其在结直肠癌中的抗肿瘤活性尚未完全阐明。本研究通过探究二甲双胍相关的微小RNA及其在信号通路中作用的靶基因对，揭示了二甲双胍减缓结直肠癌细胞增殖的潜在分子机制。 方法：本研究分析了经亚致死剂量二甲双胍处理的结直肠癌细胞中微小RNA和编码转录组的变化，并对潜在的微小RNA-靶基因对进行了系统验证。 结果：小RNA和转录组测序数据分析显示，经二甲双胍处理72小时的结直肠癌细胞中有104个微小RNA和1221个mRNA发生差异表达。研究确定了差异表达微小RNA与潜在靶mRNA之间的相互作用网络。差异表达基因主要涉及代谢和信号传导过程，如PI3K-Akt和MAPK/ERK通路。对潜在微小RNA-靶mRNA对的进一步验证表明，二甲双胍诱导miR-2110和miR-132-3p靶向PIK3R3，从而调控结直肠癌细胞增殖、细胞周期进程及PI3K-Akt信号通路。同时，二甲双胍还诱导miR-222-3p和miR-589-3p直接靶向STMN1，抑制结直肠癌细胞增殖和细胞周期进程。 结论：本研究发现了二甲双胍处理结直肠癌细胞引起的编码转录组和小非编码RNA的新变化。这些数据集的整合揭示了二甲双胍抑制结直肠癌细胞增殖的深层机制。重要的是，研究发现了影响代谢和细胞增殖的特定基因的转录后调控机制。
Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study
肿瘤(癌症)患者之家