Metformin and Colorectal Cancer Risk—Letter

In a recent publication, Bradley and colleagues (1) focused on the association of metformin and colorectal cancer risk among patients with diabetes mellitus (1). Several epidemiologic studies have labeled strong inverse relationships between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may, in part, clarify these findings (1). The authors conducted a cohort study to reexamine this association using methods to minimize these biases (1). They observed that the long-term use of metformin appeared to be linked to reduced risk of colorectal cancer in the full population, among current users, and in men but not in women, underlining an inverse relationship between long-term use of metformin and colorectal cancer (1). However, they conclude that their findings, particularly the risk reduction among men, need to be confirmed in large, well-conducted studies (1). Metformin has emerged as the preferred first-line oral blood glucose-lowering agent to manage type II diabetes (2). Metformin counters insulin resistance and address adult-onset hyperglycemia (2). miR-26b is associated with insulin resistance (3). miR-26b is a miRNA that has been shown to be involved in insulin sensitivity and cancer (3, 4). miR-26b levels appear to be significantly lower in patients with insulin resistance in comparison with those without insulin resistance (3). miR-26b is also downregulated in colorectal cancer (4). miR-26b has been shown to have a potent inhibitory effect on colon cancer cell proliferation (4). miR-26b expression is decreased and lymphoid enhancer factor1 (LEF-1) expression is increased in colon cancer cells (4). LEF-1 is frequently expressed in colorectal carcinoma with prognostic value as a trend of worse overall survival (5). miR-26b directly inhibits endogenous LEF-1 (4). LEF-1 relates to β-catenin and activates Wnt-responsive target genes (5). LEF-1 is also linked to the presence of KRAS mutations (5). Endogenous LEF-1 is significantly reduced by miR-26b overexpression and the Wnt/β catenin target genes Cyclin D1 and C-Myc are also repressed (4). Taken together, I hypothesize that metformin may be of therapeutic benefit in colorectal cancer among patients with diabetes mellitus as a result of upregulation of miR-26b induced by metformin through reducing insulin resistance by inhibiting of LEF-1 and blocking LEF-1 activation of the Wnt/β-catenin target genes Cyclin D1 and c-Myc. I suppose that men and women might respond differently to metformin as a result of sex dimorphism of LEF1 gene expression resulting in metformin failure in women. Strict metabolic control should be inserted among tailored interventions for the management of colorectal cancer.