Reduced Insulin-like Growth Factor I Receptor and Altered Insulin Receptor Isoform mRNAs in Normal Mucosa Predict Colorectal Adenoma Risk

Abstract

Background Hyperinsulinemia resulting from obesity and insulin resistance is associated with increased risk of many cancers, but the biology underlying this risk is unclear. We hypothesized that increased mRNA levels of the insulin-like growth factor 1 receptor (IGF1R) versus the insulin receptor (IR) or elevated ratio of IR-A:IR-B isoforms in normal rectal mucosa would predictadenoma risk, particularly in individuals with high body mass index (BMI) or plasma insulin. Methods Biopsies from normal rectal mucosa were obtained from consenting patients undergoing routine colonoscopy at UNC Hospitals. Subjects with colorectal adenomas were classified as cases (n = 100) and were matched to adenoma-free controls (n = 98) based on age, sex and BMI. IGF1R and IR mRNA levels were assessed by qRT-PCR, and IR-A:IR-B mRNA ratios by standard PCR. Plasma insulin and crypt apoptosis were measured by ELISA and TUNEL, respectively. Logistic regression models examined relationships between receptor mRNAs, BMI, plasma insulin and adenoma risk. Results Unexpectedly, cases were significantly more likely to have lower IGF1R mRNA levels than controls. No overall differences in total IR mRNA or IR-A:IR-B ratios were observed between cases and controls. Interestingly, in patients with high plasma insulin, increased IR-A:IR-B ratio was associated with increased likelihood of having adenomas. Conclusions Our work shows novel findings that reduced IGF1R mRNA and, during high plasma insulin, increased IR-A:IR-B ratios in normal rectal mucosa are associated with colorectal adenoma risk. Impact Our work provides evidence supporting a link between IGF1R and IR isoform expression levels and colorectal adenoma risk.

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

“…Rat models have demonstrated that insulin can induce proliferation of colorectal epithelial cells and the development of aberrant crypt foci, the primary neoplastic lesions in colorectal development ( 39 ). In colonic tumor cells, the expression of the insulin receptor protein is elevated, particularly isoform A, which exerts mitogenic effects ( 40 , 41 ).…”

Aspects of dietary carbohydrate intake are not related to risk of colorectal polyps in the Tennessee Colorectal Polyp Study

“…However, glycemic index and glycemic load, which are alternative concepts to quantify the impact of carbohydrate-foods on postprandial glucose responses [19], have also been shown to be unrelated to colorectal cancer and adenoma risk in a systematic review [20]. Moreover, a recent US case-control study documented an unexpected inverse association between IGF-1 receptor levels and colorectal adenoma risk [21], thereby conflicting with earlier evidence of a direct association with colorectal cancer risk [7]. Collectively, the biological and epidemiological evidence to date appear to be contrasting.…”

Understanding the Key to Targeting the IGF Axis in Cancer: A Biomarker Assessment

“…In contrast to breast cancer, in squamous cell lung carcinoma, high INSR-A:INSR-B ratio was associated with lower epithelial-mesenchymal transition (EMT) gene signature and longer survival ( 56 ). A recent case control study of colorectal adenoma in patients found no difference in the total INSR mRNA; however, in patients with high plasma insulin, increased INSR-A:INSR-B ratio was associated with increased likelihood of having adenomas ( 79 ). Therefore, the usefulness of INSR-A:INSR-B ratio likely varies by tumor type and should be evaluated separately.…”