LncRNA ANRIL promotes glucose metabolism and proliferation of colon cancer in a high-glucose environment and associated with worse outcome in diabetic colon cancer patients

Abstract

Background:The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. Epigenetic changes, such as deregulation of long non-coding RNA (lncRNA) and microRNA (miR), have been linked to the advancement of CC; however, the effects of high glucose levels on their deregulation and, as a result, colon cancer, have yet to be investigated. Methods: The study comprised 110 colon cancer patients who were separated into two groups: 50 patients with colon cancer and T2DM, and 60 patients with colon cancer but no diabetic mellitus. QRT-PCR was used to examine the expression of lncRNA ANRIL and miR-186-5p in tissue samples. ANRIL, miR-186-5p, and their downstream target genes HIF-1, PFK, HK, Bcl-2, and Bax were also measured in CC cell lines under various glucose conditions. In CC cell lines, glucose uptake, lactate generation, and cell proliferation were measured. Results: A significant upregulation of ANRIL expression levels (p<0.001) and a significant downregulation of miR-186-5p expression (p<0.001) in diabetic colon cancer specimens compared to those in non-diabetic colon cancer group were shown. MiR-186-5p expression levels were inversely correlated with ANRILexpression levels, blood glucose levels and HbA1c%. Concerning in vitro model, a significant upregulation of ANRIL, downregulation of miR-186-5p, upregulation of HIF-1α, glycolytic enzymes and activation of antiapoptotic pathway was detected in higher glucose concentrations than lower one. There was a significant increase of glucose uptake, lactate accumulation and proliferation of the Caco2 and SW620 cell lines in a dose dependent manner of glucose concentrations. Moreover, a significant positive correlation between glucose uptake and ANRIL expression was shown. Conclusions: A high-glucose environment can increase the tumor-promoting effect of ANRIL. ANRIL can promote glucose metabolism and colon cancer proliferation by downregulating miR 186-5p with subsequent upregulation of glycolysis enzymes expression and inhibition of apoptosis.