Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Asian Pac J Cancer Prev. 2024 Apr 1;25(4):1371-1381. doi: 10.31557/APJCP.2024.25.4.1371.
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, in turn, colon cancer remain unexplored.
Fifty patients had a dual diagnosis of CC and T2DM, and 60 patients with CC without diabetes mellitus were included in the study. 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-1α, PFK, HK, Bcl-2, and Bax were also determined in CC cell lines under various glucose conditions. Glucose uptake, lactate production and cells proliferation were estimated in CC cell lines.
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 observed. MiR-186-5p expression levels were inversely correlated with ANRIL expression 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.
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.
先前已有报道指出 2 型糖尿病（T2DM）可能是结肠癌（CC）的一个风险因素。表观遗传变化，如长非编码 RNA（lncRNA）和 microRNA（miR）的失调，与 CC 的进展有关；然而，高血糖水平对它们失调的影响，以及对结肠癌的影响仍未被探索。
本研究纳入了 50 例同时患有 CC 和 T2DM 的患者和 60 例无糖尿病的 CC 患者。使用 qRT-PCR 检测组织样本中 lncRNA ANRIL 和 miR-186-5p 的表达。还在不同葡萄糖条件下检测 CC 细胞系中 ANRIL、miR-186-5p 及其下游靶基因 HIF-1α、PFK、HK、Bcl-2 和 Bax 的表达。在 CC 细胞系中评估葡萄糖摄取、乳酸生成和细胞增殖。
与非糖尿病结肠癌组相比，糖尿病结肠癌标本中 ANRIL 表达水平显著上调（p<0.001），miR-186-5p 表达水平显著下调（p<0.001）。miR-186-5p 表达水平与 ANRIL 表达水平、血糖水平和 HbA1c%呈负相关。在体外模型中，与低浓度葡萄糖相比，高浓度葡萄糖时检测到 ANRIL 显著上调、miR-186-5p 下调、HIF-1α、糖酵解酶上调和抗凋亡途径激活。Caco2 和 SW620 细胞系的葡萄糖摄取、乳酸积累和增殖呈剂量依赖性增加。此外，还显示葡萄糖摄取与 ANRIL 表达之间存在显著正相关。
高糖环境可增强 ANRIL 的促肿瘤作用。ANRIL 可通过下调 miR-186-5p 促进葡萄糖代谢和结肠癌增殖，随后上调糖酵解酶的表达并抑制细胞凋亡。
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