Cheng Hsiu-Chung, Chang Tsung-Kun, Su Wei-Chih, Tsai Hsiang-Lin, Wang Jaw-Yuan
School of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan.
Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung City 807, Kaohsiung, Taiwan.
Transl Oncol. 2021 Jul;14(7):101089. doi: 10.1016/j.tranon.2021.101089. Epub 2021 Apr 7.
Diabetes mellitus (DM) and hyperglycemia have been shown to have significant effects on the incidence, chemoresistance, and prognosis of colorectal cancer (CRC), as well as the outcomes of localized and metastatic CRC. Inflammation and endocrine effects may act as central mechanisms of DM and cancer and stimulate the insulin-like growth factor 1-phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (IGF-1-PI3K-AKT-mTOR) pathway. Dysregulation of the AMP-activated protein kinase (AMPK) pathway leads to metabolic imbalance and indicates cancer risk. The use of metformin for chemoprevention has been shown to reduce CRC and adenoma incidence through the upregulation of AMPK, which causes cell cycle arrest in the Gap 1-S (G1-S) phase and inhibits the mTOR pathway, even potentially reversing the epithelial-mesenchymal transition. However, evidence of the effects of metformin remain controversial in cancer prognosis. Several genes, such as transcription factor 7-like 2(TCF7L2), tumor protein P53 inducible nuclear protein 1(TP53INP1), gremlin 1 (GREM1), and potassium voltage-gated channel subfamily Q member 1(KCNQ1), are pleiotropically related to DM as well as cancer risk and prognosis. Epigenetic modification of members of the Let-7 family such as miR-497, miR-486, and miR-223 is strongly associated with impaired glucose tolerance and CRC risk. Herein we review the pathophysiological and epidemiological evidence as well as potential underlying molecular mechanisms by which DM and hyperglycemia affect CRC risk. We also suggest potential roles of glucose modulation in CRC therapy and propose an agenda for future research and clinical practice.
糖尿病（DM）和高血糖已被证明对结直肠癌（CRC）的发病率、化疗耐药性和预后以及局限性和转移性CRC的结局有显著影响。炎症和内分泌效应可能是DM与癌症的核心机制，并刺激胰岛素样生长因子1-磷脂酰肌醇3-激酶-Akt-雷帕霉素哺乳动物靶点（IGF-1-PI3K-AKT-mTOR）通路。AMP激活的蛋白激酶（AMPK）通路失调会导致代谢失衡，并提示癌症风险。已证明使用二甲双胍进行化学预防可通过上调AMPK来降低CRC和腺瘤的发病率，AMPK可导致细胞周期停滞在G1-S期并抑制mTOR通路，甚至可能逆转上皮-间质转化。然而，二甲双胍在癌症预后方面的作用证据仍存在争议。一些基因，如转录因子7样2（TCF7L2）、肿瘤蛋白P53诱导核蛋白1（TP53INP1）、gremlin 1（GREM1）和钾电压门控通道亚家族Q成员1（KCNQ1），与DM以及癌症风险和预后存在多效性关联。Let-7家族成员如miR-497、miR-486和miR-223的表观遗传修饰与糖耐量受损和CRC风险密切相关。在此，我们综述了DM和高血糖影响CRC风险的病理生理和流行病学证据以及潜在的分子机制。我们还提出了血糖调节在CRC治疗中的潜在作用，并为未来的研究和临床实践提出了议程。
