Department of Biomedical Science, BK21-Plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
Exp Mol Med. 2024 Feb;56(1):220-234. doi: 10.1038/s12276-023-01153-3. Epub 2024 Jan 10.
Diabetes might be associated with increased cancer risk, with several studies reporting hyperglycemia as a primary oncogenic stimulant. Since glucose metabolism is linked to numerous metabolic pathways, it is difficult to specify the mechanisms underlying hyperglycemia-induced cancer progression. Here, we focused on the polyol pathway, which is dramatically activated under hyperglycemia and causes diabetic complications. We investigated whether polyol pathway-derived fructose facilitates hyperglycemia-induced gastric cancer metastasis. We performed bioinformatics analysis of gastric cancer datasets and immunohistochemical analyses of gastric cancer specimens, followed by transcriptomic and proteomic analyses to evaluate phenotypic changes in gastric cancer cells. Consequently, we found a clinical association between the polyol pathway and gastric cancer progression. In gastric cancer cell lines, hyperglycemia enhanced cell migration and invasion, cytoskeletal rearrangement, and epithelial-mesenchymal transition (EMT). The hyperglycemia-induced acquisition of metastatic potential was mediated by increased fructose derived from the polyol pathway, which stimulated the nuclear ketohexokinase-A (KHK-A) signaling pathway, thereby inducing EMT by repressing the CDH1 gene. In two different xenograft models of cancer metastasis, gastric cancers overexpressing AKR1B1 were found to be highly metastatic in diabetic mice, but these effects of AKR1B1 were attenuated by KHK-A knockdown. In conclusion, hyperglycemia induces fructose formation through the polyol pathway, which in turn stimulates the KHK-A signaling pathway, driving gastric cancer metastasis by inducing EMT. Thus, the polyol and KHK-A signaling pathways could be potential therapeutic targets to decrease the metastatic risk in gastric cancer patients with diabetes.
糖尿病可能与癌症风险增加有关，有几项研究报告高血糖是主要的致癌刺激因素。由于葡萄糖代谢与许多代谢途径有关，因此很难确定高血糖引起癌症进展的机制。在这里，我们专注于多元醇途径，该途径在高血糖下显著激活，并导致糖尿病并发症。我们研究了多元醇途径衍生的果糖是否促进高血糖诱导的胃癌转移。我们对胃癌数据集进行了生物信息学分析，并对胃癌标本进行了免疫组织化学分析，然后进行了转录组和蛋白质组分析，以评估胃癌细胞的表型变化。结果，我们发现多元醇途径与胃癌进展之间存在临床关联。在胃癌细胞系中，高血糖增强了细胞迁移和侵袭、细胞骨架重排和上皮-间充质转化 (EMT)。高血糖诱导获得转移潜能是由多元醇途径衍生的果糖增加介导的，果糖刺激核酮己糖激酶-A (KHK-A) 信号通路，从而通过抑制 CDH1 基因诱导 EMT。在两种不同的癌症转移异种移植模型中，发现过表达 AKR1B1 的胃癌在糖尿病小鼠中具有高度转移性，但 AKR1B1 的这些作用被 KHK-A 敲低所减弱。总之，高血糖通过多元醇途径诱导果糖形成，进而刺激 KHK-A 信号通路，通过诱导 EMT 驱动胃癌转移。因此，多元醇和 KHK-A 信号通路可能是减少糖尿病胃癌患者转移风险的潜在治疗靶点。
