강예림 (서울대학교 의과대학) | 한빛사논문 > 한빛사

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조회437

강예림Ye-Lim Kang

서울대학교 의과대학

Exp. Mol. Med., Jan 10 2024, | https://doi.org/10.1038/s12276-023-01153-3 The polyol pathway and nuclear ketohexokinase A signaling drive hyperglycemia-induced metastasis of gastric cancer

Ye-Lim Kang ^1,2,5, Jiyoung Kim^1,2,5, Su-Bin Kwak ^1,2, Yi-Sook Kim ^1,2, June Huh ³ and Jong-Wan Park ^1,2,4

¹Department of Biomedical Science, BK21-Plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Korea.

²Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Korea.

³Department of Chemical and Biological Engineering, Korea University, Anam-ro, Seongbuk-gu, Seoul 02841, Korea.

⁴Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul 03080, Korea.

⁵These authors contributed equally: Ye-Lim Kang, Jiyoung Kim.

Corresponding author : Correspondence to Jong-Wan Park.

Abstract

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-15)
연구진국내 연구진
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