Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
Department of Gynecology, The Second Hospital of Shandong University, Jinan, Shandong, China.
Cancer Sci. 2022 Jul;113(7):2297-2310. doi: 10.1111/cas.15384. Epub 2022 May 29.
The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high-glucose (HG)-related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high-throughput sequencing revealed significantly higher hexokinase domain-containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG-induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis-induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate-rich environments to further accelerate EC progression. Subsequently, miR-876-5p was predicted to target the HKDC1 mRNA, and HOXC-AS2 was identified to potentially inhibit the miR-876-5p/HKDC1 axis in regulating cell pyroptosis in HG-related EC. Collectively, we elucidated the regulatory role of the HOXC-AS2/miR-876-5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.
肿瘤微环境（TME）与慢性炎症有关，目前被认为是子宫内膜癌（EC）发生和发展的危险因素。细胞焦亡是一种新的炎症形式的程序性细胞死亡，在多种疾病的进展中起着关键作用。然而，细胞焦亡在高糖（HG）相关 EC 中的重要作用及其潜在的分子机制仍不清楚。在本研究中，转录组高通量测序显示，糖尿病 EC 患者的己糖激酶结构域包含 1（HKDC1）表达明显高于血糖正常的 EC 患者。在机制上，HKDC1 通过调节 EC 中活性氧的产生和细胞焦亡诱导的细胞因子释放来调节 HG 诱导的细胞焦亡。此外，HKDC1 通过增强糖酵解来调节 TME 的形成，在富含乳酸的环境中促进代谢优势，从而进一步加速 EC 的进展。随后，预测 miR-876-5p 靶向 HKDC1 mRNA，HOXC-AS2 被鉴定为可能抑制 miR-876-5p/HKDC1 轴在调节 HG 相关 EC 细胞焦亡中的作用。总之，我们从分子水平阐明了 HOXC-AS2/miR-876-5p/HKDC1 信号转导轴在 EC 细胞焦亡中的调节作用，这可能为诊断为 EC 的糖尿病患者提供有效的治疗靶点。
