Department of Pharmacology, West China School of Basic Science and Forensic Medicine, Sichuan University, Chengdu, China.
Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
Cancer Med. 2024 Jun;13(11):e7382. doi: 10.1002/cam4.7382.
Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, characterized by its complex etiology and slow research progress. Diabetes, as an independent risk factor for CRC, has been widely certified. Consequently, this study centers on elucidating the intricacies of CRC cells initiation and progression within a high-glucose environment.
A battery of assays was employed to assess the proliferation and metastasis of CRC cells cultured under varying glucose concentrations. Optimal glucose levels conducive to cells' proliferation and migration were identified. Western blot analyses were conducted to evaluate alterations in apoptosis, autophagy, and EMT-related proteins in CRC cells under high-glucose conditions. The expression of PI3K/AKT/mTOR pathway-associated proteins was assessed using western blot. The effect of high glucose on xenograft growth was investigated in vivo by MC38 cells, and changes in inflammatory factors (IL-4, IL-13, TNF-α, IL-5, and IL-12) were measured via serum ELISA.
Our experiments demonstrated that elevated glucose concentrations promoted both the proliferation and migration of CRC cells; the most favorable glucose dose is 20 mM. Western blot analyses revealed a decrease in apoptotic proteins, such as Bim, Bax, and caspase-3 with increasing glucose levels. Concurrently, the expression of EMT-related proteins, including N-cadherin, vimentin, ZEB1, and MMP9, increased. High-glucose cultured cells exhibited elevated levels of PI3K/AKT/mTOR pathway proteins. In the xenograft model, tumor cells stimulated by high glucose exhibited accelerated growth, larger tumor volumes, and heightened KI67 expression of immunohistochemistry. ELISA experiments revealed higher expression of IL-4 and IL-13 and lower expression of TNF-α and IL-5 in the serum of high-glucose-stimulated mice.
The most favorable dose and time for tumor cells proliferation and migration is 20 mM, 48 h. High glucose fosters CRC cell proliferation and migration while suppressing autophagy through the activation of the PI3K/AKT/mTOR pathway.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，其病因复杂，研究进展缓慢。糖尿病是 CRC 的独立危险因素，已得到广泛证实。因此，本研究集中于阐明高糖环境中 CRC 细胞起始和进展的复杂性。
采用一系列实验评估不同葡萄糖浓度下培养的 CRC 细胞的增殖和迁移。确定有利于细胞增殖和迁移的最佳葡萄糖水平。进行 Western blot 分析以评估 CRC 细胞在高糖条件下凋亡、自噬和 EMT 相关蛋白的变化。使用 Western blot 评估 PI3K/AKT/mTOR 通路相关蛋白的表达。通过 MC38 细胞在体内研究高糖对异种移植物生长的影响，并通过血清 ELISA 测量炎症因子（IL-4、IL-13、TNF-α、IL-5 和 IL-12）的变化。
我们的实验表明，升高的葡萄糖浓度促进 CRC 细胞的增殖和迁移；最有利的葡萄糖剂量为 20mM。Western blot 分析显示，随着葡萄糖水平的升高，凋亡蛋白如 Bim、Bax 和 caspase-3 的表达减少。同时，EMT 相关蛋白，包括 N-钙粘蛋白、波形蛋白、ZEB1 和 MMP9 的表达增加。高糖培养的细胞中 PI3K/AKT/mTOR 通路蛋白水平升高。在异种移植模型中，高糖刺激的肿瘤细胞表现出更快的生长速度、更大的肿瘤体积和更高的 Ki67 免疫组织化学表达。ELISA 实验显示，高糖刺激小鼠血清中 IL-4 和 IL-13 的表达升高，而 TNF-α 和 IL-5 的表达降低。
肿瘤细胞增殖和迁移的最佳剂量和时间为 20mM，48 小时。高糖通过激活 PI3K/AKT/mTOR 通路促进 CRC 细胞增殖和迁移，同时抑制自噬。
