高葡萄糖通过激活 BMP4 信号促进结直肠癌的进展，而胰高血糖素样肽-1 受体激动剂可抑制其进展。

BACKGROUND: The detailed molecular mechanism between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) is still uncertain. Bone morphogenetic protein 4 (BMP4) dysregulation is implicated in T2DM and CRC, respectively. This study aims to investigate whether BMP4 can mediate the interaction of CRC with T2DM. METHODS: We firstly explored the expression of BMP4 in The Cancer Genome Altas (TCGA) databases and CRC patients with or without DM from the Shanghai Tenth People's Hospital. The diabetic model of CRC cell lines in vitro and the mice model in vivo were developed to explore the BMP4 expression during CRC with or without diabetes. Further inhibition of BMP4 to observe its effects on CRC. Also, glucagon-like peptide-1 receptor agonist (GLP-1RA) was used to verify the underlying mechanism of hypoglycemic drugs on CRC via BMP4. RESULTS: BMP4 expression was upregulated in CRC patients, and significantly higher in CRC patients with diabetes (P < 0.05). High glucose-induced insulin resistance (IR)-CRC cells and diabetic mice with metastasis model of CRC had increased BMP4 expression, activated BMP4-Smad1/5/8 pathway, and improved proliferative and metastatic ability mediated by epithelial-mesenchymal transition (EMT). And, treated CRC cells with exogenously BMP inhibitor-Noggin or transfected with lentivirus (sh-BMP4) could block the upregulated metastatic ability of CRC cells induced by IR. Meanwhile, GLP-1R was downregulated by high glucose-induced IR while unregulated by BMP4 inhibitor noggin, and treated GLP-1RA could suppress the proliferation of CRC cells induced by IR through downregulated BMP4. CONCLUSIONS: BMP4 increased by high glucose promoted the EMT of CRC. The mechanism of the BMP4/Smad pathway was related to the susceptible metastasis of high glucose-induced IR-CRC. The commonly used hypoglycemic drug, GLP-1RA, inhibited the growth and promoted the apoptosis of CRC through the downregulation of BMP4. The result of our study suggested that BMP4 might serve as a therapeutic target in CRC patients with diabetes.

背景：2 型糖尿病（T2DM）和结直肠癌（CRC）之间的详细分子机制仍不确定。骨形态发生蛋白 4（BMP4）的失调分别与 T2DM 和 CRC 有关。本研究旨在探讨 BMP4 是否可以介导 CRC 与 T2DM 的相互作用。

方法：我们首先在癌症基因组图谱（TCGA）数据库中探索了 BMP4 的表达，并从上海第十人民医院的 CRC 患者中有无 DM 患者进行了探索。在体外培养 CRC 细胞系和体内糖尿病模型的基础上，观察了糖尿病条件下 BMP4 的表达情况。进一步抑制 BMP4 观察其对 CRC 的影响。同时，通过 BMP4 使用胰高血糖素样肽-1 受体激动剂（GLP-1RA）验证降糖药物对 CRC 的潜在机制。

结果：BMP4 在 CRC 患者中的表达上调，且在糖尿病患者中明显更高（P<0.05）。高葡萄糖诱导的胰岛素抵抗（IR）-CRC 细胞和糖尿病伴 CRC 转移模型的 BMP4 表达增加，激活了 BMP4-Smad1/5/8 通路，并通过上皮-间充质转化（EMT）改善了增殖和转移能力。并且，用外源性 BMP 抑制剂 Noggin 处理 CRC 细胞或用慢病毒（sh-BMP4）转染可阻断 IR 诱导的 CRC 细胞上调的转移能力。同时，高葡萄糖诱导的 IR 下调 GLP-1R，而 BMP4 抑制剂 noggin 上调 GLP-1R，并用 GLP-1RA 处理可通过下调 BMP4 抑制 IR 诱导的 CRC 细胞增殖。

结论：高葡萄糖增加的 BMP4 促进了 CRC 的 EMT。BMP4/Smad 通路的机制与高葡萄糖诱导的 IR-CRC 的易转移有关。常用的降糖药物 GLP-1RA 通过下调 BMP4 抑制 CRC 的生长并促进其凋亡。我们的研究结果表明，BMP4 可能成为糖尿病 CRC 患者的治疗靶点。