Liu Yiling, Qian Shengnan, Wei Jia, He Jianting, Li Minghui, Gao Xiaobing, Cai Hong, Wang Yiqing, Han Yue, Tan Tianyuan, Yang Minhui
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Biomedicines. 2025 May 17;13(5):1217. doi: 10.3390/biomedicines13051217.
Colorectal cancer (CRC) heterogeneity is strongly influenced by molecular subtypes and tumor stroma interactions. The meprin/A5/PTPmu (MAM) domain, a conserved structural motif in transmembrane proteins, remains undercharacterized in CRC pathogenesis. We analyzed RNA-seq data from TCGA-COAD to evaluate MAM domain gene expression. Immunohistochemistry and Western blotting were conducted to validate the results of the database analysis. Bioinformatics analysis revealed that MAM domain-containing protein 2 (MAMDC2) was enriched in mesenchymal subtype 4 (CMS4) colorectal cancer ( < 0.001). IHC confirmed MAMDC2 overexpression in MSS colorectal cancer with a high tumor stroma ratio (TSR) and peritoneal metastatic lesions ( < 0.01). WB and real-time PCR analyses confirmed that MAMDC2 has a role in regulating epithelial-mesenchymal transition (EMT) development in CRC. Importantly, we identified that cancer cell-derived MAMDC2 promotes MYLK expression in cancer-associated fibroblasts (CAFs) through paracrine signaling. Our findings suggest MAMDC2 may function as a stromal-associated regulator in MSS colorectal cancer with a high tumor stromal ratio (TSR).
结直肠癌（CRC）的异质性受到分子亚型和肿瘤基质相互作用的强烈影响。膜金属蛋白酶/载脂蛋白A5/跨膜蛋白酪氨酸磷酸酶μ（MAM）结构域是跨膜蛋白中一种保守的结构基序，在CRC发病机制中的特征仍不明确。我们分析了来自TCGA-COAD的RNA测序数据，以评估MAM结构域基因的表达。进行了免疫组织化学和蛋白质免疫印迹法以验证数据库分析结果。生物信息学分析显示，含MAM结构域蛋白2（MAMDC2）在间充质亚型4（CMS4）结直肠癌中富集（<0.001）。免疫组化证实MAMDC2在肿瘤基质比例（TSR）高的微卫星稳定（MSS）结直肠癌及腹膜转移灶中过表达（<0.01）。蛋白质免疫印迹法和实时定量聚合酶链反应分析证实MAMDC2在CRC上皮-间质转化（EMT）发展过程中发挥作用。重要的是，我们发现癌细胞来源的MAMDC2通过旁分泌信号促进癌症相关成纤维细胞（CAFs）中肌球蛋白轻链激酶（MYLK）的表达。我们的研究结果表明，MAMDC2可能在肿瘤基质比例（TSR）高的MSS结直肠癌中作为一种与基质相关的调节因子发挥作用。
