Pang Jinlong, Zhao Xinli, Zhang Zhen, Wang Haojie, Zhou Xingqi, Yang Yumei, Li Shanshan, Chang Xiaoqiang, Li Feng, Li Xian
School of Pharmacy, Bengbu Medical University.
Anhui Provincial Engineering Research Center for Biochemical Pharmaceuticals, Bengbu 233030, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jul 20;45(7):1479-1489. doi: 10.12122/j.issn.1673-4254.2025.07.14.
OBJECTIVES: To investigate the inhibitory effect of multimerin-2 (MMRN2) overexpression on growth and metastasis of cutaneous melanoma cells. METHODS: Clinical data of patients with cutaneous melanoma were obtained from the GEO database to compare MMRN2 expressions between normal and tumor tissues. A protein-protein interaction network was constructed using the STRING database, and the intersecting genes from GEPIA2.0 were subjected to GO and KEGG enrichment analysis. The prognostic relevance of MMRN2 expression level was assessed using Cox regression and "timeROC". The correlations of MMRN2 expression level with immune infiltration and angiogenesis-related genes were analyzed using GSCA database and the ssGSEA algorithm. Colony-forming assay, Transwell assay, and wound healing assay were used to examine the changes in proliferation and migration of cultured cutaneous melanoma cells following MMRN2 knockdown. In a mouse model bearing cutaneous melanoma xenograft, the effect of MMRN2 knockdown on vital organ pathologies, survival of the mice and GM-CSF, CXCL9, and TGF‑β1 protein expressions were analyzed. RESULTS: MMRN2 was significantly upregulated in metastatic cutaneous melanoma (<0.001). Protein interaction network analysis identified 15 intersecting genes, which were enriched in endothelium development and cell-cell junctions. In patients with cutaneous melanoma, a high MMRN2 expression was correlated with a poor prognosis, an advanced T stage, a greater Breslow depth, and ulceration (<0.05). MMRN2 expression level was strongly correlated with 24 immune cell types (<0.001), fibroblasts, endothelial cells, and expressions of the pro-angiogenic genes (KCNJ8, SLCO2A1, NRP1, and COL3A1; <0.001). In cultured B16F10 cells, MMRN2 knockdown significantly suppressed cell proliferation, migration and invasion and caused remo-deling of the immunosuppressive microenvironment. CONCLUSIONS: MMRN2 overexpression drives progression of cutaneous melanoma by enhancing tumor metastasis, angiogenesis and immune evasion, highlighting its potential as a therapeutic target for melanomas.
目的：研究多聚蛋白-2（MMRN2）过表达对皮肤黑色素瘤细胞生长和转移的抑制作用。 方法：从GEO数据库获取皮肤黑色素瘤患者的临床数据，比较正常组织和肿瘤组织中MMRN2的表达。使用STRING数据库构建蛋白质-蛋白质相互作用网络，并对GEPIA2.0中的交集基因进行GO和KEGG富集分析。使用Cox回归和“timeROC”评估MMRN2表达水平的预后相关性。使用GSCA数据库和ssGSEA算法分析MMRN2表达水平与免疫浸润和血管生成相关基因的相关性。采用集落形成试验、Transwell试验和伤口愈合试验检测MMRN2敲低后培养的皮肤黑色素瘤细胞增殖和迁移的变化。在携带皮肤黑色素瘤异种移植的小鼠模型中，分析MMRN2敲低对重要器官病理、小鼠存活以及GM-CSF、CXCL9和TGF-β1蛋白表达的影响。 结果：MMRN2在转移性皮肤黑色素瘤中显著上调（<0.001）。蛋白质相互作用网络分析确定了15个交集基因，这些基因富集于内皮发育和细胞-细胞连接。在皮肤黑色素瘤患者中，MMRN2高表达与预后不良、T分期进展、Breslow深度增加和溃疡相关（<0.05）。MMRN2表达水平与24种免疫细胞类型（<0.001）、成纤维细胞、内皮细胞以及促血管生成基因（KCNJ8、SLCO2A1、NRP1和COL3A1；<0.001）的表达密切相关。在培养的B16F10细胞中，MMRN2敲低显著抑制细胞增殖、迁移和侵袭，并导致免疫抑制微环境重塑。 结论：MMRN2过表达通过增强肿瘤转移、血管生成和免疫逃逸驱动皮肤黑色素瘤进展，突出了其作为黑色素瘤治疗靶点的潜力。
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