Wu Lingxia, Liu Chenxiaoxiao, Hu Weicai
Dermatology, Changzhi Second People's Hospital, Changzhi, 046000, Shanxi, China.
The First Clinical Institute, Zunyi Medical University, Zunyi, 520300, Guizhou, China.
Sci Rep. 2025 Jan 16;15(1):2152. doi: 10.1038/s41598-025-85887-2.
The dysregulation of matrix metalloproteinases (MMPs) in skin cutaneous melanoma (SKCM) represents a critical aspect of tumorigenesis. In this study, we investigated the diagnostic, prognostic, and therapeutic aspects of the MMPs in SKCM. Thirteen SKCM cell lines and seven normal skin cell lines were cultured under standard conditions for experimental analyses. RNA and DNA were extracted, followed by RT-qPCR to assess MMP expression and promoter methylation analysis to determine methylation levels. Functional assays, including cell proliferation, colony formation, and wound healing, were conducted post-MMP7 knockdown using siRNA in A375 cells. Databases like GEPIA2, HPA, MEXPRESS, and miRNet were employed for expression, survival, methylation, and miRNA-mRNA network analyses. We investigated the expression and promoter methylation landscape of MMPs in SKCM cell lines, revealing significant (p-value < 0.05) up-regulation of MMP1, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, and MMP25, alongside down-regulation of MMP2, MMP3, and MMP21. Furthermore, our analysis demonstrated a significant (p-value < 0.05) inverse correlation between MMP expression levels and promoter methylation status, suggesting a potential regulatory role of DNA methylation in MMP dysregulation. Notably, MMP7, MMP11, and MMP14 exhibited significant (p-value < 0.05) associations with the overall survival of SKCM patients, emphasizing their prognostic significance. Additionally, Receiver operating characteristic (ROC) curve analysis highlighted the significant (p-value < 0.05) diagnostic potential of MMP7, MMP11, and MMP14 in distinguishing SKCM from normal individuals. Subsequent validation across multiple cohorts confirmed significant (p-value < 0.05) elevated MMP expression levels in SKCM tissues, particularly in advanced disease stages, further emphasizing their role in tumor progression. Furthermore, we elucidated potential regulatory pathways involving miR-22-3p, which targets MMP7, MMP11, and MMP14 genes in SKCM. Our findings also revealed associations between MMP expression and immune modulation, drug sensitivity, and functional states of SKCM cells. Lastly, MMP7 knockdown in A375 cells significantly significant (p-value < 0.05) impacted several characteristics, including cell proliferation, colony formation, and wound healing. Our findings highlight the diagnostic, prognostic, and therapeutic potential of MMP7, MMP11, and MMP14 in SKCM. These MMPs could serve as biomarkers for early detection and targets for therapy. Future efforts should focus on preclinical and clinical validation to translate these insights into personalized diagnostic and therapeutic strategies.
基质金属蛋白酶（MMPs）在皮肤黑色素瘤（SKCM）中的失调是肿瘤发生的一个关键方面。在本研究中，我们调查了MMPs在SKCM中的诊断、预后和治疗方面。在标准条件下培养13种SKCM细胞系和7种正常皮肤细胞系用于实验分析。提取RNA和DNA，随后进行RT-qPCR以评估MMP表达，并进行启动子甲基化分析以确定甲基化水平。在A375细胞中使用siRNA敲低MMP7后进行功能测定，包括细胞增殖、集落形成和伤口愈合。使用GEPIA2、HPA、MEXPRESS和miRNet等数据库进行表达、生存、甲基化和miRNA-mRNA网络分析。我们研究了SKCM细胞系中MMPs的表达和启动子甲基化情况，发现MMP1、MMP7、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14和MMP25显著上调（p值<0.05），同时MMP2、MMP3和MMP21下调。此外，我们的分析表明MMP表达水平与启动子甲基化状态之间存在显著的负相关（p值<0.05），表明DNA甲基化在MMP失调中可能具有调节作用。值得注意的是，MMP7、MMP11和MMP14与SKCM患者的总生存期显著相关（p值<0.05），强调了它们的预后意义。此外，受试者工作特征（ROC）曲线分析突出了MMP7、MMP11和MMP14在区分SKCM与正常个体方面的显著诊断潜力（p值<0.05）。在多个队列中的后续验证证实，SKCM组织中MMP表达水平显著升高（p值<0.05），特别是在疾病晚期，进一步强调了它们在肿瘤进展中的作用。此外，我们阐明了涉及miR-22-3p的潜在调控途径，其在SKCM中靶向MMP7、MMP
