目的:恶性黑色素瘤是一种具有高转移特征的致命癌症。大约80%的皮肤癌死亡是由转移性黑色素瘤引起的。已经确定黑素瘤的转移能力受复杂的基因互连网络调节。因此,本研究的目的是鉴定和验证与转移性黑色素瘤相关的hub基因,并进一步阐明其潜在机制.
方法:应用加权基因共表达网络分析(WGCNA)方法探索潜在的调控靶点,并探讨与黑色素瘤转移能力相关的关键模块和hub基因之间的关系。
结果:在绿松石模块中,最初选择了26个hub基因,其中6个被鉴定为蛋白质-蛋白质相互作用网络中具有高连通性的“真实”集线器基因。在验证方面,在所有“真实”hub基因中,PKP1与转移的相关性最高。从GEPIA数据库和基因表达综合数据库获得的数据显示,与正常皮肤组织相比,在黑素瘤组织中PKP1的表达较低。结果还显示,与癌症基因组图谱(TCGA)数据库(n=470)中的原发性黑素瘤(n=103)相比,转移性黑素瘤(n=367)中的PKP1下调。此外,ROC曲线显示PKP1表达在原发性黑素瘤(p=5.30e-06,AUC=0.8)和转移性黑素瘤(p=1.13e-10,AUC=0.925)的诊断中均具有良好的功效.我们还发现PKP1可以区分低级和高级转移性黑色素瘤,并与炎性黑色素瘤有关。此外,在荷瘤小鼠模型中,黑色素瘤组织也显示PKP1的mRNA表达低于邻近正常皮肤。最后,基因组富集分析表明,在具有高表达的PKP1的转移性黑素瘤中,钙信号传导显著富集。
结论:PKP1被确定为人类黑色素瘤的一种新的潜在肿瘤抑制因子,可能通过调节钙信号通路。
OBJECTIVE: Malignant melanoma is a fatal cancer with high metastatic characteristics. Approximately 80% of skin cancer deaths are caused by metastatic melanoma. It has been established that the metastatic ability of melanoma is regulated by an intricate gene interconnection network. Thus, the aim of this study was to identify and validate hub genes associated with metastatic melanoma and to further illustrate its potential mechanisms.
METHODS: The method of weighted gene coexpression network analysis (WGCNA) was applied to explore potential regulatory targets and investigate the relationship between the key module and hub genes associated with the metastasis ability of melanoma.
RESULTS: In the turquoise module, 26 hub genes were initially selected, and 6 of them were identified as \"real\" hub genes with high connectivity in the protein-protein interaction network. In terms of validation,
PKP1 had the highest correlation with metastasis among all the \"real\" hub genes. Data obtained from the GEPIA database and the Gene Expression Omnibus database showed a lower expression of PKP1 in melanoma tissues compared to normal skin tissues. The results also showed that PKP1 was downregulated in metastatic melanomas (n = 367) compared with primary melanomas (n = 103) in The Cancer Genome Atlas (TCGA) database (n = 470). Furthermore, an ROC curve showed that
PKP1 expression had good power in the diagnostics of both primary melanoma (p = 5.30e-06, AUC = 0.8) and metastatic melanoma (p = 1.13e-10, AUC = 0.925). We also found that
PKP1 could distinguish low- and high-grade of metastatic melanomas and was associated with inflammatory melanoma. Moreover, in a tumor-bearing mouse model, melanoma tissues also showed lower mRNA expression of
PKP1 than the adjacent normal skin. Finally, Gene Set Enrichment Analysis indicated that the calcium signaling was significantly enriched in metastatic melanoma with highly expressed
PKP1.
CONCLUSIONS: PKP1 was identified as a new potential tumor suppressor in human melanoma, likely through regulating calcium signaling pathways.