Gao Mengru, Liu Jisong, Yang Miaomiao, Zhang Xiangzhou, Zhang Yulian, Zhou Zhuliang, Deng Jiabin
Clinical Pathology Center, The First Affiliated Hospital of Anhui Medical University Hefei 230012, Anhui, China.
Anhui Public Health Clinical Center Hefei 230012, Anhui, China.
Am J Cancer Res. 2024 Aug 25;14(8):3665-3693. doi: 10.62347/ECDF2762. eCollection 2024.
Skin cutaneous melanoma (SKCM) is a highly fatal form of skin cancer that develops from the malignant transformation of epidermal melanocytes. There is substantial evidence linking autophagy to cancer etiology and immunotherapy efficacy. This study aimed to conduct a comprehensive analysis of autophagy-related genes (ARGs) using TCGA datasets and further explore the potential function of critical ARGs in SKCM progression. We performed comprehensive bioinformatics analysis uses the TCGA dataset. RT-PCR was applied to examine the expression of CAPNS1 in SKCM cells. Lost-of-function experiments were performed to detect the expression of the related proteins. In this search, we screed 70 differentially expressed autophagy-related genes (DE-ARGs), including 33 up-DE-ARGs and 37 down-DE-ARGs. Enrichment assays revealed that these 70 DE-ARGs may exert influence on critical cellular processes such as autophagy, protein kinase activity, and signaling pathways, impacting cell growth, differentiation, survival, and tumor development. Then, we further explore the prognostic value of 70 DE-ARGs and confirmed 18 survival-related DE-ARGs in SKCM patients. Nearly all the 18 DE-ARGs' methylation was negatively correlated with their corresponding expression in SKCM. The 12 survival-related DE-ARGs were used to develop a unique predictive model that effectively classified SKCM patients into high- and low-risk groups with regard to overall survival. Furthermore, tumor environment analysis indicated that the risk score was associated with several immune cells. Among the 12 survival-related DE-ARGs, our attention focused on CAPNS1 which was highly expressed in SKCM patients and predicted a poor prognosis. In addition, we confirmed that knockdown of CAPNS1 distinctly suppressed the proliferation, metastasis and EMT of SKCM cells, and promoted autophagy via regulating Notch signaling pathway. Overall, this study enhances our understanding of the intricate molecular landscape of SKCM progression and presents promising avenues for future research and clinical applications.
皮肤黑色素瘤（SKCM）是一种高度致命的皮肤癌，由表皮黑素细胞的恶性转化发展而来。有大量证据表明自噬与癌症病因和免疫治疗疗效有关。本研究旨在利用TCGA数据集对自噬相关基因（ARGs）进行全面分析，并进一步探索关键ARGs在SKCM进展中的潜在功能。我们使用TCGA数据集进行了全面的生物信息学分析。应用RT-PCR检测SKCM细胞中CAPNS1的表达。进行功能丧失实验以检测相关蛋白的表达。在这项研究中，我们筛选出70个差异表达的自噬相关基因（DE-ARGs），包括33个上调的DE-ARGs和37个下调的DE-ARGs。富集分析表明，这70个DE-ARGs可能对自噬、蛋白激酶活性和信号通路等关键细胞过程产生影响，从而影响细胞生长、分化、存活和肿瘤发展。然后，我们进一步探讨了70个DE-ARGs的预后价值，并在SKCM患者中确认了18个与生存相关的DE-ARGs。在SKCM中，几乎所有18个DE-ARGs的甲基化与其相应表达呈负相关。这12个与生存相关的DE-ARGs被用于建立一个独特的预测模型，该模型能够有效地将SKCM患者按总生存期分为高风险和低风险组。此外，肿瘤环境分析表明风险评分与几种免疫细胞有关。在这12个与生存相关的DE-ARGs中，我们重点关注了在SKCM患者中高表达且预后不良的CAPNS1。此外，我们证实敲低CAPNS1可明显抑制SKCM细胞的增殖、转移和上皮-间质转化，并通过调节Notch信号通路促进自噬。总体而言，本研究加深了我们对SKCM进展复杂分子格局的理解，并为未来的研究和临床应用提供了有前景的途径。
