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Abstract：
Skin cutaneous melanoma (SKCM) is a highly malignant form of skin cancer, known for its unfavorable prognosis and elevated mortality rate. RARRES1, a gene responsive to retinoic acid receptors, displays varied functions in various cancer types. However, the specific role and underlying mechanisms of RARRES1 in SKCM are still unclear. GSE15605 was utilized to analyze the expression of RARRES1 in SKCM. Subsequently, the TCGA and GEO databases were employed to investigate the relationships between RARRES1 and clinicopathological parameters, as well as the prognostic implications and diagnostic efficacy of RARRES1 in SKCM. GO, KEGG, and GSEA analyses were conducted to explore the potential functions of RARRES1. Furthermore, the associations between RARRES1 and immune infiltration were examined. Genomic alterations and promoter methylation levels of RARRES1 in SKCM were assessed using cBioPortal, UALCAN, and the GEO database. Finally, RARRES1 expression in SKCM was validated through immunohistochemistry, and its functional role in SKCM progression was elucidated via in vivo and in vitro experiments. We found that RARRES1 was downregulated in SKCM compared with normal tissues, and this low expression was associated with worse clinicopathological features and poor prognosis of SKCM. The diagnostic efficacy of RARRES1, as determined by ROC analysis, was 0.732. Through GO, KEGG, and GSEA enrichment analysis, we identified 30 correlated genes and pathways that were mainly enriched in the tumor immune microenvironment, proliferation, apoptosis, and autophagy. Additionally, RARRES1 expression was found to be positively related to the infiltration of various immune cells in SKCM, particularly macrophages and T helper cells, among others. Analysis of genomic alterations and promoter methylation revealed that shallow deletion and hypermethylation of the RARRES1 promoter could lead to reduced RARRES1 expression. IHC validation confirmed the downregulation of RARRES1 in SKCM. Moreover, overexpression of RARRES1 inhibited the proliferation and migration of A375 cells, promoted apoptosis, and inhibited autophagic flux. In the mouse xenograft model, RARRES1 overexpression also suppressed SKCM tumor growth. Collectively, these findings suggest that RARRES1 may function as a suppressor and could potentially serve as a prognostic biomarker and therapeutic target for SKCM.
摘要：
皮肤黑素瘤（SKCM）是一种高度恶性的皮肤癌，以预后不良和死亡率升高而闻名。RARRES1，一种对视黄酸受体有反应的基因，在各种癌症类型中显示不同的功能。然而,RARRES1在SKCM中的具体作用和潜在机制尚不清楚。GSE15605用于分析RARRES1在SKCM中的表达。随后，TCGA和GEO数据库用于研究RARRES1与临床病理参数之间的关系，以及RARRES1在SKCM中的预后意义和诊断效能。GO,KEGG,进行GSEA分析以探索RARRES1的潜在功能。此外，研究了RARRES1与免疫浸润之间的关联.使用cBioPortal评估SKCM中RARRES1的基因组改变和启动子甲基化水平，UALCAN,和GEO数据库。最后,通过免疫组织化学验证SKCM中RARRES1的表达，通过体内和体外实验阐明了其在SKCM进展中的功能作用。我们发现与正常组织相比，RARRES1在SKCM中下调，这种低表达与SKCM的临床病理特征较差和预后不良有关。通过ROC分析确定RARRES1的诊断效能，是0.732。通过GO，KEGG,和GSEA富集分析，我们确定了30个主要富集在肿瘤免疫微环境中的相关基因和通路，扩散,凋亡，和自噬。此外,发现RARRES1表达与SKCM中各种免疫细胞的浸润呈正相关，特别是巨噬细胞和T辅助细胞，在其他人中。基因组改变和启动子甲基化的分析表明，RARRES1启动子的浅缺失和超甲基化可能导致RARRES1表达降低。IHC验证证实了SKCM中RARRES1的下调。此外，过表达RARRES1抑制A375细胞的增殖和迁移,促进细胞凋亡，并抑制自噬通量。在小鼠异种移植模型中,RARRES1过表达也抑制SKCM肿瘤生长。总的来说，这些研究结果表明,RARRES1可能起到抑制因子的作用,并可能作为SKCM的预后生物标志物和治疗靶点.
