Table4_Comprehensive analysis of LAMC1 expression and prognostic value in kidney renal papillary cell carcinoma and clear cell carcinoma.XLSX

Background: Laminin subunit gamma 1 (LAMC1) protein is associated with tumor cell invasion and metastasis. However, its role in kidney cancer remains unclear. In this work, we sought to probe the expression as well as its carcinogenic mechanisms of LAMC1 in kidney renal papillary cell carcinoma (KIRP) and kidney renal clear cell carcinoma (KIRC).
Methods: Public databases including TIMER, Oncomine, UALCAN, TISIDB, TCGA, Kaplan–Meier plotter, UCSC Xena, cBioPortal, SurvivalMeth, KEGG, GeneMANIA, Metascape, GSCALite and GDSC were adopted, and the expression, clinical pathological correlation, prognostic signatures, dominant factors influencing LAMC1 expression, DNA methylation levels, gene mutations, copy number variations, functional networks, and drug sensitivity were analyzed. Expression of LAMC1 protein in clinical KIRP and KIRC was validated using tissue array.
Results:LAMC1 expression in KIRP and KIRC were significantly higher than those in normal tissues. High LAMC1 expression indicated poor overall survival in KIRP patients and better overall survival in KIRC patients. Through the univariate and multivariate Cox analysis, we found that high LAMC1 expression was a potential independent marker for poor prognosis in KIRP, however it implied a better prognosis in KIRC by univariate Cox analysis. In addition, the LAMC1 expression in KIRP and KIRC was negatively correlated with methylation levels of LAMC1 DNA. Interestingly, LAMC1 expression was positively correlated with the infiltration of CD8+ T cells, dendritic cells and neutrophils in KIRP; however, it was positively correlated with the infiltration of CD4+ T cells, macrophages and neutrophils but negatively correlated with B cells in KIRC. Moreover, high level of CD8+ T cells is beneficial for KIRC prognosis but opposite for KIRP. LAMC1 may participate in signaling pathways involved in formation of adherens junction and basement membrane in KIRP and KIRC, and the high expression of LAMC1 is resistant to most drugs or small molecules of the Genomics of Drug Sensitivity in Cancer database.
Conclusion: Enhanced LAMC1 expression suggests a poor prognosis in KIRP while a better prognosis in KIRC, and these opposite prognostic signatures of LAMC1 may be related to different immune microenvironments.

背景：层粘连蛋白γ1亚基（Laminin subunit gamma 1, LAMC1）蛋白与肿瘤细胞侵袭及转移密切相关，但其在肾癌中的作用尚未明确。本研究旨在探讨层粘连蛋白γ1亚基（LAMC1）在肾乳头状细胞癌（kidney renal papillary cell carcinoma, KIRP）及肾透明细胞癌（kidney renal clear cell carcinoma, KIRC）中的表达情况及其致癌机制。
方法：本研究采用包括TIMER、Oncomine、UALCAN、TISIDB、癌症基因组图谱（The Cancer Genome Atlas, TCGA）、Kaplan–Meier绘图器（Kaplan–Meier plotter）、UCSC Xena、cBioPortal、SurvivalMeth、京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）、GeneMANIA、Metascape、GSCALite以及癌症药物敏感性基因组学数据库（Genomics of Drug Sensitivity in Cancer, GDSC）在内的多个公共数据库，对LAMC1的表达水平、临床病理相关性、预后特征、影响LAMC1表达的主导因素、DNA甲基化水平、基因突变、拷贝数变异、功能调控网络以及药物敏感性展开分析。同时，本研究通过组织芯片验证了LAMC1蛋白在临床KIRP及KIRC样本中的表达情况。
结果：KIRP及KIRC组织中LAMC1的表达水平显著高于正常对照组织。高表达LAMC1的KIRP患者总体生存期较差，而KIRC患者高表达LAMC1则总体生存期更佳。经单因素及多因素Cox回归分析发现，LAMC1高表达是KIRP患者不良预后的潜在独立标志物；而单因素Cox分析显示，LAMC1高表达与KIRC患者更优的预后相关。此外，KIRP及KIRC组织中LAMC1的表达水平与该基因DNA甲基化水平呈负相关。值得注意的是，KIRP组织中LAMC1的表达与CD8+T细胞、树突状细胞及中性粒细胞的浸润程度呈正相关；而在KIRC组织中，LAMC1的表达与CD4+T细胞、巨噬细胞及中性粒细胞的浸润程度呈正相关，与B细胞浸润程度呈负相关。此外，高浸润水平的CD8+T细胞对KIRC患者预后有益，但对KIRP患者预后则产生不利影响。LAMC1可能参与KIRP及KIRC中黏着连接与基底膜形成相关的信号通路，且LAMC1高表达对癌症药物敏感性基因组学数据库中的多数药物及小分子化合物均表现出耐药性。
结论：LAMC1表达上调提示KIRP患者预后不良，而KIRC患者则预后更佳，LAMC1的这种相反的预后特征可能与两种肿瘤不同的免疫微环境密切相关。