Liu Fangteng, Wu Hengyu
Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang 330009, Jiangxi, People's Republic of China.
Faculty of Medicine, University of Munich, Munich 80336, Germany.
J Inflamm Res. 2021 Jan 14;14:97-114. doi: 10.2147/JIR.S284889. eCollection 2021.
Janus kinases (JAKs) are a family of non-receptor tyrosine kinases involved in multiple malignancies. However, clinical values of JAKs as prognostic markers and potential mechanism as molecular targets in breast invasive carcinoma (BC) are not completely clarified.
TIMER, UALCAN and GEPIA were used to assess the expression and methylation levels of JAKs in BC. Kaplan-Meier Plotter, bc-GenExMiner, SurvExpress, TRGAted, MethSurv, and SurvivalMeth were used to assess the multilevel prognostic significance of JAKs in breast cancer patients. And cBioPortal, TIMER, STRING, GeneMANIA, NetworkAnalysis, LinkedOmics, DAVID 6.8, and Metascape were applied for multilayer networks and functional enrichment analyses. Correlations between immune cell infiltrates/their gene markers and JAKs were evaluated by TIMER.
We first explored the expression and methylation level of JAKs in breast cancer and found significantly reduced JAK1 and JAK2 expression at mRNA and protein levels, significantly higher JAK3 protein expression, and significantly increased TYK2 expression at mRNA level but decreased at protein level. In addition, hypermethylation of JAK3 and TYK2 and hypomethylation of JAK1 were found in tumor samples. In terms of prognostic values of JAKs in BC patients, low transcriptional levels of JAK1, JAK2, JAK3, and TYK2 indicated worse OS/DMFS/PPS/RFS/DFS, inferior DFS, worse RFS, and shorter OS/DMFS/RFS, respectively. The mRNA signature analysis showed that high-risk group had unfavorable OS/RFS/MFS. Low JAK2 protein level indicated unfavorable DSS/PFS in BC patients. Five CpGs of JAK1, four CpGs of JAK2, 20 CpGs of JAK3, and 13 CpGs of TYK2 were significantly associated with prognosis in BC patients. The DNA methylation signature analysis also suggested worse prognosis in the high-risk group. For potential biological roles of JAKs, interaction analyses, functional enrichment analyses for biological process, cellular component, molecular function, and KEGG pathway analyses of JAKs and their neighbor genes in BC were conducted. Kinase targets, gene-miRNA interactions, and transcription factor-gene interactions of JAKs were also identified. Furthermore, JAKs were found to be significantly related to immune infiltrates as well as the expression levels of multiple immune markers in BC.
JAKs showed multilevel prognostic value and important biological roles in BC. They might serve as promising prognostic markers and possible targets in breast cancer.
Janus激酶（JAKs）是一类参与多种恶性肿瘤的非受体酪氨酸激酶。然而，JAKs作为预后标志物的临床价值以及在乳腺浸润性癌（BC）中作为分子靶点的潜在机制尚未完全阐明。
使用TIMER、UALCAN和GEPIA评估BC中JAKs的表达和甲基化水平。使用Kaplan-Meier Plotter、bc-GenExMiner、SurvExpress、TRGAted、MethSurv和SurvivalMeth评估JAKs在乳腺癌患者中的多层次预后意义。并应用cBioPortal、TIMER、STRING、GeneMANIA、NetworkAnalysis、LinkedOmics、DAVID 6.8和Metascape进行多层网络和功能富集分析。通过TIMER评估免疫细胞浸润/其基因标志物与JAKs之间的相关性。
我们首先探究了BC中JAKs的表达和甲基化水平，发现JAK1和JAK2在mRNA和蛋白质水平的表达显著降低，JAK3蛋白表达显著升高，TYK2在mRNA水平表达显著增加但在蛋白质水平降低。此外，在肿瘤样本中发现JAK3和TYK2的高甲基化以及JAK1的低甲基化。就JAKs在BC患者中的预后价值而言，JAK1、JAK2、JAK3和TYK2的低转录水平分别表明总生存期/远处无复发生存期/无进展生存期/无复发生存期/疾病无进展生存期更差、疾病无进展生存期更差、无复发生存期更差以及总生存期/远处无复发生存期/无复发生存期更短。mRNA特征分析表明高危组的总生存期/无复发生存期/无转移生存期不佳。低JAK2蛋白水平表明BC患者的疾病特异性生存期/无进展生存期不佳。JAK1的5个CpG、JAK2的4个CpG、JAK3的20个CpG和TYK2的13个CpG与BC患者预后显著相关。DNA甲基化特征分析也表明高危组预后更差。对于JAKs的潜在生物学作用，进行了BC中JAKs及其邻近基因的相互作用分析、生物学过程、细胞成分、分子功能的功能富集分析以及KEGG通路分析。还鉴定了JAKs的激酶靶点、基因- miRNA相互作用和转录因子-基因相互作用。此外，发现JAKs与BC中的免疫浸润以及多种免疫标志物的表达水平显著相关。
JAKs在BC中显示出多层次预后价值和重要生物学作用。它们可能是有前景的预后标志物和乳腺癌的潜在靶点。
