Tombaz Melike, Yanyatan Cagdas, Keskus Ayse Gokce, Konu Ozlen
Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
Neuroscience Program, Bilkent University, Ankara, Turkey.
Bioelectricity. 2022 May 26;4(2):92-102. doi: 10.1089/bioe.2022.0013. eCollection 2022 May.
Regulation of intracellular calcium concentrations, is important in maintaining the viability of normal as well as cancer cells and can be mediated by tumor microenvironment. Calcium release-activated calcium channel protein (ORAI) calcium channels on the plasma membrane (PM) become physically connected by stromal interaction molecules (STIMs) to the endoplasmic reticulum (ER), on which paralogous receptors of inositol phosphate and of ryanodine are also present along with ATP2A/SERCA (sarco/endoplasmic reticulum calcium ATPases) subunits (also known as PM-ER geneset). Proper expression of this functionally and physically interconnected geneset is essential for the maintenance of , yet has not been interrogated as a whole for its role in cancer prognosis using multivariable Cox regression. In the present study, we examined whether the expression profile of the PM-ER geneset exhibited prognostic significance across different cancers found in The Cancer Genome Atlas (TCGA) by generating gene-cancer-by-survival networks, in which the nodes represented either genes or cancers and the edges, the logarithmically transformed hazard ratios for overall survival (OS). We then applied network clustering to identify the gene-cancer subnetworks with high connectivity, among which uveal melanoma (UVM) emerged exhibiting the highest degree of genes ( = 10). , a well-known regulator and a tumor suppressor, was not found to be significant in predicting OS by PM-ER geneset for UVM, yet it was for several others, including mesothelioma (MESO). Moreover, the best subset of the PM-ER geneset obtained by lasso predicted OS in the TCGA UVM cohort with an area under the receiver operating characteristics (AUC) of 91.4%, comparable to or better than previous prognostic signatures in the literature. Our findings indicate that homeostasis of is an essential determinant of prognosis in multiple cancers and particularly in UVM. The proposed gene-cancer-by-survival network approach can be extended with other gene sets as well as different survival types.
细胞内钙浓度的调节对于维持正常细胞和癌细胞的活力都很重要，并且可能由肿瘤微环境介导。质膜（PM）上的钙释放激活钙通道蛋白（ORAI）钙通道通过基质相互作用分子（STIM）与内质网（ER）建立物理连接，内质网上还存在肌醇磷酸和兰尼碱的同源受体以及ATP2A/ SERCA（肌浆/内质网钙ATP酶）亚基（也称为PM-ER基因集）。这个功能和物理上相互连接的基因集的正确表达对于维持……至关重要，但尚未使用多变量Cox回归对其在癌症预后中的作用进行整体研究。在本研究中，我们通过生成基因-癌症-生存网络来检查PM-ER基因集的表达谱在《癌症基因组图谱》（TCGA）中发现的不同癌症中是否具有预后意义，其中节点代表基因或癌症，边代表总生存（OS）的对数转换风险比。然后，我们应用网络聚类来识别具有高连通性的基因-癌症子网，其中葡萄膜黑色素瘤（UVM）出现的基因数量最多（n = 10）。……，一种著名的……调节剂和肿瘤抑制因子，在通过PM-ER基因集预测UVM的OS时未发现具有显著性，但在其他几种癌症中具有显著性，包括间皮瘤（MESO）。此外，通过套索回归获得的PM-ER基因集的最佳子集在TCGA UVM队列中预测OS的受试者工作特征曲线下面积（AUC）为91.4%，与文献中先前的预后特征相当或更好。我们的研究结果表明，……的稳态是多种癌症尤其是UVM预后的重要决定因素。所提出的基因-癌症-生存网络方法可以扩展到其他基因集以及不同的生存类型。
