Reduced expression of IQGAP2 and higher expression of IQGAP3 correlates with poor prognosis in cancers

IQGAPs is a family of proteins which comprises three members, in humans. The expression pattern and role of IQGAP1 has been well established in many cancers, whereas those of IQGAP2 and IQGAP3, have mostly remained unexplored. We used available large datasets, to explore the pan-cancer status of these two genes in-silico. Here we have analysed their mRNA expression and correlation with survivability in eight different cancers, including lung, breast, gastric, brain, colorectal, prostate, liver and kidney cancers and, their subtypes. The mRNA expression of IQGAP2 and IQGAP3 in individual cancers were analysed in two different publicly available databases viz. Oncomine and TCGA. The prognostic value of these genes in lung, breast and gastric cancer was analysed using Kaplan-Meier Plotter database, whereas for brain, colorectal, liver, prostate and kidney cancers, SurvExpress database was used. These results were validated by immunohistochemistry in cancer tissues (stomach, prostate, brain, colorectal). Moreover, we did IQGAP2 and IQGAP3 genomic alteration and, promoter methylation analysis using cBioportal and Wanderer web tool, respectively. Most of the cancer types (lung, breast, prostate, brain, gastric, liver, kidney and colorectal) showed increased IQGAP3 mRNA expression. In contrast, the IQGAP2 transcript levels were reduced across different cancers viz. lung, breast, gastric, liver, kidney and colorectal cancer. IQGAP2 expression correlated positively with survivability, on the contrary, IQGAP3 expression levels correlated inversely with survivability, in most of the cancers. Collectively, enhanced IQGAP3 and reduced IQGAP2 levels were frequently observed in multiple cancers with the former predicting poor survivability and the later opposite. Methylation pattern was significantly altered in most of the cancer types. We found copy no. variation and mutations in specific cancers, for IQGAP2 and IQGAP3. Our in-vivo (IHC) data confirmed the in-silico findings completely. Hence, IQGAP2 and IQGAP3 have potential to be used as prognostic markers or therapeutic targets in specific cancers.

IQGAPs是一类蛋白质家族，在人类中共包含三个成员。IQGAP1的表达模式与功能已在多种癌症中得到充分阐明，而IQGAP2与IQGAP3的相关研究则大多尚未得到深入探索。本研究借助现有大型公共数据集，对这两个基因的in silico（硅基）泛癌表达状态开展了探究。我们分析了它们在8种不同癌症（包括肺癌、乳腺癌、胃癌、脑癌、结直肠癌、前列腺癌、肝癌及肾癌）及其亚型中的mRNA表达水平，以及与患者生存率的相关性。IQGAP2与IQGAP3在各单一癌种中的mRNA表达情况，分别通过Oncomine与TCGA（癌症基因组图谱，The Cancer Genome Atlas）两个公开数据库进行了分析。针对肺癌、乳腺癌和胃癌，我们采用Kaplan-Meier Plotter数据库分析了这两个基因的预后价值；而对于脑癌、结直肠癌、肝癌、前列腺癌及肾癌，则使用SurvExpress数据库完成了相关分析。上述结果通过immunohistochemistry（免疫组化，IHC）在癌症组织（胃、前列腺、脑、结直肠组织）中得到了验证。此外，我们还分别借助cBioportal与Wanderer网页工具，对IQGAP2和IQGAP3的基因组改变及启动子甲基化水平进行了分析。大多数癌种（肺癌、乳腺癌、前列腺癌、脑癌、胃癌、肝癌、肾癌及结直肠癌）中，IQGAP3的mRNA表达水平显著升高；与之相反，在肺癌、乳腺癌、胃癌、肝癌、肾癌及结直肠癌等多种癌种中，IQGAP2的转录本水平则显著降低。IQGAP2的表达与患者生存率呈正相关，而IQGAP3的表达水平则与大多数癌种的患者生存率呈负相关。综上，在多种癌症中均频繁观察到IQGAP3表达上调、IQGAP2表达下调的现象：前者提示患者预后不良，后者则与之相反。大多数癌种的甲基化模式均发生了显著改变。我们还在特定癌种中发现了IQGAP2与IQGAP3的拷贝数变异及突变情况。本研究的in vivo（体内）免疫组化实验数据完全验证了in silico分析结果。因此，IQGAP2与IQGAP3有望成为特定癌症的预后标志物或治疗靶点。