Abstract
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.
Highlights
IQGAPs (IQ Motif Containing GTPase Activating Proteins) are evolutionarily conserved proteins [1]
We focused our analysis on overall patient survival (OS), first progression (FP), post progression survival (PPS), distance metastasis free survival (DMFS) and relapse free survival (RFS), using best JetSet probe
Oncomine was used to find out differences in mRNA expression of IQGAP2 and IQGAP3, between tumor and normal tissue, in multiple cancers (Fig 1)
Summary
IQGAPs (IQ Motif Containing GTPase Activating Proteins) are evolutionarily conserved proteins [1]. In majority of the vertebrates, three related isoforms of IQGAP protein family viz. IQGAP1, IQGAP2 and IQGAP3 are expressed. The two other members IQGAP2 and IQGAP3 were identified later and their expression is limited to some organs i.e. liver, gastric, prostate, brain, lung and testis [3,4,5,6,7]. All these members share high identity in five conserved domains viz. Despite of sharing five highly identical domains, the roles of these isoforms vary significantly [1]
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