The IQGAP1-Claudin4-JNK Signaling Axis as a Differential Biomarker in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a highly heterogeneous malignant neoplasm with multiple morphological and molecular subtypes; however, the basis of this heterogeneity remains incompletely defined, hindering effective diagnosis and treatment. The signaling scaffold IQGAP1 and claudins are tight junction protein partners involved in epithelial cell polarity and polarized secretion whose overexpression has been associated with RCC, though the molecular mechanism is obscure. RNA-seq data on the TCGA database shows that the RNA expression levels of IQGAP1 and claudin-2, -4, and -8 differentially change significantly in normal versus RCC tumors, suggesting a regulatory loop between IQGAP1 and each of these claudins. Previously, we reported that IQGAP1 differentially regulates claudin -2 and -4 localization and expression at the tight junctions and imparts on kidney epithelial structure and function. Here, we show that IQGAP1 localization, and not mere expression level, accompanies RCC phenotypes and differential expression of several junctional proteins where claudin-4 localization remains intact or stabilized. Notably, IQGAP1 expression appears inversely correlated with that of claudin-4, supporting a dynamic interaction at the tight junctions. These findings support the notion that IQGAP1 localization influences claudin dynamics, and its dysfunction imparts on RCC. Altogether, these findings pave the way for exploring the differential expression and localization of the IQGAP1/claudin complex as personalized diagnostics or therapeutics to address RCC heterogeneity.