Mahasin A. Osman

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.

Dysfunction of epithelial cell contacts associates with a myriad of human diseases. Cisplatin is an effective antineoplastic agent where it interferes with

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Translation: The University of Toledo Journal of Medical Sciences is the online journal launched by the University of Toledo. Manuscripts will be considered on the understanding that they report original work and are not under consideration for publication by any other journal. The journal publishes original articles reporting experimental results of basic or clinical research, case reports, and reviews. The journal uses a single blind peer review system and each manuscript, based on the results presented in its original submission, will be evaluated by two student reviewers and one faculty reviewer. This process will provide an opportunity for medical students, graduate students, residents, fellows and faculty to publish research observation in a timely manner.

Kidney damage resulting from nephrotoxicity is a major side effect of chemotherapy. Cisplatin is an effective antineoplastic agent broadly used in oncology where it interferes with DNA replication in dividing cells, however, its mechanism in kidney damage remains unclear. We tested the hypothesis that cisplatin displaces cell-contact proteins such as IQGAP1-claudin complex in the kidney tubules, causing epithelial cell dissociation and kidney damage. Employing a multifaceted approach, using mutant analyses and optimal cisplatin dose, this hypothesis was tested in cell culture and iqgap1 ^−/- mouse models. Cisplatin inhibited cell proliferation and migration in an IQGAP1-dependent manner, displaced IQGAP1 from cell junctions and altered the expression level of key junctional markers, including claudins 2/4/8 and nephrin. Similar effects were observed in animal models where cisplatin treatment and loss of IQGAP1 had additive effects. These functional outcomes are accounted for by suppression of Akt1/PKB survival and ERK1/2 proliferation signals and activation of JNK-GSK3αβ stress and inflammatory signal, widely implicated in kidney injury. These findings present IQGAP1-claudin axis as biomarkers and therapeutic targets in kidney damage and pave the way for formulating new analogs that eliminate cisplatin adverse side effects while preserving its antineoplastic efficacy.

Gene expression alterations in postmortem schizophrenia tissue are well-documented and are influenced by genetic, medication, and epigenetic factors. The Wingless/Integrated (WNT) signaling pathway, critical for cell growth and development, is involved in various cellular processes including neurodevelopment and synaptic plasticity. Despite its importance, WNT signaling remains understudied in schizophrenia, a disorder characterized by metabolic and bioenergetic defects in cortical regions. In this study, we examined the gene expression of 10 key WNT signaling pathway transcripts: IQGAP1, CTNNβ1, GSK3β, FOXO1, LRP6, MGEA5, TCF4, βTRC, PPP1Cβ, and DVL2 in the dorsolateral prefrontal cortex (DLPFC) using postmortem tissue from schizophrenia subjects (n = 20, 10 males, 10 females) compared to age, pH, and postmortem interval (PMI)-matched controls (n = 20, 10 males, 10 females). Employing the R-shiny application Kaleidoscope, we conducted in silico “lookup” studies from published transcriptomic datasets to examine cell- and region-level expression of these WNT genes. In addition, we investigated the impact of antipsychotics on the mRNA expression of the WNT genes of interest in rodent brain transcriptomic datasets. Our findings revealed no significant changes in region-level WNT transcript expression; however, analyses of previously published cell-level datasets indicated alterations in WNT transcript expression and antipsychotic-specific modulation of certain genes. These results suggest that WNT signaling transcripts may be variably expressed at the cellular level and influenced by antipsychotic treatment, providing novel insights into the role of WNT signaling in the pathophysiology of schizophrenia.

Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine.

Glioblastoma multiform (GBM) is an incurable heterogenous brain cancer with few clinical target options. IQGAP1 is a scaffold oncoprotein involved in GBM with unclear mechanism. Here we report that the antipsychotic drug Haldol differentially alters IQGAP1 signaling and inhibits GBM cell proliferation, thus providing novel molecular signatures for GBM classification and potential targeted therapy in personalized medicine.

The signaling scaffold oncoprotein IQGAP1 was identified as a classification and therapeutic biomarker in triple negative breast cancer (TNBC) cell lines. Here, we report that the antipsychotic drug Haldol induces novel protein-protein interactions with IQGAP1 and inhibits cell proliferation in TNBC cell lines. The identified proteins share known functions of IQGAP1 in secretion, transcription and apoptosis and provide further classification tools and potential precision therapeutic targets for Haldol in TNBC.

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