Cell Polarity Protein Pals1-Associated Tight Junction Expression Is a Favorable Prognostic Marker in Clear Cell Renal Cell Carcinoma

Abstract

Introduction: The Pals1-associated tight junction (PATJ) is a Crumbs (CRB) complex component that regulates epithelial cell apico-basal polarity and directional migration. This study assessed PATJ expression in clear cell renal cell carcinoma (ccRCC) vs. normal tissues and associated with ccRCC progression and prognosis. Methods: The effects of PATJ knockdown were investigated on regulation of normal kidney epithelial cell viability and protein expression in vitro. The PATJ mRNA data in ccRCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and analyzed with UALCAN, LinkedOmics, Kaplan-Meier Plotter, GEPIA, and SurvExpress tools. Immunohistochemistry was performed for PATJ in tissue microarray sections (n = 150 ccRCC and 30 normal renal specimens). Normal human kidney tubular epithelial cell (HKC) cells were transfected with PATJ and negative control siRNA for cell viability CCK-8 assay, flow cytometry, and western blots. Results: The data showed that PATJ mRNA and protein were downregulated in ccRCC tissues and cell lines. Downregulation of PATJ mRNA was associated with male patients, advanced tumor stages, grades, and ccB subtypes as well as poorer overall and diseasefree survival of patients. Furthermore, PATJ protein was also significantly downregulated in ccRCC tissues and associated with advanced tumor pathologic, TNM stages and poorer overall. In vitro, knockdown of PATJ expression promoted HKC proliferation and the activation of mitogen-activated protein kinases (MAPK) pathway proteins. Conclusions: This study revealed that a decrease of PATJ in ccRCC, which was associated with male patients, advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC. Keywords: cell polarity protein Pals1-associated tight junction, clear cell renal cell carcinoma, prognosis, tumor cell proliferation, mitogen-activated protein kinases Li et al.

Acyl-CoA Thioesterase 8 and 11 as Novel Biomarkers for Clear Cell Renal Cell Carcinoma

“…For example, given the regulatory role of autophagy in ccRCC, the researchers focused on autophagy-related genes and finally demonstrated that P4HB is a novel diagnostic and independent prognostic marker for ccRCC via bioinformatics analysis ( Xie et al, 2020 ). Similarly, the fact that dysregulation of cell polarity plays a critical role in ccRCC cell proliferation and apoptosis gave rise to the finding that a decrease of the cell polarity protein PATJ is associated with poorer overall survival in ccRCC patients ( Li et al, 2020 ). ccRCC, however, is not just a disease with aberrant proliferation of kidney cells, being fundamentally a metabolic disorder ( Lucarelli et al, 2019 ).…”

Exome sequencing of glioblastoma-derived cancer stem cells reveals rare clinically relevant frameshift deletion in MLLT1 gene

“…Only PATJ variant, p.Gly1178Ser, is a missense substitution in exon 6, and with allelic frequency 1 (Additional file 3: Table S3) in all center samples and described in clear cell renal cell carcinoma (ccRCC) and acute_mye-loid_leukaemia. A decrease of PATJ in ccRCC was associated with the male advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC [11]. Another clinically relevant variant was found in DLX6/DLX6-AS1, p.Tyr118fs, in exon 1, introducing a frameshift mutation.…”

Exome Sequencing of Glioblastoma-Derived Cancer Stem Cells Reveals Rare Clinically Relevant Frameshift Deletion in MLLT1 Gene

“…Only PATJ variant, p.Gly1178Ser, is a missense substitution in exon 6, and with allelic frequency 1 (Supplementary Table 3) in all center samples and described in clear cell renal cell carcinoma (ccRCC) and acute_myeloid_leukaemia. A decrease of PATJ in ccRCC was associated with the male advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC (11). Another clinically relevant variant was found in DLX6/DLX6-AS1, p.Tyr118fs, in exon 1, introducing a frameshift mutation.…”