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 disease-free 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.
Highlights
The Pals1-associated tight junction (PATJ) is a Crumbs (CRB) complex component that regulates epithelial cell apico-basal polarity and directional migration
We revealed 533 cases of clear cell Renal cell carcinoma (RCC) (ccRCC) and 72 normal kidney tissues and found that PATJ mRNA levels were significantly (p = 1.625e-12) reduced in ccRCC tissues compared to normal tissues (Figure 1A)
We performed a bioinformatic analysis of PATJ expression in 72 ccRCC patients using the GSE53757 data set and revealed a significant decrease in PATJ mRNA levels in ccRCC tissues compared with matched normal tissues (p < 0.0001; Figure 1B)
Summary
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. Renal cell carcinoma (RCC) is a frequently diagnosed kidney cancer in men 65 years or older and clear cell RCC (ccRCC) is the most common histologic subtype (Cohen and McGovern, 2005; Hsieh et al, 2017), counting for approximately 90% of kidney cancers and up to 4% of all newly diagnosed cancer cases in 2018 worldwide (Siegel et al, 2018). Patients with advanced tumor progression (tumor has spread outside of the kidney or the locoregional disease) have a great risk of recurrence (more than 40%) after initial treatment (Lam et al, 2005b; Gupta et al, 2008), leading to a 12% of the 5-year survival rate (Joosten et al, 2017). The identification and evaluation of tumor markers for preliminary screening, early metastasis detection, and monitoring of treatment responses and prognosis are sorely needed
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