Upregulated Transcription Factor PITX1 Predicts Poor Prognosis in Kidney Renal Clear Cell Carcinoma-Based Bioinformatic Analysis and Experimental Verification

Abstract

Paired-like homeodomain transcription factor 1 (PITX1) is involved in numerous biological processes, including cell growth, progression, and invasion in various malignant tumors. Nevertheless, the relationship between PITX1 and kidney renal clear cell carcinoma (KIRC) remains unclear. The clinical role and functions of PITX1 were analyzed by integrating multiple open-access online datasets. Further experimental verification was performed via quantitative real-time PCR (qRT-PCR) to detect the expression of PITX1 in 10 pairs of KIRC tissues. Our results revealed that PITX1 mRNA was overexpressed in tumor tissues compared with normal tissues in the TCGA-KIRC database ( $p<0.001$ ) and numerous independent cohorts ( $p<0.05$ ). Further, high expression of PITX1 mRNA was detected in KIRC tissues compared with adjacent normal tissues in our center by qRT-PCR ( $N=10$ , $p<0.05$ ). Logistic regression analysis demonstrated that the PITX1 level was positively associated with KIRC patients, T and M stages, histologic grade, and pathologic stage (all $p<0.05$ ). Survival analysis showed that upregulation of PITX1 mRNA was associated with poor overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) (all $p<0.05$ ). Univariate/multivariate Cox hazard regression analysis revealed that PITX1 was an independent risk factor for OS in patients with KIRC ( $\text{HR}=1.998$ , $p=0.003$ ). Accordingly, the time-independent receiver operating characteristic (ROC) curve confirmed that PITX1 had good predictive efficacy for OS and DSS. Meanwhile, a prediction model constructed by nomogram was used to predict the OS of KIRC patients, and the calibration plot indicated this model shows high accuracy. We also revealed some downstream target genes of PITX1-related signaling pathways. Our finding suggested that high PITX1 mRNA expression may act as an independent predictive factor of poor prognosis in patients with KIRC. The prognostic model based on the nomogram would be instrumental in evaluating the survival rate in KIRC patients.