Abstract
While hundreds of consistently altered autophagy-related genes (ARGs) have been identified in cancers, their prognostic value in bladder urothelial carcinoma (BUC) remains unclear. In the present study, we collected 232 ARGs from the Human Autophagy Database (HADb), and identified 37 differentially expressed ARGs in BUC based on The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that among the 37 differentially expressed ARGs, prolyl 4-hydroxylase, beta polypeptide (P4HB), and regulator of G protein signaling 19 (RGS19) were significantly negatively correlated with overall survival (OS) and disease-free survival (DFS). Overexpression of P4HB and RGS19 in BUC was further validated using independent data sets, including those from the Oncomine and Gene Expression Omnibus (GEO) databases. cBioPortal and UALCAN analyses indicated that altered P4HB and RGS19 mRNA expression was significantly associated with mutations and clinical characteristics (nodal metastasis and cancer stage). Moreover, co-expression network analysis and gene set enrichment analysis (GSEA) predicted that the potential functions of P4HB and RGS19 are involved in the endoplasmic reticulum (ER) stress response, cytokine-mediated signaling pathway and inflammatory response. More importantly, multivariate Cox proportional hazards regression analysis demonstrated that P4HB, but not RGS19, is an independent and unfavorable BUC biomarker based on clinical characteristics (age, gender, cancer stage, and pathological TNM stage). Finally, we validated that the mRNA and protein expression levels of P4HB were upregulated in four bladder cancer cell lines (T24, J82, EJ, and SW780) and found that knockdown of P4HB dramatically inhibited the invasion and proliferation of bladder cancer cells. In summary, our study screened ARGs and identified P4HB as a biomarker that can predict the progression and prognosis of BUC and may provide a better understanding of the autophagy regulatory mechanisms involved in BUC.
Highlights
MATERIALS AND METHODSBladder cancer is the most common malignancy of the urinary system and the leading cause of cancer-associated mortality in the elderly population of China [1]
The expression level of each of the 232 autophagy-related genes (ARGs) was compared between bladder urothelial carcinoma (BUC) and normal bladder tissues in the The Cancer Genome Atlas (TCGA) dataset, which contained 411 BUC samples and 19 adjacent non-tumor bladder tissue samples
We performed GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to determine the potential functions of these dysregulated ARGs in the development of BUC
Summary
MATERIALS AND METHODSBladder cancer is the most common malignancy of the urinary system and the leading cause of cancer-associated mortality in the elderly population of China [1]. The most common pathological type of bladder cancer is BUC, which has unique characteristics, such as drug resistance, a high recurrence rate, a higher frequency of metastasis, and poor prognosis [2, 3]. Traditional clinicopathological risk factors could not sufficiently identify BUC patients with high risk and predict the prognosis of BUC. Molecular biomarkers have been shown to aid the diagnosis and therapy and guide the prediction of the prognosis for BUC [4]. Zhang et al revealed that high expression of HEF1 is associated with advanced stage and shortened progression-free survival poor for BUC patients [6].
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