Abstract
Prostate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression.
Highlights
Prostate cancer (PCa) is one of the most common cancer types worldwide and the second leading cause of death among men in the United States and Europe [1, 2]
Expression of PDIA3N was correlated to tumor stage, being more expressed in metastatic cell lines (DU145, PC3 and LNCaP) compared to cell lines derived from normal prostate tissue (PNT2) and the cell line derived from an early stage of androgen negative prostate cancer (P4E6)
The expression pattern of different isoforms may change depending on the stage or severity of disease and relation between expression of two gene isoforms can be correlated with a specific disease pattern [9, 34, 35]
Summary
Prostate cancer (PCa) is one of the most common cancer types worldwide and the second leading cause of death among men in the United States and Europe [1, 2]. A major clinical challenge in PCa screening is the lack of diagnostic tests that distinguish between benign and aggressive tumors [1, 4]. Standard approaches used are tissue pathology and Gleason score, imaging and prostate specific antigen (PSA) serum levels [1,2,3, 5]. Analyses of tissue pathology and Gleason score classifications are more reliable but require invasive techniques to extract biopsies from the tumor. PSA screening is the most effective non-invasive method used for more than 20 years. PSA screening has low sensitivity and marginal specificity resulting in high number of false positives associated with other uropathies [4]. There is a need of finding candidate biomarkers with both high sensitivity and specificity to follow PCa progression
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