Prostate cancer is one of the leading causes of mortality among US males. There is an urgent unmet need to develop sensitive and specific biomarkers for the early detection of prostate cancer to reduce overtreatment and accompanying morbidity. We identified a group of differentially expressed long noncoding RNAs in prostate cancer cell lines and patient samples and further characterized six long noncoding RNAs (AK024556, XLOC_007697, LOC100287482, XLOC_005327, XLOC_008559, and XLOC_009911) in prostatic adenocarcinoma tissue samples (Gleason score >6.0) and compared them with matched normal (healthy) tissues. Interestingly, these markers were also successfully detected in patient urine samples and were found to be up-regulated when compared with normal (healthy) urine. AK024556 (SPRY4-IT1) was highly up-regulated in human prostate cancer cell line PC3 but not in LNCaP, and siRNA knockdown of SPRY4-IT1 in PC3 cells inhibited cell proliferation and invasion and increased cell apoptosis. Chromogenic in situ hybridization assay was developed to detect long noncoding RNAs in primary prostatic adenocarcinoma tissue samples, paving the way for clinical diagnostics. We believe that these results will set the stage for more extensive studies to develop novel long noncoding RNA-based diagnostic assays for early prostate cancer detection and will help to distinguish benign prostate cancer from precancerous lesions.
Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. Urine samples are a non-invasive means to obtain abundant and readily accessible "liquid biopsies". Herein we used urine liquid biopsies to identify and characterize a novel group of urineenriched RNAs and metabolites in patients with PCa and normal individuals with or without benign prostatic disease. Differentially expressed RNAs were identified in urine samples by deep sequencing and metabolites in urine were measured by mass spectrometry. mRNA and metabolite profiles were distinct in patients with benign and malignant disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Functional validation supported a role for glutamate metabolism and glutamate oxaloacetate transaminase 1 (GOT1)-dependent redox balance in PCa, which could be exploited for novel biomarkers and therapies. In this study, we discovered cancerspecific changes in urinary RNAs and metabolites, paving the way for the development of sensitive and specific urinary PCa diagnostic biomarkers either alone or in combination. Our methodology was based on single void urine samples (i.e., without prostatic massage). The integrated analysis of metabolomic and transcriptomic data from these liquid biopsies revealed a glutamate metabolism and tricarboxylic acid cycle node that was specific to prostate-derived cancer cells and cancer-specific metabolic changes in urine.More than 180,000 men are diagnosed with prostate cancer (PCa) in U.S. in the 2016, where 26,000 of these patients will die of the disease 1 . PCa is one of the second most frequently diagnosed cancer deaths among men worldwide 2 . The radiotherapy and surgery for localized PCa are known to be effective, however the prognosis for patients with the progressive disease is poor. A test to detect PCa with high sensitivity and specificity at an early stage is a clinical imperative. Moreover, there is a vital need for novel therapeutic tactics to manage this insidious and prevalent disease. open Scientific RepoRtS | (2020) 10:3716 | https://doi.org/10.1038/s41598-020-60616-z www.nature.com/scientificreports www.nature.com/scientificreports/ Serum prostate specific antigen (PSA) levels are been used for PCa diagnosis and screening for over thirty years, and digital rectal examination (DRE) for even longer 3 . However, PSA has modest sensitivity and specificity and does not discriminate indolent from aggressive cancers 3,4 . Prostate cancer antigen 3 (PCA3), a prostate-specific non-coding RNA, was approved by the FDA in 2012 as the first PCa molecular diagnostic test for a particular clinical indication (need for recurrence prostate biopsies in men aged >50 years with assumed PSA levels and/or DRE and/or one or more earlier negative biopsies) 5 . Nevertheless, the importance of the PCA3 test is limited by substantial individual variability, better performan...
Although molecular biologic techniques may have the capacity to identify a subgroup who may benefit from a bladder-sparing approach, cystectomy is normally required for optimal results.
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