Multivariate competing endogenous RNA network characterization for cancer MicroRNA biomarker discovery: a novel bioinformatics model with application to prostate cancer metastasis

Background MicroRNAs (miRNAs) are post-transcriptional regulators with the potential as biomarkers for cancer management. Data-driven competing endogenous RNA (ceRNA) network modeling is an effective way to decipher the complex interplay between miRNAs and spongers. However, no general rules are discovered for ceRNA network-based biomarker prioritization. Methods and Results In this study, a novel bioinformatics model was developed by integrating gene expression with multivariate miRNA-target data for ceRNA network-based biomarker discovery. Compared with traditional methods, the structural vulnerability in human lncRNA-miRNA-mRNA network was comprehensively analyzed, and the single-line regulatory or competing mode among miRNAs, lncRNAs and mRNAs was characterized and quantified as statistical evidence for miRNA biomarker identification. The application of this model to prostate cancer (PCa) metastasis identified a total of 12 miRNAs as putative biomarkers from metastatic PCa-specific lncRNA-miRNA-mRNA network and nine of them have been previously reported as biomarkers for PCa metastasis. The receiver operating characteristic curve and cell line qRT-PCR experiments demonstrated the power of miR-26b-5p, miR-130a-3p, and miR-363-3p as novel candidates for predicting PCa metastasis. Moreover, PCa-associated pathways such as prostate cancer signaling, ERK/MAPK signaling, and TGF-β signaling were significantly enriched by targets of identified miRNAs, indicating the underlying mechanisms of miRNAs in PCa carcinogenesis. Conclusions A novel ceRNA-based bioinformatics model was proposed and applied to screen candidate miRNA biomarkers for PCa metastasis. Functional validations using human samples and clinical data will be performed for future translational studies on the identified miRNAs.

Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p

Background More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. Methods Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Results Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. Conclusions Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

Prostate Cancer Metastasis to the Pituitary Gland Manifesting as Corticosteroid Withdrawal, and the Impact of the Switch from Prednisone to Dexamethasone on Survival Time

Despite improvements in the diagnosis and treatment of cancers, the incidence of pituitary metastasis has increased. Prostate cancer metastasis to the pituitary, however, is rare, and these tumors usually grow rapidly. They are also more likely to be located in the posterior pituitary, and the presenting symptoms are often nonspecific, which makes early diagnosis challenging. The management of this condition is usually multidisciplinary, and requires careful assessment and decision making. We present a case of a patient who developed prostate cancer metastasis to the pituitary. In this report, we show that patients with prostate cancer on corticosteroid therapy who develop withdrawal symptoms or other endocrine symptoms should be assessed for pituitary and other brain metastasis. This case report also discusses the impact of switching from prednisone and abiraterone to dexamethasone and abiraterone. Our report shows that patients on abiraterone and prednisone whose PSA has increased, but who have no radiologic progression, may have their PSA controlled and thereby improved survival time when they are switched to abiraterone and dexamethasone.

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

This manuscript demonstrates how integrated bioinformatic and statistical reanalysis of publicly available genomic datasets can be utilized to identify molecular pathways and biomarkers that may be clinically relevant to metastatic prostate cancer (mPrCa) progression. The most notable observation is that the transition from primary prostate cancer to mPrCa is characterized by upregulation of processes associated with DNA replication, metastasis, and events regulated by the serine/threonine kinase PLK1. Moreover, our analysis also identified over-expressed genes that may be exploited for potential targeted therapeutics and minimally invasive diagnostics and monitoring of mPrCa. The primary data analyzed were two transcriptional datasets for tissues derived from normal prostate, primary prostate cancer, and mPrCa. Also incorporated in the analysis were the transcriptional, gene dependency, and drug response data for hundreds of cell lines, including those derived from prostate cancer tissues.

Metastatic Adenocarcinoma of Prostate posing as upper tract ureteral mass

Prostate cancer metastasis to the ureter is extremely rare because only 45 such cases have been reported worldwide in the last century. It accounts for 30% of ureteral metastasis. Neuroendocrine differentiation is approximately 1% of the entire primary prostate adenocarcinoma pathology. Metastatic prostate cancer may pose as upper tract urothelial carcinoma. Prostate may look normal on clinic-radiological examination in prostate cancer. Majority of such cases are managed with nephroureterectomy. Herein, we report a case of 62-year gentleman, who presented with refractory left flank pain with repeated imaging suggestive of neoplastic left ureteric stricture and normal prostate on clinic-radiological examinations. The case was later found with the diagnosis of metastatic prostate adenocarcinoma with neuroendocrine differentiation after left sided nephroureterectomy done for a provisional diagnosis of Upper Tract Urothelial Carcinoma (UTUC).