PiR-hsa-4447944 serves as an oncogenic mediator in prostate cancer and promotes the development of castration resistance by inhibiting NEFH expression
Ontology highlight
ABSTRACT: PiR-hsa-4447944 showed a significantly higher expression level in both CRPC tissues and CRPC cell lines. Functionally, piR-hsa-4447944 overexpression conferred, whereas piR-hsa-4447944 suppression inhibited castration resistance ability in vitro and in vivo. Enforced piR-hsa-4447944 expression in vitro promoted PCa cells migration and invasion, as well as reduced cell apoptosis. To explore the potential targets of piR-hsa-4447944, two PCa cells 22RV1 and LNCaP were transfected with control or piR-hsa-4447944 mimic, and then the extracted total RNA was used for mRNA sequencing and bioinformatic analysis.
Project description:PiR-hsa-4447944 serves as an oncogenic mediator in prostate cancer and promotes the development of castration resistance by inhibiting NEFH expression
Project description:The integration of diverse ‘omic’ datasets will increase our understanding of the key signaling pathways that drive disease. Here, we used clinical tissue cohorts corresponding to lethal metastatic castration resistant prostate cancer (CRPC) obtained at rapid autopsy to integrate mutational, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed transcriptional master regulators, functionally mutated genes, and differentially ‘activated’ kinases in CRPC tissues to synthesize a robust signaling network consisting of pathways with known and novel gene interactions. For 6 individual CRPC patients for which we had transcriptomic and phosphoproteomic data we observed distinct pathway activation states for each patient profile. In one patient, the activated pathways were strikingly similar to a prostate cancer cell line, 22Rv1, providing us with a good pre-clinical model to test targeted, combination therapies. In all, synthesis of multiple ‘omic’ datasets revealed a plethora of pathway information suitable for targeted therapies in lethal prostate cancer.
Project description:Extracellular vesciles (EVs) have an important role in the tumor progression. However, the precise regulatrory mechanisms of EV secretion has not been clarified yet. We performed quantitive high-throughput screening to eluciade the key miRNAs for EV biogenesis in castration resistant prostate cancer (CRPC) using 22RV1 cells, and miR-1908 was selected as the miRNA regulating EV biogenesis in CRPC. To identify the genes that could be targeted by miR-1908, we performed mRNA micorarray analysis in 22RV1 after transfected of miR-1908 mimic or control miRNA.
Project description:The integration of diverse ‘omic’ datasets will increase our understanding of the key signaling pathways that drive disease. Here, we used clinical tissue cohorts corresponding to lethal metastatic castration resistant prostate cancer (CRPC) obtained at rapid autopsy to integrate mutational, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed transcriptional master regulators, functionally mutated genes, and differentially ‘activated’ kinases in CRPC tissues to synthesize a robust signaling network consisting of pathways with known and novel gene interactions. For 6 individual CRPC patients for which we had transcriptomic and phosphoproteomic data we observed distinct pathway activation states for each patient profile. In one patient, the activated pathways were strikingly similar to a prostate cancer cell line, 22Rv1, providing us with a good pre-clinical model to test targeted, combination therapies. In all, synthesis of multiple ‘omic’ datasets revealed a plethora of pathway information suitable for targeted therapies in lethal prostate cancer.
Project description:We compared 22 primary Pca (hormone-dependent) versus 29 metastatic Pca (CRPC). The expression of genes related to cell cycle, proliferation, DNA synthesis, and androgen metablism are significantly increased in CRPC group. The expression of AR-stimulated genes were partially reactivated. TMPRSS2-ERG fusion status was determined for the samples by PCR. The expression of ERG was highly increased in fusion positive versus negative. 120 snap-frozen CT-guided bone marrow biopsies from patients with castration-resistant prostate cancer were collected as a source of material. 29 independent biopsies containing mostly tumor were identified as CRPC group through carefully microscopical examination. 4 samples containing no tumor were identified as normal bone marrow group. Primary tumor was isolated by LCM from frozen biopsies of hormone-naive patients. 22 samples were selected as primary PCa group.
Project description:Generally, only exonic circular RNA is believed to play the role as molecular sponge, while the main function of intronic circular RNA is regulating the expression of its parental gene. We aimed to find out whether intronic circular RNA could also act as molecular sponge in castration-resistance prostate cancer. Gene chip of castration-resistant and hormone-sensitive prostate cancer cell lines was sequenced to identify the differentially expressed circular RNA. We demonstrated that intronic circular RNA hsa_circ_0092339, located in the nucleus, was highly expressed in castration-resistance prostate cancer (CRPC) cell lines by using high throughput RNA sequencing. By knocking down hsa_circ_0092339, we found that this intronic circular RNA did not regulate the expression of its parental gene. By RIP and RNA pull-down experiment, we further found hsa_circ_0092339 realized its function by acting as molecular sponge. Hsa_circ_0092339 prevented degradation of C-MYC by absorbing hsa-mir-940 and preventing it enter the cytoplasm from nucleus. The combination of hsa-mir-940 and C-MYC was certified by dual-luciferase assay. In addition, we proved this axis was also effective in CRPC xenografted model. The effectiveness of this pathway in tissues was verified by animal experiments.
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Although initially hormone-deprovation therapy is effective to inhibit cancer progression, most of cancers relapse as castration-resistant prostate cancer (CRPC). Therefore, we examined the effect of AR interacting partner OCT1 in CRPC cells. In order to investigate the OCT1 function in CRPC cells, we performed gene expression in AR-positive CRPC cell line, 22Rv1, after siOCT1 treatment. We also treated cells with vehicle or dihydrotestosterone (DHT) to analyzed the effects of OCT1 on AR function.
Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL
Project description:In order to find out taget genes of Runx/Cbfb2 complexes in PIR+IL7R+ subset. In particular, genes that would explain why the size of thymus was small by lack of Cbfb2. Upon finding of decresed IL7R+PIR+ subset, which was reported as thymus-homing progenitor, in Cbfb2 deficient embruos embryos, we focused on these population.
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Although initially hormone-deprovation therapy is effective to inhibit cancer progression, most of cancers relapse as castration-resistant prostate cancer (CRPC). In this study, we examined the effect of OCT4 or NRF1 knockdown in CRPC cells. In order to investigate the OCT4 and NRF1 function in CRPC cells, we performed gene expression in AR-positive CRPC cell line, 22Rv1, AR-negative CRPC cell lines, PC3-CR (Cabazitaxel resistant), DU145, and DU145-CR, after siOCT4 (10 nM) or siNRF1 (10 nM) treatment. We also treated cells with vehicle, ribavirin (riba), or dihydrotestosterone (DHT) to analyzed the effects of thiese drug treatments.