Prostate Cancer Tumorigenesis Research Articles

Poly(ADP-Ribose) Polymerase Inhibitors in Prostate Cancer: Molecular Mechanisms, and Preclinical and Clinical Data.

Genomic instability is one of the hallmarks of cancer. The incidence of genetic alterations in homologous recombination repair genes increases during cancer progression, and 20% of prostate cancers (PCas) have defects in DNA repair genes. Several somatic and germline gene alterations drive prostate cancer tumorigenesis, and the most important of these are BRCA2, BRCA1, ATM and CHEK2. There is a group of BRCAness tumours that share phenotypic and genotypic properties with classical BRCA-mutated tumours. Poly(ADP-ribose) polymerase inhibitors (PARPis) show synthetic lethality in cancer cells with impaired homologous recombination genes, and patients with these alterations are candidates for PARPi therapy. Androgen deprivation therapy is the mainstay of PCa therapy. PARPis decrease androgen signalling by interaction with molecular mechanisms of the androgen nuclear complex. The PROFOUND phase III trial, comparing olaparib with enzalutamide/abiraterone therapy, revealed increased radiological progression-free survival (rPFS) and overall survival (OS) among patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1, BRCA2 or ATM mutations. The clinical efficacy of PARPis has been confirmed in ovarian, breast, pancreatic and recently also in a subset of PCa. There is growing evidence that molecular tumour boards are the future of the oncological therapeutic approach in prostate cancer. In this review, we summarise the data concerning the molecular mechanisms and preclinical and clinical data of PARPis in PCa.

Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

BackgroundProstate cancer is one of the leading causes of cancer death in males. Recent studies have reported aberrant expression of lncRNAs in prostate cancer. This study explores the role of LINC00261 in prostate cancer progression.MethodsThe differentially expressed genes, transcription factors, and lncRNAs related to prostate cancer were predicted by bioinformatics analysis. Prostate cancer tissue samples and cell lines were collected for the determination of the expression of LINC00261 by reverse transcription quantitative polymerase chain reaction. The binding capacity of LINC00261 to the transcription factor GATA6 was detected by RIP, and GATA6 binding to the DKK3 promoter region was assessed by ChIP. In addition, luciferase reporter system was used to verify whether LINC00261 was present at the DKK3 promoter. After gain- and loss-of function approaches, the effect of LINC00261 on prostate cancer in vitro and in vivo was assessed by the determination of cell proliferation, invasion and migration as well as angiogenesis.ResultsLINC00261, GATA6, and DKK3 were poorly expressed in prostate cancer. LINC00261 could inhibit transcriptional expression of DKK3 by recruiting GATA6. Overexpression of LINC00261 inhibited prostate cancer cells proliferation, migration, and invasion as well as angiogenesis, which could be reversed by silencing DKK3. Furthermore, LINC00261 could also suppress the tumorigenicity of cancer cells in vivo.ConclusionsOur study demonstrates the inhibitory role of LINC00261 in prostate cancer progression, providing a novel biomarker for early detection of prostate cancer.

β2 -adrenergic receptor signaling drives prostate cancer progression by targeting the Sonic hedgehog-Gli1 signaling activation.

BackgroundConsiderable evidence suggests that the sympathetic nervous system, mainly via adrenergic signaling, contributes to prostate cancer (PCa) progression. However, the underlying molecular mechanisms remain unknown.MethodsThe expression level of β2‐adrenergic receptor (β2‐AR) in tissue microarray was evaluated by immunohistochemistry. The effects of isoproterenol (ISO) or Sonic Hedgehog (Shh) signaling inhibitor on tumor growth were analyzed in proliferation and colony formation assays. The apoptosis of cells was analyzed by flow cytometry. Small hairpin RNA‐based knockdown of β2‐AR or Gli1 was validated by Western blot analysis and real‐time PCR. Effects of β2‐AR on prostate carcinogenesis in vivo were observed in a mouse xenograft model. The expression levels of the indicated proteins in xenograft tissues were evaluated by immunohistochemistry. Expression levels of Shh signaling components and downstream proteins were assessed by immunoblotting.ResultsWe determined that β2‐AR was expressed at significantly higher levels in carcinoma than in normal prostate tissues. β2‐AR signaling also played an essential role in sustaining PCa cell proliferation in vivo and in vitro. We also found that inhibition of Shh signaling or knockdown of Gli1 expression significantly restrained ISO‐induced cell proliferation in vitro. ISO alleviated the apoptosis induced by suppressing or knocking down of Gli1. The β2‐AR agonist ISO upregulated the transcription and protein expression of target genes of Shh signaling, including c‐Myc, Cyclin D1, and VEGFA. Conversely, knocking down β2‐AR markedly suppressed the expression of Shh components in vivo and in vitro. In Gli1 knockdown cells, ISO failed to increase the expression of target genes of Shh signaling.ConclusionsIn this study, we uncovered an important role of β2‐AR signaling in regulating the Shh pathway activity in PCa tumorigenesis and provide further insight into the mechanism of the involvement of the Hh signaling pathway. Furthermore, given the efficacy of β2‐adrenergic modulation on PCa, our study might also add evidence for potential therapeutic options of β‐blockers for PCa.

Abstract 1558: RNA expression differences between African Americans and European Americans prostate cancers in both their tumor-adjacent stroma and in their tumors

Abstract Background. Prostate cancer (PCa) of African Americans (AA) is diagnosed at an earlier median age and more advanced stage than PCa of European American (EA), and has a poorer prognosis and significantly higher mortality. 35% of AA PCa patients fall out of active surveillance, compared to 15% of EA men. Stromal cells adjacent to tumor, including reactive stroma, play a critical role in tumorigenesis of prostate cancer. We searched for differences in RNA expression in the stroma and tumor of AA compared to EA prostate cancer patients to uncover regulatory differences that might contribute to a higher rate of aggressive PCa in AA men. Methods. RNA-Seq data was generated for tumor-adjacent stroma of prostate cancer FFPE tissues from 9 AA and 8 EA patients. RNA-Seq of tumor epithelium from 22 AA and 46 EA PCa FFPE tissues was obtained from GEO database accession GSE54460. Samples were matched clinically for Gleason score, age, and relapse status. Geographic origin was determined using the program Locating Ancestry from Sequencing Reads (LASER) which provides the fraction of ancestry based on single nucleotide polymorphisms (SNPs).The program CIBERSORT, which is an estimate of fraction of immune cells in tissues, was used to estimate the relative fractions of 22 immune cell types in each RNA-Seq sample. Pathway analysis was performed using Strand-NGS and Ingenuity Pathway Analysis (IPA) tools. Results. PCa-adjacent stroma from 9 AA were compared to 8 EA. Similarly, tumor tissues from 22 AA were compared to 46 EA. Comparisons of AA and EA tumor-adjacent stroma identified 721 downregulated and 790 upregulated genes in AA, using a corrected p value of < 0.05. We found significant association of downregulated genes in AA tumor stroma with immune response pathways. Among upregulated genes in AA relative to EA, several metabolic pathways, signaling by TGF beta receptor complex, cytokine, and inflammatory responses, were significantly enriched. CIBERSORT analysis, revealed M2 macrophages (i.e. immunosuppressive and proangiogenic macrophages were enriched in both AA and EA tumor stroma, and represented 25% and 27% of screened immune cells, respectively. The frequency of activated DCs in tumor-adjacent stroma of EA was 7-fold higher than in tumor stroma of AA patients (21% vs 3%). 22 AA and 46 EA prostate tumor tissue samples were similarly compared. 425 upregulated and 514 downregulated genes were identified (corrected p value of 0.05). Although, stroma and tumor have very different transcription patterns, there were 17 genes up-regulated both in tumor-adjacent stroma and tumor epithelium of AA compared to EA and these were enriched in the IL-6 signaling pathway. 21 down-regulated genes were enriched in miRNA targeted genes. In contrast, to tumor-adjacent stroma, immune response pathways in tumor of AA compared to EA was different, suggesting a distinct immune response in tumor-adjacent stroma compared to tumor in men of different races. Citation Format: Farah Rahmatpanah, Gabriela De Robles, Dan Mercola, Michael Lilly, Michael McClelland. RNA expression differences between African Americans and European Americans prostate cancers in both their tumor-adjacent stroma and in their tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1558.

Abstract 1621: Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models

Abstract Background: Prostate cancer (PCa) is one of the most common male-specific malignancies in developed country. The progression of PCa involves complex mechanisms. Contactin 1 (CNTN1) is a neural cell adhesion protein reported to promote lung cancer metastasis and associate with poor prognosis in several cancers. In view of our recent publication reporting CNTN1 as a novel factor promoting PCa metastasis, we have constructed prostate-specific CNTN1 overexpression (CNTN1TG/TG) and PTEN−/− mice to explore CNTN1's role in PC tumorigenesis and progression. Materials and Methods: CNTN1 transgenic C57BL/6 mice was constructed by insertion of a transgene unit into the intron of Rosa26 locus. The CNTN1 transgene (TG) cassette consists of a CAG promoter, a STOP unit flanked by two LoxP sites, followed by CNTN1, which will only be expressed upon removal of the STOP unit by Cre recombinase. The homozygous CNTN1STOP-TG/STOP-TG [without transgene (TG) expression] mice were crossed with prostate-specific Cre mice (PB-Cre4). Prostate expression of CNTN1 was clearly demonstrated only in CNTN1TG/− and CNTN1TG/TG mice but not in CNTN1STOP-TG/STOP-TG animals. In a similar system, PTENflox/flox were crossed with PB-Cre4 to generate prostate-specific PTEN−/- mice. At 21-weeks old when invasive tumors were formed, PTEN−/− mice were surgically castrated and maintained for another 12 weeks to construct the castration-resistant prostate cancer (CRPC) model. Results: At 12-weeks old both CNTN1TG/- and CNTN1TG/TG mice developed hyperplasia in the prostate, evident by an increase in cellularity, nuclear crowding, and mild dysplasia. This supports CNTN1's role in PCa tumorigenesis as prostate epithelial hyperplasia in transgenic mice is a well-regarded precursor of PCa. In line of this observation, immunohistochemistry showed upregulation of proliferation marker Ki67 and AKT phosphorylation at serine 473 (indicative of AKT activation) in the prostate of CNTN1TG/TG compared to control CNTN1STOP-TG/STOP-TG (without Cre) mice. In androgen-sensitive LNCaP cells stably expressing CNTN1, an upregulation of prostate-specific antigen (PSA), a well-regarded AR target, was observed both with and without androgen deprivation. This suggest that CNTN1 likely initiates PCa and contributes to its progression through networks involving AR signaling. The oncogenic role of CNTN1 in association with PTEN deficiency was explored using prostate-specific PTEN−/− mice which recapitulate most clinical features of PCa, including the development of castration-resistant PCa (CRPC). The expression of CNTN1 was undetectable in age-matched C57BL/6 mice but was evident in tumors produced in intact PTEN−/− mice and was further upregulated in CRPC tumors generated in castrated PTEN−/- mice. These observations are consistent with CNTN1-induced AKT activation observed in PCa cells and in CNTN1TG/TG animals. Conclusions: Collectively, these results suggest a role of CNTN1 in promoting PCa tumorigenesis and progression. Evidently, our CNTN1 transgenic mice developed a precancerous lesion of PCa. The oncogenic potential of CNTN1 is further supported by its stimulation of LNCaP cell proliferation. This research provides functional evidence for CNTN1 as an important PCa promoting factor and established a novel transgenic mouse model for PCa; this model may greatly facilitate future PCa research and drug development. Citation Format: Yan Jennifer Gu, Wenjuan Mei, Geoffrey A. Wood, Damu Tang. Contactin 1 (CNTN1) promotes prostate cancer tumorigenesis in transgenic models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1621.

Abstract 1144: Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene

Abstract Metastasis-associated protein 1 (MTA1) plays role in prostate cancer progression and metastasis. We have previously reported on the MTA1-targeted chemopreventive and therapeutic efficacy of pterostilbene (Pter) in the prostate-specific Pten heterozygous (Pten+/f; Pb-Cre+) and Pten null (Ptenf/f; Pb-Cre+) mice. To investigate the exact role of MTA1 in prostate cancer tumorigenesis and its early stages, we developed appropriate mouse models, namely prostate-specific MTA1-knocked in (MTA1-tg) and MTA1-tg on the background of prostate-specific Pten heterozygosity (MTA+/+, Pten+/f; Pb-Cre+). In the current project, we asked three major questions: 1) whether prostate MTA1 overexpression in the context of Pten loss promotes an earlier onset, greater total incidence and accelerated PIN or tumor growth rate; 2) what MTA1-associated molecules are involved in prostate cancer progression; and 3) whether Pter supplemented diet can provide beneficial effects. Identified from our ChIP-Seq data MTA1-associated molecules included CyclinD1, Notch2, and two neuroendocrine markers, namely CHGA and SYP. Using two prostate cancer cell lines, DU145 and PC3M and their corresponding MTA1 knockdown (shMTA1) clones, we validated the direct link between MTA1 and these markers on mRNA and protein levels. Further, we generated 28 prostate-specific MTA1+/+; Pten+/f; Pb-Cre+ mice and randomized them into two major groups: 1) mice on control diet (Ctrl-Diet) and 2) mice on Pter-Diet. After 5 months of feeding with corresponding diets (AIN-76A phytoestrogen free diets supplemented or not with Pter at 100 mg/kg/diet), mice were sacrificed and prostate tissues were isolated for histological, immunochemical and molecular analysis. Results demonstrated the contribution of MTA1 in more aggressive histological phenotype (Ki67, PCNA, p27, SMA, CK8), increased levels of oncogenic MTA1-guided molecules (CyclinD1, Notch2, CHGA, SYP, AR) and the potential for Pter in prostate cancer chemoprevention. Citation Format: Rutu Hemani, Ninad Inamdar, Avinash Kumar, Virginia Donovan, Anait S. Levenson. Novel prostate cancer mouse models for testing targeted chemopreventive potential of pterostilbene [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1144.

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis.

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

Circular RNA circMBOAT2 promotes prostate cancer progression via a miR-1271-5p/mTOR axis.

Patients with advanced prostate cancer (PCa) have poor prognosis. Circular RNAs (circRNAs) regulate biological processes in a variety of cancers, but the precise roles of circRNAs in PCa are poorly understood. Herein, we identified a novel circRNA, termed circMBOAT2 (has_circ_0007334), which was significantly overexpressed in PCa tissues and cell lines. Overexpression of circMBOAT2 was associated with high Gleason score, advanced pathological T stage, and poor prognosis. Overexpression of circMBOAT2 promoted proliferation, migration, and invasion of PCa cells in vitro, and enhanced tumorigenesis and metastasis in vivo. Mechanistically, circMBOAT2 overexpression upregulated the expression of mTOR by acting as a decoy for miR-1271-5p, resulting in the activation of the PI3K/Akt pathway, ultimately promoting the progression of PCa. Importantly, application of an inhibitor of mTOR significantly antagonized circMBOAT2-mediated PCa tumorigenesis in vivo. circMBOAT2 promotes proliferation and metastasis of PCa through miR-1271-5p/mTOR axis-mediated activation of the PI3K/Akt pathway. In summary, our findings uncover a molecular mechanism in the progression of PCa and indicate that circMBOAT2 may be a useful prognostic biomarker and therapeutic target in PCa.

PTPN14 acts as a candidate tumor suppressor in prostate cancer and inhibits cell proliferation and invasion through modulating LATS1/YAP signaling

Protein tyrosine phosphatase, non-receptor type 14 (PTPN14) exerts a profound effect in the progression of multiple malignant tumors. However, whether PTPN14 plays a role in prostate cancer has not been well investigated. Herein, we evaluated the function and potential underlying mechanism of PTPN14 in prostate cancer. Decreased PTPN14 expression was detected in prostate cancer, and restoration of PTPN14 expression in prostate cancer cells inhibited the proliferative and invasive potential. Mechanistically, PTPN14 increased the phosphorylation of Yes-associated protein (YAP) by activation of large tumor suppressor 1 (LATS1), an action that resulted in a significant reduction in YAP-mediated transcriptional activity. Inactivation of YAP by its inhibitor markedly abrogated the PTPN14-knockdown-induced promotion effect on prostate cancer cell proliferation and invasion. Notably, PTPN14 up-regulation also exerted a remarkable suppressive impact on tumorigenesis of prostate cancer in vivo. Taken together, the study reveals a tumor-inhibition role of PTPN14 that represses the proliferation and invasion of prostate cancer by down-regulating YAP activation.

TUG1 knockdown inhibits the tumorigenesis and progression of prostate cancer by regulating microRNA-496/Wnt/β-catenin pathway.

Our study aimed to further investigate the roles and molecular mechanisms of lncRNA taurine upregulated gene 1 (TUG1) in the development and progression of PC. RT-qPCR assay was carried out to measure expression of TUG1, miR-496, together with β-catenin, cyclin D1 and c-myc. Protein levels of β-catenin, cyclin D1 and c-myc were detected by western blot assay. Cell proliferative ability was assessed by colony formation assay and CCK-8 assay. Cell migratory and invasive capacities were evaluated by Transwell migration and invasion assay. The interaction between miR-496 and TUG1 was explored by bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay. Mouse xenograft experiments were performed to further investigate the roles and molecular basis of TUG1 in the tumorigenesis of PC in vivo. TUG1 was highly expressed in PC tissues and cells (DU145 and PC3). TUG1 knockdown inhibited proliferation, migration and invasion in DU145 and PC3 cells. Moreover, TUG1 suppressed miR-496 expression by direct interaction. TUG1 overexpression abrogated miR-96-mediated antiproliferation, anti-migration and anti-invasion effects in DU145 and PC3 cells. TUG1 knockdown inactivated Wnt/β-catenin signaling pathway by upregulating miR-496 in DU145 and PC3 cells. Additionally, TUG1 knockdown inhibited DU145 cells derived PC xenograft growth by upregulating miR-496 and inactivating Wnt/β-catenin signaling in vivo. TUG1 knockdown suppressed PC cell proliferation, migration and invasion in vitro and curbed PC xenograft growth in vivo by regulating miR-496/Wnt/ β-catenin signaling pathway, deepening our understanding on etiology of PC.

Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression

Long non-coding RNAs (lncRNAs) participate in the development and progression of prostate cancer (PCa). We aimd to identify a novel lncRNA, named lncRNA activated in metastatic PCa (lncAMPC), and investigate its mechanisms and clinical significance in PCa. First, the biological capacity of lncAMPC in PCa was demonstrated both invitro and invivo. The lncAMPC was overexpressed in tumor tissue and urine of metastatic PCa patients and promoted PCa tumorigenesis and metastasis. Then, a mechanism study was conducted to determine how the lncAMPC-activated pathway contributed to PCa metastasis and immunosuppression. In the cytoplasm, lncAMPC upregulated LIF expression by sponging miR-637 and inhibiting its activity. In the nucleus, lncAMPC enhanced LIFR transcription by decoying histone H1.2 away from the upstream sequence of the LIFR gene. The lncAMPC-activated LIF/LIFR expressions stimulated the Jak1-STAT3 pathway to simultaneously maintain programmed death-ligand 1 (PD-L1) protein stability and promote metastasis-associated gene expression. Finally, the prognostic value of the expression of lncAMPC and its downstream genes in PCa patients was evaluated. High LIF/LIFR levels indicated shorter biochemical recurrence-free survival among patients who underwent radical prostatectomy. Therefore, the lncAMPC/LIF/LIFR axis plays a critical role in PCa metastasis and immunosuppression and may serve as a prognostic biomarker and potential therapeutic target.

Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells.

Mechanistic understanding of hypoxia-responsive signaling pathways provides important insights into oxygen- and metabolism-dependent cellular phenotypes in diseases. Using SILAC-based quantitative proteomics, we provided a quantitative map identifying over 6300 protein groups in response to hypoxia in prostate cancer cells and identified both canonical and novel cellular networks dynamically regulated under hypoxia. Particularly, we identified SDE2, a DNA stress response modulator, that was significantly downregulated by hypoxia, independent of HIF (hypoxia-inducible factor) transcriptional activity. Mechanistically, hypoxia treatment promoted SDE2 polyubiquitination and degradation. Such regulation is independent of previously identified Arg/N-end rule proteolysis or the ubiquitin E3 ligase, CDT2. Depletion of SDE2 increased cellular sensitivity to DNA damage and inhibited cell proliferation. Interestingly, either SDE2 depletion or hypoxia treatment potentiated DNA damage-induced PCNA (proliferating cell nuclear antigen) monoubiquitination, a key step for translesion DNA synthesis. Furthermore, knockdown of SDE2 desensitized, while overexpression of SDE2 protected the hypoxia-mediated regulation of PCNA monoubiquitination upon DNA damage. Taken together, our quantitative proteomics and biochemical study revealed diverse hypoxia-responsive pathways that strongly associated with prostate cancer tumorigenesis and identified the functional roles of SDE2 and hypoxia in regulating DNA damage-induced PCNA monoubiquitination, suggesting a possible link between hypoxic microenvironment and the activation of error-prone DNA repair pathway in tumor cells.

CircFMN2 Sponges miR-1238 to Promote the Expression of LIM-Homeobox Gene 2 in Prostate Cancer Cells

Circular RNAs (circRNAs) regulate gene expression in different malignancies. However, the molecular mechanisms that link circRNAs with the tumorigenesis of prostate cancer (PCa) are not well understood. In the present study, we attempted to provide a novel basis for targeted therapy for PCa from the aspect of circRNA-microRNA (miRNA)-mRNA interaction. We investigated the expression of circRNAs in 5 paired PCa tissues and adjacent non-tumor tissues by microarray analysis. We focused on hsa_circ_0005100, which is located on chromosome 1 and derived from FMN2, and thus we named it circFMN2. The qRT-PCR was used to detect circFMN2 and target miRNA expression in PCa tissues and cell lines. Biological functional experiments were performed to detect the effects of circFMN2 on the biological behavior of PCa cells in vivo and in vitro. Bioinformatic analysis was utilized to predict potential miRNA target sites on circFMN2. High expression of circFMN2 was associated with PCa progression. Function assays revealed that knockdown of circFMN2 significantly reduced PCa cell growth in vitro and in vivo. Finally, we found that circFMN2 acts as a competing endogenous RNA (ceRNA) for miR-1238 to regulate LIM-homeobox gene 2 (LHX2) expression. circFMN2 regulates the miR-1238/LHX2 axis to promote PCa progression.

<p>MicroRNA-939 Directly Targets <em>HDGF</em> to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway</p>

PurposeMicroRNA-939 (miR-939) has crucial roles in several types of human cancer. However, the expression profile and precise functions of miR-939 in prostate cancer (PCa) are still unclear. This study aimed to determine miR-939 expression in PCa and explore its roles in PCa tumorigenesis.MethodsmiR-939 expression was determined in PCa tissues and cell lines using reverse transcription–quantitative polymerase chain reaction. Cell Counting Kit-8, colony formation, and flow cytometric assays were used to determine the role of miR-939 in PCa cell proliferation and apoptosis in vitro, whereas a tumor xenograft model was generated to evaluate the effect of miR-939 on tumor growth in vivo. Transwell assays were performed to investigate whether miR-939 affects the migration and invasiveness of PCa cells.ResultsmiR-939 was found to be downregulated in PCa tissues and cell lines, and this downregulation was significantly correlated with tumor stage and lymphatic metastasis. Patients with PCa exhibiting low miR-939 expression had shorter overall survival than those exhibiting high miR-939 expression. Exogenous miR-939 expression suppressed PCa cell proliferation, colony formation, migration, and invasion in vitro; enhanced apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the underlying molecular mechanisms revealed hepatoma-derived growth factor (HDGF) as a direct target gene of miR-939 in PCa. HDGF was found to be significantly upregulated in PCa tissues, and its expression was inversely correlated with miR-939 expression. HDGF silencing and miR-939 upregulation showed similar effects in PCa. Restored HDGF expression counteracted the tumor-suppressive activity of miR-939 overexpression in PCa cells. Furthermore, ectopic miR-939 expression inhibited the WNT/β-catenin pathway activation in PCa both in vitro and in vivo by downregulating HDGF.ConclusionmiR-939 functions as a tumor suppressor during PCa tumorigenesis by directly targeting HDGF and deactivating the WNT/β-catenin pathway, suggesting the miR-939/HDGF/WNT/β-catenin pathway as an effective target for PCa therapy.

MicroRNA-106a suppresses prostate cancer proliferation, migration and invasion by targeting tumor-derived IL-8.

BackgroundTumor-derived interleukin-8 (IL-8) promotes tumorigenesis and progression of prostate cancer (PCa). MicroRNAs (miRNAs) are noncoding regulatory RNAs and their dysregulation is known to be implicated in carcinogenesis. However, the post-transcriptional mechanism of IL-8 via miRNAs is not fully understood. This study was intended to investigate whether miR-106a could affect the progression of PCa via targeting IL-8 or not.MethodsUsing bioinformatics analysis, we postulated that IL-8 might be post-transcriptionally regulated by miR-106a. This was validated by dual reporter gene assays that miR-106a could bind to the predicted site of IL-8 mRNA. To determine the biological effects of miR-106a on PCa cells (PC-3 and DU145), MTT, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), migration and invasion assays were performed.ResultsWe found that miR-106a was barely expressed in PCa cells, whereas IL-8 was aberrantly upregulated. Elevated miR-106a could reduce IL-8 expression by directly binding the 3'-UTR of IL-8. Overexpression of miR-106a in PCa cells triggered cell apoptosis and suppressed cell proliferation, migration, and invasion.ConclusionsThis research showed that miR-106a could function as a tumor-suppressor by decreasing IL-8 levels in PCa.

LncRNA SNHG17 aggravated prostate cancer progression through regulating its homolog SNORA71B via a positive feedback loop

Prostate cancer (PC) is a prevalent male malignancy with high occurrence rate. Recent studies have showed that small nucleolar host genes (SNHGs) and their homolog small nucleolar RNAs (snoRNAs) elicit regulatory functions in carcinogenesis. Present study aimed to investigate the role of SNHG17 and its homolog SNORA71B in PC. Function of SNHG17 and SNORA71B in PC is detected by CCK-8, colony formation, flow cytometry analysis of apoptosis, and transwell migration assay. The mechanism whereby SNHG17 regulated SNORA71B was detected by RIP, pulldown, ChIP, and luciferase reporter assays. Results depicted that transcript 6 of SNHG17 and SNORA71B were upregulated in PC. Knockdown of SNHG17 or SNORA71B weakened proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT) and strengthened apoptosis. Mechanistically, SNHG17 and SNORA71B were transcriptionally activated by signal transducer and activator of transcription 5A (STAT5A). SNHG17 positively regulated SNORA71B in PC cell lines and other cell lines. SNHG17 sponged miR-339-5p to upregulate STAT5A and therefore to cause transactivation of SNORA71B. Rescue experiments delineated that SNORA71B was required for the regulation of SNHG17 on PC. Moreover, SNHG17 silence hindered tumorigenesis of PC in vivo. In conclusion, current study first revealed that lncRNA SNHG17 aggravated prostate cancer progression through regulating its homolog SNORA71B via a positive feedback loop, which might do help to the pursuit of better PC treatment.

Downregulation of lncRNA ZEB1-AS1 Represses Cell Proliferation, Migration, and Invasion Through Mediating PI3K/AKT/mTOR Signaling by miR-342-3p/CUL4B Axis in Prostate Cancer.

Background: Prostate cancer (PCa) is the second most common cancer among men, threatening men's health and life. Long noncoding RNA Zinc-finger E-box binding homeobox 1 antisense gene 1 (ZEB1-AS1) and Cullin 4B (CUL4B) were reported to be connected with the tumorigenesis of PCa. However, it is unclear whether ZEB1-AS1 regulates the expression of CUL4B in PCa. Materials and Methods: The levels of ZEB1-AS1 and CUL4B in PCa tissues and cells were evaluated by quantitative real-time polymerase chain reaction. Protein levels of CUL4B, p21, CyclinD1, matrix metalloprotease 9 (MMP9), E-cadherin, phosphorylated-phosphatidylinositol 3 kinase (p-PI3K), PI3K phosphorylated protein kinase B (p-AKT), AKT, p-mTOR and mammalian target of rapamycin (mTOR) in PCa tissues or cells were assessed by Western blot analysis. The proliferation, migration, and invasion abilities of PCa cells were determined with 3-(4, 5-dimethylthiazol-2-YI)-2,5-diphenyltetrazolium bromide (MTT) or transwell assay. The interaction between ZEB1-AS1 or CUL4B and microRNA-342-3p (miR-342-3p) was predicted using starBase v2.0 database and confirmed by the dual-luciferase reporter assay. Results: ZEB1-AS1 and CUL4B were upregulated and miR-342-3p was downregulated in PCa tissues and cells. Both ZEB1-AS1 and CUL4B inhibition constrained proliferation, migration, and invasion of PCa cells. Moreover, the elevation of CUL4B reversed the effects of ZEB1-AS1 silencing on the proliferation, migration, and invasion of PCa cells. Importantly, ZEB1-AS1 modulated CUL4B expression by sponging miR-342-3p in PCa cells. Besides, ZEB1-AS1 mediated PI3K/AKT/mTOR signal pathway by miR-342-3p/CUL4B axis in PCa cells. Conclusion: ZEB1-AS1 modulated PCa progression through mediating PI3K/AKT/mTOR signaling by miR-342-3p/CUL4B axis, providing a possible strategy for the treatment of PCa.

MP51-07 LOSS OF EPHRIN SIGNALING ALTERS THE LIPID RHEOSTAT ASSOCIATED WITH PROSTATE CANCER RACIAL DISPARITIES

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (MP51)1 Apr 2020MP51-07 LOSS OF EPHRIN SIGNALING ALTERS THE LIPID RHEOSTAT ASSOCIATED WITH PROSTATE CANCER RACIAL DISPARITIES Alejandro Morales, Victoria Gil, Susan Crawford, Simon Hayward, and Omar Franco* Alejandro MoralesAlejandro Morales More articles by this author , Victoria GilVictoria Gil More articles by this author , Susan CrawfordSusan Crawford More articles by this author , Simon HaywardSimon Hayward More articles by this author , and Omar Franco*Omar Franco* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000913.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The presence of abdominal central obesity in prostate cancer (PCa) patients is associated with aggressive tumors. Compared to Caucasians (CA), African American (AA) men are at highest risk of developing and dying from PCa. The Center for Disease Control reports racial disparities in adult obesity (38.4% AA vs. 28.6% in CA). In an obese environment, cancer cells store fatty acids in lipid droplets (LD), composed of triacylglycerols (TAG) and cholesterol esters, which can be used as an energy source to sustain proliferation and migration. Decreased gene expression of members of the ephrin family have been linked to PCa-RD. Here we show the functional consequences of aberrant ephrin signaling in lipid metabolism on PCa tumorigenesis in AA compared to CA. METHODS: The density and size of LD were quantified in PCa specimens from different racial backgrounds. EPHB2 signaling was manipulated in PCa cells using siRNA and CRISPR approaches. LD were quantified under basal and obesogenic (added oleic acid) environments. Molecules involved in TAG metabolism were assessed. The effects of EPHB2 loss on PCa cells growth and local invasion was tested in vitro and in vivo. RESULTS: LD density increased in high grade tumors. Under obesogenic conditions, PCa cells from AA showed increased proliferation compared to CA. Loss of EPHB2 increased the tumorigenicity of PCa cells. Quantification of LD profiles showed racial differences. Alteration of EPHB2 led to differential expression of TAG-associated molecules DGAT1, DGAT2 and ATGL in AA compared to CA. Targeting key TAG molecules associated with EPHB2-induced effects reduced the tumorigenicity of PCa cells. Centrosome amplification and microtubule organizing center (MTOC) were associated with lipid metabolic changes in cells with decreased EphB2 signaling. CONCLUSIONS: Loss of EPHB2 signaling in PCa cells triggers aberrant lipid metabolism leading to excessive accumulation of LD. Because loss of ephrin signaling is associated with PCa-RD, this lipid-rich energy status may serve as a source of energy to fuel a more aggressive phenotype observed in AA. Several TAG inhibitors are currently being evaluated in clinical trials as anti-obesity agents. The potential of these drugs to elicit anti-tumorigenic utility in patients with altered ephrin levels requires further study. Source of Funding: R01 CA242920-01 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e766-e766 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alejandro Morales More articles by this author Victoria Gil More articles by this author Susan Crawford More articles by this author Simon Hayward More articles by this author Omar Franco* More articles by this author Expand All Advertisement PDF downloadLoading ...

Intratumoral heterogeneity and genetic characteristics of prostate cancer.

Prostate cancer is a heterogeneous disease and optimum gene targeting treatment is often impermissible. We aim to determine the intratumoral genomic heterogeneity of prostate cancer and explore candidate genes for targeted therapy. Exome sequencing was performed on 37 samples from 16 patients with prostate cancer. Somatic variant analysis, copy number variant (CNV) analysis, clonal evolution analysis and variant spectrum analysis were used to study the intratumoral genomic heterogeneity and genetic characteristics of metastatic prostate cancer. Our study confirmed the high intratumoral genetic heterogeneity of prostate cancer in many aspects, including number of shared variants, tumor mutation burden (TMB), variant genes, CNV burden, weighted genome instability index (wGII), CNV profiles, clonal evolutionary process, variant spectrum and mutational signatures. Moreover, we identified several common genetic characteristics of prostate cancer. Alterations of DNA damage repair genes, RTK/RAS pathway associated gene RASGRF1 and autophagy gene EPG5 may be involved in tumorigenesis in prostate cancer. CNV burden and DNA damage repair (DDR) genes may be associated with metastasis of prostate cancer.

Endocrinotherapy resistance of prostate and breast cancer: Importance of the NF‑κB pathway (Review).

Prostate cancer (PCa) and breast cancer(BCa) are two common sex hormone‑related cancer types with high rates of morbidity, and are leading causes of cancer death globally in men and women, respectively. The biological function of androgen or estrogen is a key factor for PCa or BCa tumorigenesis, respectively. Nevertheless, after hormone deprivation therapy, the majority of patients ultimately develop hormone‑independent malignancies that are resistant to endocrinotherapy. It is widely recognized, therefore, that understanding of the mechanisms underlying the process from hormone dependence towards hormone independence is critical to discover molecular targets for the control of advanced PCa and BCa. This review aimed to dissect the important mechanisms involved in the therapeutic resistance of PCa and BCa. It was concluded that activation of the NF‑κB pathway is an important common mechanism for metastasis and therapeutic resistance of the two types of cancer; in particular, the RelB‑activated noncanonical NF‑κB pathway appears to be able to lengthen and strengthen NF‑κB activity, which has been a focus of recent investigations.