Promotes Prostate Cancer Cell Proliferation Research Articles

GPC2 promotes prostate cancer progression via MDK-mediated activation of PI3K/AKT signaling pathway

Prostate cancer is a major medical problem for men worldwide. Advanced prostate cancer is currently incurable. Recently, much attention was paid to the role of GPC2 in the field of oncology. Nevertheless, there have been no investigations of GPC2 and its regulatory mechanism in prostate cancer. Here, we revealed a novel action of GPC2 and a tumor promoting mechanism in prostate cancer. GPC2 was upregulated in prostate cancer tissues and cell lines. Higher expression of GPC2 was correlated with higher Gleason score, lymphatic metastasis, and worse overall survival in prostate cancer patients. Decreased expression of GPC2 inhibited cell proliferation, migration, and invasion in prostate cancer, whereas GPC2 overexpression promoted these properties. Mechanistically, GPC2 promoted the activation of PI3K/AKT signaling pathway through MDK. The rescue assay results in prostate cancer cells demonstrated that overexpression of MDK could attenuate GPC2 knockdown induced inactivation of PI3K/AKT signaling and partly reverse GPC2 knockdown induced inhibition of cell proliferation, migration, and invasion. In all, our study identified GPC2 as an oncogene in prostate cancer. GPC2 promoted prostate cancer cell proliferation, migration, and invasion via MDK-mediated activation of PI3K/AKT signaling pathway. GPC2 might be a promising prognosis predictor and potential therapeutic target in prostate cancer.

An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFβ Signaling.

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFβ/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

WDR1 promotes prostate cancer progression through Wnt/β-catenin signaling.

Prostate cancer (PCa) is the second most common cancer and the fifth leading cause of cancer-related death among men. A comprehensive understanding of PCa progression is crucial for the development of innovative therapeutic strategies for its treatment. While WDR1 (WD-repeat domain 1) serves as a significant cofactor of actin-depolymerizing factor/cofilin, its role in PCa progression remains unknown. In this study, we demonstrated that knockdown of WDR1 in various PCa cells substantially inhibited cell proliferation, migration, and invasion in vitro, as confirmed at both the cellular and molecular levels. Moreover, the overexpression of WDR1 promoted PCa cell proliferation and metastasis in vitro. Mechanistically, we showed that the application of lithium chloride, an activator of the Wnt/β-Catenin signaling pathway, restored the suppressive effects of WDR1 deficiency on cell proliferation and migration in PCa cells. Our findings suggest that the WDR1-β-Catenin axis functions as an activator of the malignant phenotype and represents a promising therapeutic target for PCa treatment.

Comprehensive analyses of the cancer-associated fibroblast subtypes and their score system for prediction of outcomes and immunosuppressive microenvironment in prostate cancer

BackgroundCancer-associated fibroblasts (CAFs) drive cancer progression and treatment failure on one hand, while their tumor-restraining functions are also observed on the other. Recent single cell RNA sequencing (scRNA-seq) analyses demonstrates heterogeneity of CAFs and defines molecular subtypes of CAFs, which help explain their different functions. However, it remains unclear whether these CAF subtypes have the same or different biological/clinical implications in prostate cancer (PCa) or other malignancies.MethodsPCa cells were incubated with supernatant from normal fibroblasts and CAFs to assess their effects on cell behaviors. Sequencing, genomic, and clinical data were collected from TCGA, MSKCC, CPGEA and GEO databases. CAF molecular subtypes and total CAF scores were constructed and grouped into low and high groups based on CAF-specific gene expression. Progression free interval (PFI), clinicopathological features, telomere length, immune cell infiltration, drug treatment and somatic mutations were compared among CAF molecular subtypes and low/high score groups.ResultsThe PCa CAF-derived supernatant promoted PCa cell proliferation and invasion. Based on differentially expressed genes identified by scRNA-seq analyses, we classified CAFs into 6 molecular subtypes in PCa tumors, and each subtype was then categorized into score-high and low groups according to the subtype-specific gene expression level. Such score models in 6 CAF subtypes all predicted PFI. Telomeres were significantly shorter in high-score tumors. The total CAF score from 6 CAF subtypes was also associated with PFI in PCa patients inversely, which was consistent with results from cellular experiments. Immunosuppressive microenvironment occurred more frequently in tumors with a high CAF score, which was characterized by increased CTLA4 expression and indicated better responses to CTLA4 inhibitors. Moreover, this model can also serve as a useful PFI predictor in pan-cancers.ConclusionBy combining scRNA-seq and bulk RNA-seq data analyses, we develop a CAF subtype score system as a prognostic factor for PCa and other cancer types. This model system also helps distinguish different immune-suppressive mechanisms in PCa, suggesting its implications in predicting response to immunotherapy. Thus, the present findings should contribute to personalized PCa intervention.

CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3.

Prostate cancer (PCa) is a prevalent malignancy among men, with a majority of patients presenting with distant metastases at the time of initial diagnosis. These patients are at a heightened risk of developing more aggressive castration‑resistant PCa following androgen deprivation therapy, which poses a greater challenge for treatment. Notably, the inhibition of tumor angiogenesis should not be considered an ineffective treatment strategy. The regulatory role of CDK12 in transcriptional and post‑transcriptional processes is essential for the proper functioning of various cellular processes. In the present study, the expression of CDK12 was first knocked down in cells using CRISPR or siRNA technology. Subsequently, RNA‑seq analysis, co‑immunoprecipitation, western blotting, reverse transcription‑quantitative polymerase chain reaction and the LinkedOmics database were employed to reveal that CDK12 inhibits insulin like growth factor binding protein 3 (IGFBP3). Western blot analysis also demonstrated that CDK12 promoted VEGFA expression by inhibiting IGFBP3, which involves the Akt signaling pathway. Then, CDK12 was found to promote PCa cell proliferation, cell migration and angiogenesis by inhibiting IGFBP3 through cell proliferation assays, cell migration assays and tube formation assays, respectively. Finally, animal experiments were performed for invivo validation. It was concluded that CDK12 promoted PCa and its angiogenesis by inhibiting IGFBP3.

Biological and clinical significance of the AGE-RAGE axis in the aggressiveness and prognosis of prostate cancer.

Dietary factors and chronic hyperglycemia are linked to the formation of advanced glycation end products (AGEs) and prostate cancer (PCa) risk. The activation of the receptor for AGEs (RAGE) acts as a bridge between various RAGE ligands and certain malignancies. This study showed that the interaction of AGEs and RAGE promoted PCa cell proliferation, invasion, and autophagy-mediated survival in response to chemotherapeutic agents. RAGE-overexpressed PCa cells underwent epithelial-mesenchymal transition and showed increased cancer stem cell-like properties. In mouse xenograft models, RAGE-overexpressed cells showed more substantial tumorigenic capacity than parental cells, whereas RAGE knockdown decreased tumorigenicity. The clinical data validated a positive correlation between high AGE and RAGE expressions with poor clinical outcomes. Our findings suggest that the AGE-RAGE axis facilitates PCa progression and aggressiveness. Prostatic AGEs and RAGE expression levels are associated with PCa prognosis. Adherence to a reduced-AGE diet and targeting RAGE are potential approaches to complement and synergize with the current PCa therapies.

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression

BackgroundCell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment.MethodsThe Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays.ResultsADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa.ConclusionsIn summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.

RCC2 promotes prostate cancer cell proliferation and migration through Hh/GLI1 signaling pathway and cancer stem-like cells

BackgroundRegulator of chromosome condensation 2 (RCC2) was a telophase disk-binding protein on mitosis, and functions as an oncogene in many human cancers. However, its role on prostate cancer (PCa) was unknown. The goal of this study is to explore the function of RCC 2 on PCa development.MethodsThe expression of RCC2 and its methylation level, its correlation with lymph node metastasis or disease-free survival (DFS) was analyzed using TCGA database. The effect of RCC2 on PCa cell proliferation, migration and invasion were detected using CCK-8, cell colony formation, Transwell and wood healing assays. RNA-seq and GSEA analysis were used to search the downstream genes and pathways of RCC2 in mediated PCa progression. Western blot was used to detect the proteins in PCa cells transfected with indicated siRNAs or plasmids.ResultsRCC2 had high expression and low promoter methylation level in PCa, and its expression was correlated with regional node metastasis and disease-free survival. Cell proliferation, migration, invasion and EMT of PCa cells in vitro were greatly enhanced after RCC2 overexpression, while the RCC2 knockdown suppressed these processes. RNA-seq and GSEA results showed the Hedgehog signaling regulator Gli1 and Gli3 were involved in RCC2 knockdown DU145 cells. Gli1 was also a marker of cancer stem-like cells (CSCs). Mechanistically, RCC2 induced cell growth, EMT, CSCs markers through Gli1; inhibiting Gli1 expression using siGli1 or GLI inhibitor suppressed cell progression in vitro and tumor growth in vivo.ConclusionIn summary, RCC2 promoted PCa development through Hh/Gli1 signaling pathway via regulating EMT and CSCs.

LncRNA BRCAT54 is downregulated and inhibits cancer cell proliferation by downregulating miR-130b-3p through methylation in prostate cancer.

BRCAT54 and miR-130b-3p are two recently characterized critical players in cancer biology, while their functions in prostate cancer (PC) are unknown. From preliminary sequencing analysis, we observed altered expression of BRCAT54 and miR-130b-3p in PC and an inverse correlation between them. This study was conducted to explore their involvement in PC. A total of 64 PC patients were enrolled to collect paired PC and nontumor tissues. The expression of BRCAT54 and miR-130b-3p were determined by RT-qPCR. Overexpression of BRCAT54 and miR-130b-3p was achieved in PC cells to explore their roles in regulating the expression of each other. Methylation-specific PCR (MSP) was conducted to explore the role of BRCAT54 in regulating promoter methylation of miR-130b-3p. BrdU assay was used to evaluate the role of BRCAT54 and miR-130b-3p in regulating PC cell proliferation. The results showed that PC tissues exhibited downregulation of BRCAT54 and upreglation of miR-130b-3p compared to that in nontumor tissues. They were inversely correlated across PC tissue samples. Overexpression of BRCAT54 decreased RNA accumulation of miR-130b-3p in PC cells. In addition, overexpression of BRCAT54 increased promoter methylation of miR-130b-3p. Moreover, BRCAT54 suppressed the role of miR-130b-3p in promoting PC cell proliferation. In conclusion, BRCAT54 is downregulated in PC and it may inhibit cancer cell proliferation by downregulating miR-130b-3p through methylation.

Low-dose antimony exposure promotes prostate cancer proliferation by inhibiting ferroptosis via activation of the Nrf2-SLC7A11-GPX4 pathway

Antimony (Sb) is a typical environmental pollutant. With the development of industrialization, antimony is widely used in daily life and enters the human body through the food chain, water source, air pollution, and other channels. The risk of antimony exposure has emerged as one of the public's major health concerns. Current research on antimony shows that antimony has certain biological toxicity, and antimony exposure may be one of the carcinogenic risk factors for bladder cancer, prostate cancer (PCa), and other cancers. But the molecular mechanism of antimony exposure in PCa is still unclear. Our results showed that serum antimony levels were significantly higher in PCa patients than in benign prostatic hyperplasia (BPH), and high levels of serum antimony were associated with poorer prognosis in PCa. We demonstrate that antimony exposure promotes PCa progression in vivo and in vitro. In addition, our results also showed that low-dose antimony exposure resulted in increased GSH, increased GPX4 expression, and decreased Fe2+. Since GPX4 and Fe2+ are important molecular features in the mechanism of ferroptosis, we further found that low-dose antimony exposure can inhibit RSL3-induced ferroptosis and promote PCa proliferation. Finally, our study demonstrates that low-dose antimony exposure promotes Nrf2 expression, increases the expression level of SLC7A11, and then increases the expression of GPX4, inhibits ferroptosis, and promotes PCa progression. Taken together, our experimental results suggest that low-dose antimony exposure promotes PCa cell proliferation by inhibiting ferroptosis through activation of the Nrf2-SLC7A11-GPX4 pathway. These findings highlight the link between low-dose antimony exposure and the Nrf2-SLC7A11-GPX4 ferroptosis pathway, providing a new potential direction for the prevention and treatment of PCa.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

CSNK1D-mediated phosphorylation of HNRNPA2B1 induces miR-25-3p/miR-93-5p maturation to promote prostate cancer cell proliferation and migration through m6A-dependent manner.

It has been reported that heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) is highly expressed in prostate cancer (PCa) and associated with poor prognosis of patients with PCa. Nevertheless, the specific mechanism underlying HNRNPA2B1 functions in PCa remains not clear. In our study, we proved that HNRNPA2B1 promoted the progression of PCa through in vitro and in vivo experiments. Further, we found that HNRNPA2B1 induced the maturation of miR-25-3p/miR-93-5p by recognizing primary miR-25/93 (pri-miR-25/93) through N6-methyladenosine (m6A)-dependent manner. In addition, both miR-93-5p and miR-25-3p were proven as tumor promoters in PCa. Interestingly, by mass spectrometry analysis and mechanical experiments, we found that casein kinase 1 delta (CSNK1D) could mediate the phosphorylation of HNRNPA2B1 to enhance its stability. Moreover, we further proved that miR-93-5p targeted BMP and activin membrane-bound inhibitor (BAMBI) mRNA to reduce its expression, thereby activating transforming growth factor β (TGF-β) pathway. At the same time, miR-25-3p targeted forkhead box O3 (FOXO3) to inactivate FOXO pathway. These results collectively indicated that CSNK1D stabilized HNRNPA2B1 facilitates the processing of miR-25-3p/miR-93-5p to regulate TGF-β and FOXO pathways, resulting in PCa progression. Our findings supported that HNRNPA2B1 might be a promising target for PCa treatment.

Long noncoding RNA GHET1 promotes cell proliferation through oxidative stress in prostate cancer.

Gastric carcinoma high expressed transcript 1 (GHET1) is an oncogenic Long noncoding RNA. GHET1 expression promotes multiple levels of developing a complex molecular network. The main purpose of the study was to investigate the mechanism by which long noncoding RNA (lncRNA) GHET1 promotes prostate cancer cell proliferation and related metabolism. In vitro study, lncRNA GHET1 was overexpressed in LN-cap, PC-3, 22RV1, and C4-2 cells. The cell viability was measured by MTT and trans-well assay. A flow cytometer was also used to detect cell cycles and apoptosis. Western blot analysis was used for protein expression validation. mRNA expression was detected by real-time PCR. lncRNA GHET1 enhanced cell proliferation, migration, and could resist paclitaxel-induced apoptosis and cell cycle arrest GHET1 expression stimulates reactive oxygen species (ROS) level upregulated in prostate cancer cells, increased the expression of HIFα, IL-1B and IL-6, and activated ROS/STAT-3/Twsit1 signaling pathway. Knockdown GHET1 could reduce cell proliferation and migration due to the overexpression of GHET1. lncRNA GHET1 promotes prostate cancer growth through oxidative stress signaling pathways and resists the antineoplastic drug paclitaxel, which can be used as a target for antineoplastic therapy and drug resistance therapy in the future in clinics.

LncRNA HOXA11-AS modulates the miR-148b-3p/MLPH axis to promote prostate cancer cell proliferation.

Prostate cancer refers to the epithelial malignant tumor of the prostate. It has a high incidence and mortality rate, seriously endangering the lives of men. In recent years, lncRNAs have become a hot topic for lots of scholars for their regulation functions on assorted cancers. Several lncRNAs have been proven they can take part in the regulation of prostate cancer development. Nevertheless, how HOXA11-AS (homeobox A11 antisense RNA)functioned in prostate cancer is not explained. In our research, the expression of HOXA11-AS in prostate cancer cells was evaluated through qRT-PCR. Colony formation experiments, EdU experiments, Tanswelland TUNEL experiments, as well as caspase-3 detection, were designed to test cell proliferation, migration, invasion and apoptosis. RIP, pull down and luciferase reporter experiments examined the correlations of HOXA11-AS, miR-148b-3p and MLPH. We discovered a high level of HOXA11-AS in prostate cancer cells.HOXA11-AS silence could restrain the mentioned cell malignant behavior. Mechanically, HOXA11-AS could sponge miR-148b-3p to target MLPH. MLPH was positively associated with HOXA11-AS and overexpressed it accelerated the progression of prostate cancer. Taken together, HOXA11-AS elevated MLPH expression by sponging miR-148b-3p and accelerated prostate cancer cell proliferation.

Downregulation of BUD31 Promotes Prostate Cancer Cell Proliferation and Migration via Activation of p-AKT and Vimentin In Vitro.

Among men, prostate cancer (PCa) is the second most frequently diagnosed cancer subtype and has demonstrated a high degree of prevalence globally. BUD31, also known as Functional Spliceosome-Associated Protein 17, is a protein that works at the level of the spliceosome; it is functionally implicated in pre-mRNA splicing as well as processing, while also acting as a transcriptional regulator of androgen receptor (AR) target genes. Clinically, the expression of BUD31 and its functions in the development and progression of PCa is yet to be elucidated. The BUD31 expression was assessed using IHC in a tissue microarray (TMA) constructed from a cohort of 284 patient samples. In addition, we analyzed the prostate adenocarcinoma (TCGAPRAD-) database. Finally, we used PCa cell lines to knockdown BUD31 to study the underlying mechanisms in vitro.Assesment of BUD31 protein expression revealed lower expression in incidental and advanced PCa, and significantly lower expression was observed in patients diagnosed with castrate-resistant prostate cancer. Additionally, bioinformatic analysis and GSEA revealed that BUD31 increased processes related to cancer cell migration and proliferation. In vitro results made evident that BUD31 knockdown in PC3 cells led to an increase in the G2 cell population, indicating a more active and proliferative state. Additionally, an investigation of metastatic processes revealed that knockdown of BUD31 significantly enhanced the ability of PC3 cells to migrate and invade. Our in vitro results showed BUD31 knockdown promotes cell proliferation and migration of prostate cancer cells via activation of p-AKT and vimentin. These results support the clinical data, where low expression of BUD31 was correlated to more advanced stages of PCa.

NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation

Prostate cancer (PCa) is the most common malignant tumor with a high global incidence in males. The mechanism underlying PCa progression is still not clear. This study observed that NRP1 was highly expressed in PCa and associated with poor prognosis in PCa patients. Functionally, NRP1 depletion attenuated the proliferation and migration ability of PCa cells in vitro and in vivo, while NRP1 overexpression promoted PCa cell proliferation and migration. Moreover, it was observed that NRP1 depletion induced G1 phase arrest in PCa cells. Mechanistically, HIF1α is bound to the specific promoter region of NRP1, thereby regulating its transcriptional activation. Subsequently, NRP1 interacted with EGFR, leading to EGFR phosphorylation. This study also provided evidence that the b1/b2 domain of NRP1 was responsible for the interaction with the extracellular domain of EGFR. Moreover, EGFR mediated NRP1-induced activation of the AKT signaling pathway, which promoted the malignant progression of PCa. In addition, the administration of NRP1 inhibitor EG01377 significantly inactivated the EGFR/AKT signaling axis, thereby suppressing PCa progression. In conclusion, the findings from this study highlighted the molecular mechanism underlying NRP1 expression in PCa and provide a potential predictor and therapeutic target for clinical prognosis and treatment of PCa.

In silico, in vitro and in vivo studies: Dibutyl phthalate promotes prostate cancer cell proliferation by activating Forkhead Box M1 and remission after Natura-α pretreatment

Dibutyl phthalate (DBP) is widely used in perfumes, cosmetics, shampoos and medical devices. It is ubiquitous in the environment and greatly endangers people's health. Several studies have reported that being exposed to it can promote the development of lung cancer, breast cancer, hepatoma, and multiple myeloma. However, there are still few studies on the specific molecular mechanism and prevention methods of DBP promoting the progression of prostate cancer. This study, in silico, in vitro and in vivo, aims to explore the promoting effect of DBP on prostate cancer cell proliferation. In silico analysis, we obtained a set of DBP interactive genes by utilizing TCGA, CTD and GEO database. These genes are mainly enriched in cell cycle regulatory pathways and they have high degree of homogeneity. We found that these genes shared one transcription factor - Forkhead Box M1 (FOXM1) by performing Chip-X Enrichment Analysis (Version 3.0). FOXM1, once called the 2010 Molecule of the Year, aberrantly expressed in up to 20 kinds of tumors. In vitro experiments, we used DBP at concentrations of 10−8 M and 5 * 10−7 M to treat C4–2 and PC3 cells for 6 days, respectively. Cell viability was promoted significantly. When Natura-α was added in the background of above-mentioned concentration of DBP, this effect was significantly inhibited. In addition, we also found that DBP can interfering with the efficacy of enzalutamide therapy. The introduction of Natura-α can also reverse this phenomenon. In vivo, subcutaneous tumor formation experiments in nude mice, 800 mg/kg/day DBP can promote the growth of prostate cancer. This phenomenon was suppressed when Natura-α (100 mg/kg/day) was added. Based on the results of the above three levels, we confirmed that DBP can target FOXM1 to promote prostate cancer cell proliferation. Natura-α can reverse its cancer-promoting effect. This study provides new insights into the impact of DBP on prostate cancer.

LncRNA SPRY4‑IT1 is upregulated and promotes the proliferation of prostate cancer cells under hypoxia in vitro.

The incidence and mortality rate of prostate cancer are among the highest for all cancers worldwide; this disease has a high cancer mortality rate in males, following lung cancer. Sprouty4-intron 1 (SPRY4-IT1) has been shown to play a variety of roles in tumors. Our previous study demonstrated that SPRY4-IT1 sponges microRNA-101-3p to promote the proliferation and metastasis of bladder cancer cells by upregulating enhancer of zeste homolog 2 expression; however, the role of SPRY4-IT1 in prostate cancer has not been fully established. In the present study, the expression levels, effects and mechanism of action of SPRY4-IT1 were investigated in prostate cancer tissues and cell lines using reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 and flow cytometry assays. The results indicated that SPRY4-IT1 expression was upregulated in prostate cancer tissues and cell lines. Furthermore, hypoxia increased the expression levels of SPRY4-IT1 in prostate cancer cells. Knockdown of SPRY4-IT1 expression led to S-phase arrest, decreased expression levels of the cell cycle-associated proteins CDK2 and cyclin D1. AKT phosphorylation was also reduced by SPRY4-IT1 knockdown. In summary, the findings indicate the elevation of SPRY4-IT1 expression in prostate cancer. Under hypoxic conditions in vitro, SPRY4-IT1 overexpression promoted prostate cancer cell proliferation via a mechanism involving regulation of the cell cycle and the PI3K/AKT signaling pathway. Therefore, it may provide a basis for the development of targeted therapies.

Ribosomal protein L22-like1 promotes prostate cancer progression by activating PI3K/Akt/mTOR signalling pathway.

Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22-like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy.

Exosome-derived circTFDP2 promotes prostate cancer progression by preventing PARP1 from caspase-3-dependent cleavage.

Circular RNAs (circRNAs) have been reported to play a significant role in tumorigenesis. However, the detailed function of circRNA in prostate cancer (PCa) is still largely unknown. We quantified circTFDP2 expression in PCa tissues and adjacent normal tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Colony formation, Cell Counting Kit-8 (CCK-8), flow cytometry, transwell, and in vivo progression and metastasis assays were applied to reveal the proliferation and metastatic abilities of circTFDP2 in PCa cells. Mass spectrometry, RNA pulldown, RNA-immunoprecipitation (RIP), western blotting and immunofluorescence were used for the mechanistic studies. qRT-PCR and RIP assays were used to explore the regulatory role of eIF4A3 in the biogenesis of circTFDP2. Finally, functional assays showed the effect of circTFDP2-containing exosomes on PCa cell progression. circTFDP2 was upregulated in PCa tissues compared with adjacent normal tissues. Furthermore, high circTFDP2 expression was positively correlated with the Gleason score. Functionally, circTFDP2 promoted PCa cell proliferation and metastasis both in vivo and in vitro. Mechanistically, circTFDP2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) protein in its DNA-binding domain to prevent it from active caspase-3-dependent cleavage, and finally relieved PCa cells from DNA damage. In addition, RNA-binding protein eIF4A3 can interact with the flanking region of circTFDP2 and promote the biogenesis of circTFDP2. Moreover, exosome-derived circTFDP2 promoted PCa cell progression. In general, our study demonstrated that circTFDP2 promoted PCa cell progression through the PARP1/DNA damage axis, which may be a promising therapeutic target for PCa.