Prostate Carcinoma Progression Research Articles

PSMC4 promotes prostate carcinoma progression by regulating the CBX3-EGFR-PI3K-AKT-mTOR pathway.

Proteasome 26S subunit ATPase 4 (PSMC4) could regulate cancer progression. However, the function of PSMC4 in prostate carcinoma (PCa) progression requires further clarification. In the study, PSMC4 and chromobox 3 (CBX3) levels were verified by TCGA data and tissue microarrays. Cell counting kit-8, cell apoptosis, cell cycle, wound healing, transwell and xenograft tumour model assays were performed to verify biological functions of PSMC4 in PCa. RNA-seq, PCR, western blotting and co-IP assays were performed to verify the mechanism of PSMC4. Results showed that PSMC4 level was significantly increased in PCa tissues, and patients with PCa with a high PSMC4 level exhibited shorter overall survival. PSMC4 knockdown markedly inhibited cell proliferation, cell cycle and migration in vitro and in vivo, and significantly promoted cell apoptosis. Then further study revealed that CBX3 was a downstream target of PSMC4. PSMC4 knockdown markedly reduced CBX3 level, and inhibited PI3K-AKT-mTOR signalling. CBX3 overexpression markedly promoted epidermal growth factor receptor (EGFR) level. Finally, PSMC4 overexpression showed reverse effect in DU145 cells, and the effects of PSMC4 overexpression on cell proliferation, migration and clonal formation were rescued by the CBX3 knockdown, and regulated EGFR-PI3K-AKT-mTOR signalling. In conclusion, PSMC4 could regulate the PCa progression by mediating the CBX3-EGFR-PI3K-AKT-mTOR pathway. These findings provided a new target for PCa treatment.

Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition

ABSTRACT New treatment options to battle hormone-refractory prostate carcinoma (PC) are a pressing medical need. Chronic inflammation has been implicated in PC etiology. The pro-inflammatory cytokines IL-6, IL-23 and IL-17 are key mediators to promote growth of PC. Here, we evaluate the potential of immunoproteasome inhibition for anti-inflammatory and direct anti-tumorigenic therapy of PC. The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration. Inhibition of the immunoproteasome subunit LMP7 induced apoptotic cell death in PC cell lines. In TRAMP mice, ONX 0914-treatment resulted in significant inhibition of PC growth with a decreased frequency of malignant prostatic lesions and inhibition of metastasis formation. The number of immunosuppressive myeloid cells in PC was greatly reduced in response to ONX 0914. Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

Expression and clinicopathological significance of glucocorticoid receptor, SGK1, and NDRG1 in hormone-naïve prostate carcinoma.

Glucocorticoid receptor (GR) has been implicated in prostate carcinoma growth and progression. Glucocorticoid receptor beta (GRβ) acts as an inhibitor of GR; however, its function is not well understood. Serum- and glucocorticoid-regulated kinase 1 (SGK1) is a GR-responsive gene that phosphorylates N-myc downstream-regulated gene 1 (NDRG1) and is involved in cancer growth and invasion. However, the expression of GR, GRβ, SGK1, and NDRG1 in prostate cancer and their relationship with clinicopathological and functional significance remain unknown. The association between the status of GR, GRβ, SGK1, and NDRG1 immunoreactivity and clinicopathological variables was analyzed in patients with prostate carcinoma to explore their clinical significance. In prostate carcinoma cases, the relative abundance of GR and NDRG1 immunoreactivity was inversely and significantly associated with the primary tumor stage (pT), while GR immunoreactivity was inversely and significantly associated with the Ki-67 score. The relative expression status of NDRG1 was significantly associated with that of GR. However, no significant correlation was observed between any of the clinicopathological parameters and GRβ and SGK1 expression. Our findings indicate that GR and NDRG1 expression status is correlated with clinicopathological features in patients with prostate cancer.

Comparative Pathobiology of Canine and Human Prostate Cancer: State of the Art and Future Directions.

Simple SummaryProstate cancer (PC) is one of the main types of cancer that affects the male population worldwide. In recent decades, there has been a significant evolution in the methods of diagnosis and treatment, mainly due to the development of new research in the field of molecular biology, allowing for a better understanding of how this cancer develops and progresses from a genetic point of view. In addition to humans, the canine is the only mammal that develops PC spontaneously. However, in dogs, PC has a distinct form, with high lethality rates. This work of scientific characterization of cancer in humans and dogs approaches how differences and similarities already all explain how PC develops and progresses in dogs, with a central tenet of molecular biology, that is, the transport between DNA, RNA and proteins. The understanding of these mechanisms makes it possible to identify new methods of the diagnosis and treatment of the disease, not only in men, but also in dogs.First described in 1817, prostate cancer is considered a complex neoplastic entity, and one of the main causes of death in men in the western world. In dogs, prostatic carcinoma (PC) exhibits undifferentiated morphology with different phenotypes, is hormonally independent of aggressive character, and has high rates of metastasis to different organs. Although in humans, the risk factors for tumor development are known, in dogs, this scenario is still unclear, especially regarding castration. Therefore, with the advent of molecular biology, studies were and are carried out with the aim of identifying the main molecular mechanisms and signaling pathways involved in the carcinogenesis and progression of canine PC, aiming to identify potential biomarkers for diagnosis, prognosis, and targeted treatment. However, there are extensive gaps to be filled, especially when considering the dog as experimental model for the study of this neoplasm in humans. Thus, due to the complexity of the subject, the objective of this review is to present the main pathobiological aspects of canine PC from a comparative point of view to the same neoplasm in the human species, addressing the historical context and current understanding in the scientific field.

Transcription Factors as Novel Therapeutic Targets and Drivers of Prostate Cancer Progression.

Prostate cancer is the second most diagnosed cancer among men worldwide. Androgen deprivation therapy, the most common targeted therapeutic option, is circumvented as prostate cancer progresses from androgen dependent to castrate-resistant disease. Whilst the nuclear receptor transcription factor, androgen receptor, drives the growth of prostate tumor during initial stage of the disease, androgen resistance is associated with poorly differentiated prostate cancer. In the recent years, increased research has highlighted the aberrant transcriptional activities of a small number of transcription factors. Along with androgen receptors, dysregulation of these transcription factors contributes to both the poorly differentiated phenotypes of prostate cancer cells and the initiation and progression of prostate carcinoma. As master regulators of cell fate decisions, these transcription factors may provide opportunity for the development of novel therapeutic targets for the management of prostate cancer. Whilst some transcriptional regulators have previously been notoriously difficult to directly target, technological advances offer potential for the indirect therapeutic targeting of these transcription factors and the capacity to reprogram cancer cell phenotype. This mini review will discuss how recent advances in our understanding of transcriptional regulators and material science pave the way to utilize these regulatory molecules as therapeutic targets in prostate cancer.

Evaluation of Zinc in Patients of Prostatic Carcinoma

ackground: Zinc is an essential trace element, with the primary function to manufacture proteins and nucleic acid. It has an important role in the healthy functioning of the prostate gland. Objective: To assess the correlation of serum zinc level with the progression of prostatic carcinoma. Methodology: This cross-sectional study was done on 100 subjects with enlarged prostate, who underwent prostatectomy, were selected from Urology OPD, Shaikh Zayed Hospital, Lahore from October 2011 to November 2017. A total of 70 individuals who were positive for prostate malignancy were included in the patient's group, and 30 individuals found to be negative for prostate malignancy, were included in the control group. The patient group was further divided into subgroups based on Gleason's score and stages of prostate cancer. Analysis of serum zinc was performed in the patient and the control group. SPSS version 20 was used for data analysis. Results: Mean serum zinc value (46.75±2.89 ug/dl) among prostate cancer patients was significantly lower from mean serum zinc value (88.27±7.8 ug/dl) of the control group (p-value 0.001). Serum zinc level in 1A (Stage 1), 47.89±3.96; 1B (Stage 2), 46.08±1.97; 1C (Stage 3), 45.35±3.06; and 1D (Stage 4), 42.51±2.68 had an inverse correlation to Gleason Score, showing serum zinc level decreased in subgroups as their Gleason Score, and stage of prostate carcinoma progressed. Conclusion: In this study, it may be concluded that serum zinc has a negative correlation to tumor progression and may be used as a biochemical indicator for its progression and prognosis.

LncRNA FGF14-AS2 represses growth of prostate carcinoma cells via modulating miR-96-5p/AJAP1 axis.

ObjectiveThis investigation devoted to lncRNA FGF14 antisense RNA 2 (FGF14‐AS2) in prostate carcinoma progression.MethodsThe levels of lncRNA FGF14‐AS2, miR‐96‐5p, and Adherens junction‐associated protein‐1 (AJAP1) in prostate carcinoma were tested by Western blot and qRT‐PCR. How these two genes interacted was confirmed by RNA immunoprecipitation and dualluciferase gene methods. The effect of FGF14‐AS2/miR‐96‐5p/AJAP1 axis in prostate carcinoma progression was determined by MTT, Transwell, and nude mice tumor model.ResultsFGF14‐AS2 was a downregulated lncRNA in prostate carcinoma tissue and cells. FGF14‐AS2 could restrain miR‐96‐5p expression while miR‐96‐5p hampered AJAP1. FGF14‐AS2 could effectively decrease the biological behaviors of prostate carcinoma cells, while knock‐down of FGF14‐AS2 triggered opposite results. Moreover, miR‐96‐5p mimic presented a cancer promoter role in prostate carcinoma cells. AJAP1 expression level could affect levels of proteins related to epithelial‐mesenchymal transition. In vivo experiment suggested that overexpressing FGF14‐AS2 could reverse the promotion of silenced AJAP1 on prostate carcinoma cell metastasis, thus to inhibit tumor growth.ConclusionlncRNA FGF14‐AS2 was a downregulated lncRNA in prostate carcinoma and influenced cell proliferation and metastasis. The influence relied on modulating miR‐96‐5p and its target gene AJAP1.

Relationship Between Vascular Endothelial Growth Factor Expression and Gleason Score in Prostate Carcinoma

Introduction. Prostate cancer is the most common cancer in men worldwide and ranks second in the Laboratory of Anatomical Pathology, Dr. Mohammad Hoesin with the highest incidence, especially at the age of more than 60 years. Factors that play a role as a prognostic factor and therapy in prostate carcinoma, including VEGF. The role of VEGF expression in prostate carcinoma as a prognostic and histopathological factor which is an important predictor for the progression of prostate carcinoma. This study aims to determine the relationship between VEGF expression and Gleason score in prostate carcinoma.
 Method. This study was a cross-sectional observational study. Thirty samples diagnosed with prostate adenocarcinoma were derived from the results of the tranurethral resection of the prostate (TRUP) and prostatectomy. Samples were taken from the archives in the Anatomic Pathology section of Dr. Mohammad Hoesin Palembang (period January 1, 2011 to December 31, 2013. Then the sample was stained with VEGF antibody, identified and analyzed the VEGF relationship with the Gleason.z score.
 Results. The positivity of VEGF expression in prostate adenocarcinoma tended to be more prevalent in the Gleason score group ≥ 7 (43.3%) than in the Gleason score group <(10%). There was no significant relationship between VEGF expression and high Gleason score (p> 0.05).
 Conclusion. There was no significant relationship between VEGF expression and Gleason score in prostate adenocarcinoma

LINC00467 Promotes Prostate Cancer Progression via M2 Macrophage Polarization and the miR-494-3p/STAT3 Axis.

BackgroundThe long non-coding RNA LINC00467 plays a vital role in many malignancies. Nevertheless, the role of LINC00467 in prostate carcinoma (PC) is unknown. Herein, we aimed to explore the mechanism by which LINC00467 regulates PC progression.MethodsWe used bioinformatics analyses and RT-qPCR to investigate the expression of LINC00467 in PC tissues and cells. The function of LINC00467 in the progression of PC was confirmed by loss-of-function experiments. PC cell proliferation was assessed by CCK-8 and EdU assays. The cell cycle progression of PC cells was examined by flow cytometry. Moreover, Transwell assays were used to investigate the migration and invasion of PC cells. Western blot assays were used to detect the expression of factors associated with epithelial–mesenchymal transition. The interactions of LINC00467 with prostate cancer progression and M2 macrophage polarization were confirmed by RT-qPCR. The subcellular localization of LINC00467 was investigated via the fractionation of nuclear and cytoplasmic RNA. Bioinformatics data analysis was used to predict the correlation of LINC00467 expression with miR-494-3p expression. LINC00467/miR-494-3p/STAT3 interactions were identified by using a dual-luciferase reporter system. Finally, the influence of LINC00467 expression on PC progression was investigated with an in vivo nude mouse model of tumorigenesis.ResultsWe established that LINC00467 expression was upregulated in PC tissues and cells. Downregulated LINC00467 expression inhibited PC cell growth, cell cycle progression, migration, and invasion. Downregulated LINC00467 expression similarly inhibited PC cell migration via M2 macrophage polarization. Western blot analysis showed that LINC00467 could regulate the STAT3 pathway. We established that LINC00467 is mainly localized to the cytoplasm. Bioinformatics analysis and rescue experiments indicated that LINC00467 promotes PC progression via the miR-494-3p/STAT3 axis. Downregulated LINC00467 expression was also able to suppress PC tumor growth in vivo.ConclusionsOur study reveals that LINC00467 promotes prostate cancer progression via M2 macrophage polarization and the miR-494-3p/STAT3 axis.

Progression of prostate carcinoma is promoted by adipose stromal cell-secreted CXCL12 signaling in prostate epithelium

Aggressiveness of carcinomas is linked with tumor recruitment of adipose stromal cells (ASC), which is increased in obesity. ASC promote cancer through molecular pathways not fully understood. Here, we demonstrate that epithelial–mesenchymal transition (EMT) in prostate tumors is promoted by obesity and suppressed upon pharmacological ASC depletion in HiMyc mice, a spontaneous genetic model of prostate cancer. CXCL12 expression in tumors was associated with ASC recruitment and localized to stromal cells expressing platelet-derived growth factor receptors Pdgfra and Pdgfrb. The role of this chemokine secreted by stromal cells in cancer progression was further investigated by using tissue-specific knockout models. ASC deletion of CXCL12 gene in the Pdgfr + lineages suppressed tumor growth and EMT, indicating stroma as the key source of CXCL12. Clinical sample analysis revealed that CXCL12 expression by peritumoral adipose stroma is increased in obesity, and that the correlating increase in Pdgfr/CXCL12 expression in the tumor is linked with decreased survival of patients with prostate carcinoma. Our study establishes ASC as the source of CXCL12 driving tumor aggressiveness and outlines an approach to treatment of carcinoma progression.

Hsa-miR-149-5p Suppresses Prostate Carcinoma Malignancy by Suppressing RGS17.

BackgroundMicroRNAs (miRNAs) are key players in the progression of human cancers. While several miRNAs have been reported to regulate the development of tumors, the molecular mechanisms and roles of miR-149-5p in prostate carcinoma (PCa) remain unclear. Our aim was to investigate the interaction and functions of miR-149-5p and RGS17 in PCa.MethodsMicroarray analysis was performed to identify the key miRNA and gene involved in PCa progression. The expression levels of miRNA and mRNA in PCa tissues and cells were verified by qRT-PCR. MTT assay, BrdU proliferation assay and wound-healing assay were applied to assess the effect of miR-149-5p and RGS17 on PCa cells’ viability, proliferation, and migration ability. The association between RGS17 and miR-149-5p was identify using dual-luciferase reporter assay and Western blot assay.ResultsData analysis indicated the reduction of miR-149-5p expression in PCa tissues and cells. Experimental investigations also showed that this miRNA suppressed the viability, proliferation and migration ability of PCa cells. RGS17 was found to be the target of miR-149-5p, and the low expression of miR-149-5p upregulated RGS17 in PCa tissues and cells. The results of the cell-function assays showed that RGS17 acted as an oncogene in PCa even though its promotive effect could be reversed by miR-149-5p.ConclusionThis research confirmed that by targeting and inhibiting RGS17, miR-149-5p could suppress PCa development.

Relationship Between Vascular Endothelial Growth Factor Expression and Gleason Score in Prostate Carcinoma

Introduction: Prostate cancer is the most common cancer in men worldwide and ranks second in the Laboratory of Anatomical Pathology, Dr. Mohammad Hoesin with the highest incidence, especially at the age of more than 60 years. Factors that play a role as a prognostic factor and therapy in prostate carcinoma, including VEGF. The role of VEGF expression in prostate carcinoma as a prognostic and histopathological factor which is an important predictor for the progression of prostate carcinoma. This study aims to determine the relationship between VEGF expression and Gleason score in prostate carcinoma.
 Method: This study was a cross-sectional observational study. Thirty samples diagnosed with prostate adenocarcinoma were derived from the results of the tranurethral resection of the prostate (TRUP) and prostatectomy. Samples were taken from the archives in the Anatomic Pathology section of Dr. Mohammad Hoesin Palembang (period January 1, 2011 to December 31, 2013. Then the sample was stained with VEGF antibody, identified and analyzed the VEGF relationship with the Gleason.z score.
 Results: The positivity of VEGF expression in prostate adenocarcinoma tended to be more prevalent in the Gleason score group ≥ 7 (43.3%) than in the Gleason score group <(10%). There was no significant relationship between VEGF expression and high Gleason score (p> 0.05).
 Conclusion: There was no significant relationship between VEGF expression and Gleason score in prostate adenocarcinoma

TRIM66 promotes malignant progression of prostate carcinoma through the JAK/STAT pathway

Prostate cancer is the fifth leading cause of cancer‐related deaths in males globally. Tripartite Motif Containing 66 (TRIM66) functions as transcriptional repressor and exerts its effect at least partially through promotion of deacetylase. TRIM66 has been previously reported to play an oncogenic role in a number of human cancers. Here, we investigated the potential oncogenic properties of TRIM66 in prostate cancer. We report that shRNA‐mediated knockdown of TRIM66 significantly suppressed viability and proliferation of both PC‐3 and DU145 prostate cancer cell lines. Furthermore, TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. Mechanistically, TRIM66 positively regulated signal transducer and activator of transcription 2 (STAT2) and interleukin‐2 (IL‐2) expression. The predominance of STAT2–IL‐2 in mediating the oncogenic properties of TRIM66 was determined using a rescue assay, wherein overexpression of either STAT2 or IL‐2 almost completely abolished the inhibitory effects on cell proliferation, migration and invasion elicited by TRIM66 deficiency in prostate cancer cells. Our study highlights the importance of the TRIM66–STAT2–IL‐2 signaling axis in the tumor biology of prostate cancer.

The M6A methyltransferase METTL3 promotes the development and progression of prostate carcinoma via mediating MYC methylation.

N6-methyladenosine (m6A) is the richest modification in mammalian messenger RNAs (mRNAs), and exerts key roles in many biological processes, including cancer development, whereas its roles in prostate carcinoma (PCa) remain to be unclear. Here, we found that m6A modifications are increased in PCa and methyltransferase-like 3 (METTL3), but not other major m6A modification genes including METTL14, fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5), was the major dysregulated gene associated with abnormal m6A modification. In addition, METTL3 up-regulation acted as a poor prognostic factor for overall survival and disease-free survival in PCa patients. Knockdown of METTL3 significantly inhibited PCa cells proliferation, migration, and invasion. In addition, over-expression of METTL3, but not its catalytic mutant form, significantly promoted PCa cells growth and progression. Mechanistically, we revealed that METTL3 enhanced MYC(c-myc) expression by increasing m6A levels of MYC mRNA transcript, leading to oncogenic functions in PCa. Importantly, PCa cells growth and progression inhibition by METTL3 knockdown were restored through over-expression of MYC. Our results uncovered a METTL3/m6A/MYC axis and provided insight into the mechanisms of PCa progression.

Immunohistochemical expression of androgen receptors in prostate carcinoma and benign prostatic hyperplasia

Background/Aim. Prostate carcinoma (PCa) and its parent organ are influenced by hormones, which is used for therapeutic purposes. Through androgen receptors (AR) androgens influence cell growth and function, proliferation, differentiation, apoptosis, lipid metabolism and secretory activity of the prostate, as well as development and progression of PCa. An antiandrogen therapy is carried out in patients with metastatic PCa, in order to block effects of androgens. By conducting immunohistochemical analysis of androgen receptors in the PCa tissue, we can assume how the tumour will react to an administered antiandrogen therapy, both in androgen-positive and androgen-negative, resistant tumours. Knowledge of the presence of AR in the tumour tissue may serve as a prognostic indicator in histopathological analysis. The aim of this study was to evaluate the expression of AR in patients with benign prostatic hyperplasia (BPH) and in those with PCa, before therapy. Methods. Immunohistochemical analysis was carried out by using anti-human AR monoclonal antibody AR441 (DAKO), and presence and intensity of AR were semi-quantitatively evaluated in 195 patients, 165 with BPH and 30 with PCa. Material for analysis was obtained by needle biopsy or transurethral resection of the prostate (TURP). Results. All secretory cells in patients with BPH were intensively androgen positive, while in patients with PCa they were mostly moderately to highly positive, but with foci of negativity. The observed negative correlation between AR and Gleason score and the International Society of Urologic Pathology (ISUP) grade group of PCa was not statistically significant. Conclusion. Study results indicate that PCa, before therapy, is androgen-dependent, with a high level of AR expression.

Increased Soluble CMG2 Serum Protein Concentration is Associated with the Progression of Prostate Carcinoma.

Prostate carcinoma (PCa) is one of the leading causes of cancer-related death in males, but biomarkers for the prognosis are rare. Capillary morphogenesis gene 2 (CMG2) is a modulator of extracellular matrix remodeling during angiogenesis. Four isoforms of CMG2 have been described so far, one secreted in the serum as soluble CMG2 (sCMG2). The aim of this study was to evaluate the sCMG2 serum concentrations in 179 PCa patients and 163 age-matched control subjects by ELISA and correlate it to clinical and demographic parameters. We observed that sCMG2 concentration is increased in the serum of PCa patients with metastases, while no significant differences in the concentrations were detected between the control subjects and patients with localized PCa. Furthermore, elevated sCMG2 concentrations were significantly associated with the highest T stage. Increased sCMG2 serum concentrations tended to be associated with a worsened overall and disease-specific survival of the PCa patients. In conclusion, sCMG2 may be an interesting additive biomarker for the prediction of the progression of PCa and the patients’ outcome.

MicroRNA-200c-3p/ZEB2 loop plays a crucial role in the tumor progression of prostate carcinoma.

The microRNA (miRNA) miR-200c-3p is involved in the tumorigenesis and progression of a variety of cancers. However, the underlying regulatory role of miR-200c-3p in prostate cancer (PCa) remains unclear. Online databases including Oncomine, Linkedomics and StarBase were used to investigate the clinical significance of miR-200c-3p, along with associated gene targets. PCa tissues and adjacent normal tissues were used for the detection of miR-200c-3p expression. A lentivirus overexpressing miR-200c-3p was constructed and transfected into PC3 and DU145 cells. Cell formation of proliferation, migration, and invasion were determined by cell viability and colony-formation assay, wound healing assay, and Matrigel invasion assay, respectively. Epithelial-mesenchymal transition (EMT)-associated markers were determined by qRT-PCR and Western blot. A luciferase reporter assay was performed to determine the direct relationship of miR-200c-3p and ZEB2. The tumor-suppressive role of miR-200c-3p was further confirmed by a xenograft tumor model and immunohistochemical (IHC) staining. Online database analyses showed that miR-200c-3p was associated with pathologic T and N stage in PCa, and miR-200c-3p was downregulated in PCa tissues. Overexpression of miR-200c-3p was considered a tumor suppressor and was found to significantly suppress the formation of migration and invasion in PCa cells via repression of E-cadherin-induced EMT. The bioinformatic database indicated that ZEB2 has a significant correlation with miR-200c-3p and was upregulated in PCa tissues. Further, ZEB2 expression was suppressed by the upregulation of miR-200c-3p and was identified as a direct target of miR-200c-3p. In addition, repression of ZEB2 could restore the levels of miR-200c-3p in PCa cells in turn, suggesting a potential negative loop between miR-200c-3p and ZEB2. miR-200c-3p also had an antitumor effect by negatively regulating ZEB2 in a xenograft mouse model. Taken together, the results of our study demonstrated the novel regulatory loop of miR-200c-3/ZEB2 in PCa progression, providing effective therapeutic strategies for PCa in the future.

Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis.

Leukocyte infiltration plays an active role in controlling tumor development. In the early stages of carcinogenesis, T cells counteract tumor growth. However, in advanced stages, cancer cells and infiltrating stromal components interfere with the immune control and instruct immune cells to support, rather than counteract, tumor malignancy, via cell-cell contact or soluble mediators. In particular, metabolites are emerging as active players in driving immunosuppression. Here we demonstrate that in a prostate cancer model lactate released by glycolytic cancer-associated fibroblasts (CAFs) acts on CD4+ T cells, shaping T-cell polarization. In particular, CAFs exposure (i) reduces the percentage of the antitumoral Th1 subset, inducing a lactate-dependent, SIRT1-mediated deacetylation/degradation of T-bet transcription factor; (ii) increases Treg cells, driving naive T cells polarization, through a lactate-based NF-kB activation and FoxP3 expression. In turn, this metabolic-based CAF-immunomodulated environment exerts a pro-invasive effect on prostate cancer cells, by activating a previously unexplored miR21/TLR8 axis that sustains cancer malignancy.

MiR-106a contributes to prostate carcinoma progression through PTEN.

Prostate carcinoma is a global health problem and is estimated to be diagnosed in 1.1 million men/year, making this malignancy the second most frequently diagnosed cancer in males worldwide. micro RNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. miRNAs contribute to cancer development and progression, and are expressed differently in normal tissues and cancers. In the present study, the biological function of miR-106a in the human prostate carcinoma and the associated regulatory mechanisms were investigated. miR-106a was significantly upregulated in human prostate cancer tissues when compared with normal tissues (P<0.05), and the overexpression of miR-106a was identified to promote PC-3 cell growth. Additionally, miRNA-106a inhibition significantly suppressed PC-3 cell growth. Furthermore, it was observed that the phosphatase and tensin homolog (PTEN) expression level was negatively associated with miR-106a expression level, and miRNA-106a directly targeted PTEN in the PC-3 cells. PTEN overexpression has a similar effect on PC-3 cell growth as loss of miR-106a. Taken together, the results of the present study indicate that upregulated miR-106a regulates PC-3 cell proliferation through PTEN. These results suggest that appropriate manipulation of miR-106a may provide a novel strategy in the future treatment of human prostate cancer.

ERK5‑regulated RERG expression promotes cancer progression in prostatic carcinoma.

Big mitogen‑activated protein kinase 1 [also named extracellular signal‑regulated kinase (ERK)5] is activated by mitogens and oncogenic signals and is strongly implicated in tumorigenesis. Our previous investigation indicated that ERK5 can induce prostatic carcinoma cell proliferation by promoting entry into the S phase of the cell cycle. In the present study, microarray and western blot analysis revealed that ERK5 can inhibit Ras‑like oestrogen‑regulated growth inhibitor (RERG) protein expression and that the inhibition of RERG expression promotes prostatic carcinoma cell proliferation and migration. In addition, pathological analysis indicated that the RERG expression level was associated with the malignancy of prostatic carcinoma. Furthermore, an apoptotic assay and western blot analysis demonstrated that the downregulation of RERG expression inhibits apoptosis by regulating the protein expression levels of Bcell lymphoma‑2 and c‑Myc. Moreover, a luciferase activity assay indicated that the nuclear factor‑κB pathway is associated with RERG‑mediated apoptosis in prostatic carcinoma. Therefore, these data suggested that ERK5‑regulated RERG expression plays a role in the progression of prostatic carcinoma, indicating that RERG may be a potential biomarker for the prognosis of patients with prostatic carcinoma.