The epigenetic regulatory mechanism of PIWI/piRNAs in human cancers.

PIWI proteins have a strong correlation with PIWI-interacting RNAs (piRNAs), which are significant in development and reproduction of organisms. Recently, emerging evidences have indicated that apart from the reproductive function, PIWI/piRNAs with abnormal expression, also involve greatly in varieties of human cancers. Moreover, human PIWI proteins are usually expressed only in germ cells and hardly in somatic cells, so the abnormal expression of PIWI proteins in different types of cancer offer a promising opportunity for precision medicine. In this review, we discussed current researches about the biogenesis of piRNA, its epigenetic regulatory mechanisms in human cancers, such as N6-methyladenosine (m6A) methylation, histone modifications, DNA methylation and RNA interference, providing novel insights into the markers for clinical diagnosis, treatment and prognosis in human cancers.

Serum Neuroendocrine Markers Predict Therapy Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis.

PURPOSE: To evaluate whether serum neuroendocrine markers could effectively predict treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: The PubMed, Cochrane Library and Embase databases were sought to identify eligible studies concerning serum neuroendocrine markers and the prognosis of post-treatment mCRPC from inception to April 2018. The association between serum neuroendocrine markers, that is, chromogranin A (CgA) and neurone-specific enolase (NSE), levels and the prognosis of post-treatment mCRPC were summarized using a random-effects model and hazard ratio (HR) with 95% CI Sensitivity analyses were conducted to assess potential bias. RESULTS: A total of 234 participants are included in this meta-analysis (mean age = 71.3 years) from 6 studies. The pooled results show that higher markers' levels at baseline in patients were associated with unfavorable overall survival (OS; univariate analysis: HR 3.775, 95% CI 1.469-9.698, p = 0.006; multivariate analysis: HR 3.838, 95% CI 1.774-8.304, p = 0.001), and a similar situation was observed in progression-free survival (PFS; univariate analysis: HR 2.785, 95% CI 1.315-5.898, p = 0.007; multivariate analysis: HR 1.266, 95% CI 1.017-1.577, p = 0.035). Estimates of the total effects were generally consistent in the sensitivity analysis. Publication bias was observed when performing the univariate analysis of PFS, and we have the explanation accordingly. CONCLUSIONS: The results of this pooled analysis confirm serum neuroendocrine markers could be the effective predictor of treatment outcome in patients with mCRPC. In addition, a combination of CgA and NSE is more valuable to predict worse OS. Further randomized case-control trials are required to validate this relationship.

Bone marrow mesenchymal stem cells reduce ureteral stricture formation in a rat model via the paracrine effect of extracellular vesicles.

With no effective therapy to prevent or treat ureteral stricture (US), a multifactorial fibrotic disease after iatrogenic injury of the ureter, the need for new therapies is urgent. Mesenchymal stem cells (MSCs) have been widely studied for treating tissue defects and excessive fibrosis, and recent studies established that one of the main therapeutic vectors of MSCs is comprised in their secretome and represented by extracellular vesicles (EVs). Thus, we have determined to explore the specific role of MSCs-derived EVs (MSC-EVs) treatment in a pre-clinical model of US. The results firstly showed that either a bolus dose of MSCs or a bolus dose of MSC-EVs (administration via renal-arterial) significantly ameliorated ureteral fibrosis and recuperated ureter morphological development in a US rat model. We confirmed our observations through MSCs or MSC-EVs treatment alleviated hydronephrosis, less renal dysfunction and blunted transforming growth factor-ß1 induced fibration. Due to MSC-EVs are the equivalent dose of MSCs, and similar curative effects of transplantation of MSCs and MSC-EVs were observed, we speculated the curative effect of MSCs in treating US might on account of the release of EVs through paracrine mechanisms. Our study demonstrated an innovative strategy to counteract ureteral stricture formation in a rat model of US.

Association Between Multiple Sclerosis and Risk of Female Sexual Dysfunction: A Systematic Review and Meta-Analysis.

INTRODUCTION: It has been reported that multiple sclerosis (MS) would increase the susceptibility to female sexual dysfunction (FSD). AIM: To assess whether MS was a risk factor for FSD through a comprehensive literature review and meta-analysis. METHODS: MEDLINE (PubMed), Embase, Cochrane Library, and PsychINFO databases were systematically searched for all studies reporting sexual function in women with MS. The protocol for this meta-analysis is available from PROSPERO (CRD42018094392). MAIN OUTCOME MEASURES: The association between MS and risk of FSD was summarized using relative risk or standard mean differences with 95% CI. Subgroup and sensitivity analyses were conducted to detect potential bias. RESULTS: Overall, 1,485 women participants (the mean age ranged from 29.15 to 45.89 years) were included from 9 studies (4 cross-sectional and 5 case-control studies); 826 of them were patients with MS, with a mean disease duration from 2.7 to 16.51 years. Synthesis of results revealed that MS was significantly associated with an increased risk of FSD (relative risk 1.87, 95% CI 1.25-2.78, P = .002; heterogeneity: I2 = 89.0%, P < .001). Women with MS had significantly lower values in total Female Sexual Function Index scores as compared with healthy controls (standard mean differences -2.41,95% CI -3.87 to -0.96, P = .017; heterogeneity: I2 = 97.2%, P = .001). The grading of recommendations assessment, development, and evaluation-relevant outcomes revealed that the absolute effect of MS on FSD was 434 more per 1000 (from 125 more to 888 more); and the overall quality of the evidence was judged as low. CLINICAL IMPLICATIONS: The present meta-analysis indicates that women patients with MS have a significant elevated risk of sexual dysfunction, which should raise awareness of the potential association between MS and FSD by both neurologists and urologists. STRENGTHS & LIMITATIONS: This the first study to summarize all available evidence for combining the odds on the association between MS and the risk of developing FSD. However, all the included studies were observational design, which may downgrade this evidence. CONCLUSION: Results of this meta-analysis revealed a potential hazardous effect of MS for developing FSD. High-quality stringently controlled studies with large sample size are still warranted to validate this relationship. Zhao S, Wang J, Liu Y, et al. Association Between Multiple Sclerosis and Risk of Female Sexual Dysfunction: A Systematic Review and Meta-analysis. J Sex Med;15:1716-1727.

Risk of secondary rectal cancer and colon cancer after radiotherapy for prostate cancer: a meta-analysis.

PURPOSE: To investigate whether radiotherapy for prostate cancer increases the risk of therapy-related rectal cancer and colon cancer. METHODS: A systematic literature search was carried out using the Medline (PubMed), EMBASE, and the Cochrane Library to identify studies examining the association between radiotherapy for prostate cancer and secondary colorectal cancer (rectal cancer and colon cancer) published before March 19, 2018. The risk of second colorectal cancer after radiotherapy was summarized using unadjusted odds ratio (OR) and adjusted hazard ratio (HR) with their 95% confidence interval (CI). Subgroup and sensitivity analyses were conducted to detect potential bias and heterogeneity. RESULTS: After study selection, 16 reports were retrieved for analysis. When patients received radiotherapy compared with those unexposed to radiation, there was an increased risk of the rectal cancer (OR 1.37, 95%CI 1.01 to 1.85), but not colon cancer. According to adjusted HR, there was an increased risk of the rectal cancer (HR 1.64, 95%CI 1.39 to 1.94), and colon cancer (HR 1.33, 95%CI 1.02 to 1.76). The OR for rectal cancer showed an increased risk with longer latent period (5 years lag time versus 10 years lag time, OR: 1.56 versus 2.22). Brachytherapy had no association with second cancer across all analyses. CONCLUSIONS: Radiotherapy was associated with an increased risk of subsequent rectal cancer compared with patients unexposed to radiation. Colon may be free from the damage of radiation. Brachytherapy had no association with second rectal cancer or colon cancer.

5-alpha Reductase Inhibitors and risk of male breast cancer: a systematic review and meta-analysis.

OBJECTIVE: To assess the relationship between 5α-reductase inhibitors (5ARIs) and the risk of male breast cancer (MBC). MATERIAL AND METHODS: We systematically searched Medline via PubMed, Embase and the Cochrane Library Central Register up to May 2017 to identify published articles related to 5ARIs and the risk of MBC. RESULTS: Summary effect estimates were calculated by a random-effect model, and tests for multivariable-unadjusted pooled risk ratios (RR) and heterogeneity, as well as the sensitivity analyses were conducted to assess publication bias. All four studies were conducted in a quality assessment according to the Newcastle Ottawa Scale system. The strength of association between 5ARIs and the prevalence of MBC was evaluated by using summarized unadjusted pooled RR with a 95% confidence interval [CI]. Four studies involving 595.776 participants, mean age range from 60 to 73.2 years old, were included in a meta-analysis, which produced a summary unadjusted RR of the risk of MBC for the treatment of 5ARIs of 1.16 (95% CI 0.85-1.58, P=0.36) and the multivariable-adjusted RR is 1.03, (95% CI 0.75-1.41, p=0.86). There was no heterogeneity among included studies (I2=0%, P=0.49). Estimates of total effects were generally consistent with the sensitivity. CONCLUSION: We did not observe a positive association between the use of 5ARIs and MBC. The small number of breast cancer cases exposed to 5ARIs and the lack of na association in our study suggest that the development of breast cancer should not influence the prescribing of 5ARIs therapy.

PSCA regulates IL-6 expression through p38/NF-κB signaling in prostate cancer.

BACKGROUND: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. We previously reported that PSCA involved in proliferation and invasion of PCa cells, however, the underlying mechanisms are unknown. In this study, we aimed to explore the regulating role of PSCA gene expression in interleukin-6 (IL-6) autocrine of PCa cells. METHODS: The stable knockdown-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa DU145 and PC-3M cells. The effects of PSCA overexpression or knockdown were determined in proliferation, invasion, and metastasis assays. The effect of PSCA on the expression and secretion of IL-6 was evaluated by immunoblotting and ELISA. Subcellular localization and expression pattern of PSCA and IL-6 protein were examined by immunohistochemistry. Its clinical significance was statistically analyzed. RESULTS: The results showed that stable knockdown of PSCA delayed proliferation, migration, and invasion while overexpressing PSCA enhanced the proliferation, migration, and invasion in vitro and the lung metastasis in vivo of PCa cells. Importantly, the PSCA involved in the IL-6 secretion and positively regulated p38/NF-κB/IL-6 signaling, leading to enhanced PCa cell invasion and metastasis. Both the expression of PSCA and IL-6 were significantly associated with poor biochemical recurrence-free survival of patients with PCa. PSCA protein expression showed a prognostic value in overall survival as indicated by Kaplan-Meier analysis. CONCLUSIONS: These results indicate that PSCA regulates the expression and secretion of IL-6 in human PCa cells through p38/NF-κB signaling pathways. PSCA may be a potential diagnostic marker and therapeutic target for PSCA-positive PCa.

PSCA promotes prostate cancer proliferation and cell-cycle progression by up-regulating c-Myc.

BACKGROUND: The Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored protein. Increasing evidence has indicated PSCA plays an important role in tumorigenesis. However, its function and the underlying molecular mechanisms in prostate cancer (PCa) are still not fully elucidated. In this study, we aimed to explore the effect of PSCA on cell cycle of PCa cells and its mechanism research. METHODS: Immunohistochemistry, quantitative reverse transcription-PCR (qRT-PCR) and Western blotting were used to quantify PSCA expression pattern in PCa tissues and cell lines. The association of PSCA expression with the biochemical recurrence (BCR)-free survival and overall survival (OS) of PCa patients were analyzed using Kaplan-Meier method. The roles of PSCA in PCa were confirmed based on both in vitro and in vivo systems. RESULTS: Immunohistochemistry results showed that PSCA was upregulated in PCa tissue. PSCA overexpression were significantly associated with high Gleason score (GS) (P = 0.028), positive BCR (P = 0.002), and poor OS (P = 0.032) and high c-Myc expression (P = 0.019). PSCA promoted PCa cell cycle progression and tumor growth via increased c-Myc expression. Additional, PI3K/AKT signaling pathways was involved in PSCA-mediated c-Myc expression and cell proliferation. CONCLUSIONS: PSCA is a novel cell cycle regulator with a key role in mediating c-Myc-induced proliferation. PSCA may be a potential diagnostic marker and therapeutic target for patients with PCa.

Association Between HIV Infection and Prevalence of Erectile Dysfunction: A Systematic Review and Meta-Analysis.

BACKGROUND: The prevalence of erectile dysfunction (ED) in men positive for HIV has been reported to exceed the baseline of the general population. However, no meta-analysis or conclusive review has investigated whether individuals with HIV infection have a significantly higher prevalence of ED. AIM: To explore the exact association between HIV infection and the prevalence of ED. METHODS: The PubMed, Embase, Medline, and Cochrane Library databases were searched to identify studies concerning the association between HIV infection and the prevalence of ED that were published up to December 2016. Manual searches also were performed. Relative risks and corresponding 95% confidence intervals were used to estimate the strength of association between HIV infection and the prevalence of ED. The methodologic quality of the included cohort studies was assessed through the Newcastle-Ottawa Scale. The cross-sectional study quality methodology checklist was used to assess the quality of cross-sectional studies. Sensitivity analyses were conducted to assess potential bias. This study was conducted according to the guidelines for Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE). OUTCOMES: The strength of association between HIV infection and the prevalence of ED was evaluated using summarized unadjusted pooled relative risks and 95% confidence intervals. RESULTS: Two cohort studies and three cross-sectional studies involving 4,252 participants were included. Mean age of patients ranged from 35.2 to 52 years in the included studies. Based on the random-effects model, analyses of all studies showed that HIV infection was significantly associated with an increased prevalence of ED (relative risk = 2.32, 95% confidence interval = 1.52-3.55, P < .001). There was significant heterogeneity among included studies (I2 = 84%, P < .001). Estimates of total effects were generally consistent with the sensitivity. CLINICAL IMPLICATIONS: Individuals with HIV infection had a significantly increased prevalence of ED, which suggests that ED should be of concern to clinicians when managing men with HIV infection. STRENGTHS AND LIMITATIONS: A strength of this study is that it is the first meta-analysis to explore the relation between HIV infection and the prevalence of ED. A limitation is that all included studies were observational studies, which can induce recall bias or selection bias. CONCLUSION: Evidence from the observational studies suggested that individuals with HIV infection had a significantly increased prevalence of ED despite significant heterogeneity. More research is warranted to clarify the relation between HIV infection and the prevalence of ED. Luo L, Deng T, Zhao S, et al. Association Between HIV Infection and Prevalence of Erectile Dysfunction: A Systematic Review and Meta-Analysis. J Sex Med 2017;14:1125-1132.

Association Between Opioid Use and Risk of Erectile Dysfunction: A Systematic Review and Meta-Analysis.

BACKGROUND: Opioid analgesics have been widely used to relieve chronic pain conditions; however, a connection between opioid analgesic administration and increased susceptibility to erectile dysfunction (ED) has been hypothesized. AIM: To evaluate whether opioid use was a risk factor for ED in a systematic review and meta-analysis. METHODS: The PubMed, Cochrane Library, and Embase databases were searched to identify eligible studies concerning opioid use and risk of ED from inception to April 2017. The association between opioid use and risk of ED was summarized using the relative risk with 95% CI. Sensitivity analyses were conducted to assess potential bias. The Begg and Egger tests were used for publication bias analysis. The GRADE evidence profile tool was used to assess the quality of the evidence. OUTCOMES: The overall combined risk estimates for the effect of opioid use on ED were calculated using a random-effects model. RESULTS: This meta-analysis included 8,829 men (mean age = 41.6 years) from 10 studies, 2,456 of whom received opioid management (duration of intervention = 4 months to 9.5 years). Pooled results demonstrated that the use of opioids was significantly associated with an increased risk of ED (relative risk = 1.96, 95% CI = 1.66-2.32, P < .001). Estimates of the total effects were generally consistent in the sensitivity analysis. No evidence of publication bias was observed. The overall quality of evidence was rated as low. CLINICAL IMPLICATIONS: We found that men with opioid use had a significantly increased prevalence of ED, which suggests that patients and clinicians should be aware of the potential role played by opioid administration in the development of ED. STRENGTHS AND LIMITATIONS: This is the first meta-analysis performed to describe the relation between opioid use and ED risk based on all available epidemiologic studies. However, the direction of causality between opioid use and risk of ED should be interpreted with caution because most included studies used a cross-sectional design. CONCLUSION: Evidence from the included observational studies indicated that men with opioid use had a significantly increased risk of ED. Further randomized controlled trials are still needed to confirm this relation. Zhao S, Deng T, Luo L, et al. Association Between Opioid Use and Risk of Erectile Dysfunction: A Systematic Review and Meta-Analysis. J Sex Med 2017;14:1209-1219.

Knockdown of PSCA induces EMT and decreases metastatic potentials of the human prostate cancer DU145 cells.

BACKGROUND: Prostate stem cell antigen (PSCA) expression has been shown to correlate with prostatic carcinogenesis and prostate cancer (PCa) progression. The underlying mechanisms for these processes are currently unknown. Epithelial to mesenchymal transition (EMT) has been associated with the invasiveness and the distant metastasis of PCa. In this study, we investigated the effects of knocking down the PSCA on the cell migration, the invasiveness, and the EMT of the PCa cell line DU145 in vitro and in vivo. METHODS: Four target sequences of the small hairpin RNA for PSCA were designed, and the best effect knockdown sequence shRNA#1 was screened to construct the stable transfected DU145 cell line (DU145 shRNA#1), the scramble sequence was also designed to construct the stable transfected DU145 cell line(DU145 scramble). Cell migration and invasion were studied using Transwell assay. Quantitative RT-PCR, Western blot (WB) were used to quantify PSCA, E-cadherin, ß-catenin, Vimentin, Fibronectin expression in DU145, DU145 scramble, DU145 shRNA#1 in vitro and in vivo. RT-PCR, immunofluorescent staining were used to quantify PSCA, E-cadherin, and Vimentin expression in vitro. EMT-related genes Snail, Slug, and Twist, were quantified by quantitative RT-PCR in vitro. RESULTS: The constructed stable knockdown of the PSCA in the DU145 cell had a silencing effect up to 90.5 %. DU145 shRNA#1 became scattered from the tightly packed colonies. It was associated with decreased cell migration and invasion. There was also an increased Vimentin and Fibronectin expression, an inhibited E-cadherin and ß-catenin expression at both the mRNA and the protein levels when compared to the DU145 and the DU145 scramble in vitro and vivo. Furthermore, with the exception of the Snail, the expression of EMT-related Slug and Twist genes were upregulated. CONCLUSIONS: Our data indicated that knockdown of PSCA induced EMT and reduced metastatic potentials of the DU145 cells, suggesting that PSCA played an important role in prostatic carcinogenesis and progression.

Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials.

INTRODUCTION: 5α-Reductase inhibitors (5ARIs) are widely used for the treatment of benign prostatic hyperplasia (BPH) and androgenetic alopecia (AGA). AIM: To review all the available data on the effect of 5ARIs on sexual function and assess whether 5ARIs increase the risk of sexual dysfunction. METHODS: A systematic search of the literature was conducted using the Medline, Embase, and Cochrane databases. The search was limited to articles published in English and up to October 2015. Article selection proceeded according to the search strategy based on Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Data were analyzed using Stata 12.0. A fixed- or a random-effects model was used to calculate the overall combined risk estimates. Publication bias was assessed using Begg and Egger tests. MAIN OUTCOME MEASURES: Sexual dysfunction, erectile dysfunction, and decreased libido. RESULTS: After screening 493 articles, 17 randomized controlled trials with 17,494 patients were included. Nine studies evaluated the efficacy of 5ARIs in men with BPH. The other eight reported using 5ARIs in the treatment of men with AGA. The mean age of participants was 60.10 years across all studies. We included 10 trials (6,779 patients) on the efficacy and safety of finasteride, 4 trials (6,222 patients) on the safety and tolerability of dutasteride, and 3 trials (4,493 patients) using finasteride and dutasteride for AGA. The pooled relative risks for sexual dysfunction were 2.56 (95% CI = 1.48-4.42) in men with BPH and 1.21 (95% CI = 0.85-1.72) in men with AGA; those for erectile dysfunction were 1.55 (95% CI = 1.14-2.12) in men with BPH and 0.66 (95% CI = 0.20-2.25) in men with AGA; and those for decreased libido were 1.69 (95% CI = 1.03-2.79) in men with BPH and 1.16 (95% CI = 0.50-2.72) in men with AGA. Estimates of the total effects were generally consistent with the sensitivity analysis. No evidence of publication bias was observed. CONCLUSION: Evidence from the randomized controlled trials suggested that 5ARIs were associated with increased adverse effects on sexual function in men with BPH compared with placebo. However, the association was not statistically significant in men with AGA. Well-designed randomized controlled trials are indicated to study further the mechanism and effects of 5ARIs on sexual function.

Sexual Dysfunction in Patients with Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis.

INTRODUCTION: Sexual dysfunction is an under-recognized problem in men and women with obstructive sleep apnea (OSA). Epidemiologic findings were inconclusive regarding the risk for sexual dysfunction associated with OSA. AIM: The aim of this study was to examine the association between OSA and sexual dysfunction. METHODS: The PubMed, Cochrane Library, and Embase databases were searched for observational studies on the OSA and the risk of sexual dysfunction. The methodologic quality of the case-control and cohort studies was assessed with Newcastle-Ottawa Scale (NOS). The cross-sectional study quality methodology checklist was used for cross-sectional study. Data were pooled for the random-effects model. Sensitivity analyses were conducted to assess potential bias. MAIN OUTCOME MEASURE: The association between OSA and sexual dysfunction was summarized using relative risk (RR) with a 95% confidence interval (CI). RESULTS: This meta-analysis included 1,275 participants from nine studies. Five studies reported the incidence of erectile dysfunction (ED); the remaining four studies reported the incidence of female sexual dysfunction (FSD). Pooled results demonstrated that OSA was associated with increased risk of ED (pooled RR = 1.82, 95% CI: 1.12-2.97) as well as FSD (pooled RR = 2.00, 95% CI: 1.29-3.08). Estimates of the total effects were generally consistent in the sensitivity analysis. No evidence of publication bias was observed. CONCLUSIONS: Evidence from the observational studies suggested that OSA individuals might have an increased incidence of sexual dysfunction despite significant heterogeneity. More researches are warranted to clarify the relationship between OSA and the increased risk of sexual dysfunction.

In vivo immunotoxicity of SiO2@(Y0.5Gd0.45Eu0.05)2O3 as dual-modality nanoprobes.

We have successfully synthesized SiO2@(Y0.5Gd0.45Eu0.05)2O3 nanocomposites as a potential dual-modality nanoprobe for molecular imaging in vitro. However, their immunotoxicity assessment in vivo remains unknown. In this article, the in vitro biocompatibility of our dual-modality nanoprobes was assayed in terms of cell viability and apoptosis. In vivo immunotoxicity was investigated by monitoring the generation of reactive oxygen species (ROS), cluster of differentiation (CD) markers and cytokines in Balb/c mice. The data show that the in vitro biocompatibility was satisfactory. In addition, the immunotoxicity data revealed there are no significant changes in the expression levels of CD11b and CD71 between the nanoprobe group and the Gd in a diethylenetriaminepentaacetic acid (DTPA) chelator (Gd-DTPA) group 24 h after injection in Balb/c mice (p>0.05). Importantly, there are significant differences in the expression levels of CD206 and CD25 as well as the secretion of IL-4 and the generation of ROS 24 h after injection (p<0.05). Transmission electron microscopy (TEM) images showed that few nanoprobes were localized in the phagosomes of liver and lung. In conclusion, the toxic effects of our nanoprobes may mainly result from the aggregation of particles in phagosomes. This accumulation may damage the microstructure of the cells and generate oxidative stress reactions that further stimulate the immune response. Therefore, it is important to evaluate the in vivo immunotoxicity of these rare earth-based biomaterials at the molecular level before molecular imaging in vivo.

Novel insights into RB1 in prostate cancer lineage plasticity and drug resistance.

Prostate cancer is the second most common malignancy among men in the world, posing a serious threat to men's health and lives. RB1 is the first human tumor suppressor gene to be described, and it is closely associated with the development, progression, and suppression of a variety of tumors. It was found that the loss of RB1 is an early event in prostate cancer development and is closely related to prostate cancer development, progression and treatment resistance. This paper reviews the current status of research on the relationship between RB1 and prostate cancer from three aspects: RB1 and prostate cell lineage plasticity; biological behavior; and therapeutic resistance. Providing a novel perspective for developing new therapeutic strategies for RB1-loss prostate cancer.

The Therapeutic Potential of Bone Marrow Mesenchymal Stem Cells for Articular Cartilage Regeneration in Osteoarthritis.

Osteoarthritis (OA), characterized by the degeneration and destruction of articular cartilage, is one of the most significant public health issues around the world. In the course of OA, inflammatory response is an important factor leading to cartilage destruction and exacerbation of symptoms. The low immunogenicity, multi-directional differentiation and high portability properties make bone marrow mesenchymal stem cells (BMSCs) ideal seed cells for OA. Here, we review recent literature relating to the application of BMSCs for OA cell therapy and consider the following aspects: migration and homing of BMSCs, immunomodulatory and anti-inflammatory effects of BMSCs, anti-fibrotic effects of BMSCs, the application of biological scaffolds in cartilage regeneration by BMSCs and chondrogenic differentiation of BMSCs. Injecting BMSCs into joints with an inflammatory environment may increase the risk of osteoproliferation and ectopic calcification in patients. Further evidence and studies are needed to ensure the improvement and maintenance of the intra-articular environment for cartilage repair and regeneration.

SP600125 Restored TNF-α-Induced Impaired Chondrogenesis in Bone Mesenchymal Stem Cells and Its Antiosteoarthritis Effect in Mice.

Inflammation, the main factor in the progression of osteoarthritis (OA), impairs the chondrogenesis of bone mesenchymal stem cells (BMSCs), which is an appealing process to target to regenerate impaired articular cartilage. This article aimed to investigate whether SP600125, a competitive ATP-specific inhibitor of the JNK pathway, could promote the chondrogenesis of BMSCs by enhancing their anti-inflammatory capacity. Chondrogenic differentiation was assessed by Alcian blue staining, immunofluorescence staining, and Western blot. The inflammation level was associated with the expression of matrix metalloproteinases (Mmp), evaluated by Western blot. Intra-articular injection of BMSCs pretreated with or without SP600125 was carried out on C57BL/6 mice after inducing OA by surgical destabilization of the medial meniscus. Safranin O-fast green (SO) and hematoxylin-eosin staining were employed to evaluate the cartilage destruction and immunohistochemical analysis was adopted to detect the expression of Col2 and Mmp-13 proteins in the mouse knee joint. We showed that SP600125 could inhibit inflammation induced by tumor necrosis factor-α (TNF-α) and promote the chondrogenesis of BMSCs. In the presence of TNF-α, the expression of aggrecan (Agc) and collagen type II alpha 1 (Col2) was significantly decreased compared with that in the control group and increased with the addition of SP600125. Moreover, the expression of Mmp-1, Mmp-3, and Mmp-13 was increased in BMSCs treated only with TNF-α and downregulated in SP600125-treated BMSCs. In vivo study showed that SP600125 could enhance protective effects of BMSCs on OA mice. Our results indicated that SP600125 rescued the chondrogenesis of BMSCs by inhibiting inflammation induced by TNF-α, which provides a theoretical basis for solving the problem of cartilage repair under inflammatory conditions.

METTL3 enhances cell adhesion through stabilizing integrin ß1 mRNA via an m6A-HuR-dependent mechanism in prostatic carcinoma.

Bone metastasis is the major cause of morbidity and mortality in patients with prostate cancer (PCa). However, the underlying mechanism of bone-specific metastasis remain vague. Recently, with the deep research of N6-methyladenine (m6A) mRNA methylation, many studies directly focus on the role of m6A modification in human diseases, especially in cancers. Here we found that methyltransferase-like 3 (METTL3) expression is higher in PCa than in normal prostate tissues, especially in PCa with bone metastasis. High METTL3 expression was positively correlated with advanced progression and a poor prognosis of PCa. Functional assays demonstrated that METTL3 regulates the expression of Integrin ß1 (ITGB1) through m6A-HuR-dependent mechanism, which affects the binding of ITGB1 to Collagen I and tumor cell motility, so as to promote the bone metastasis of PCa. The findings of this study reveal a novel mechanism of PCa osteotropism and suggest METTL3 as a therapeutic target for PCa bone metastasis.

A PSCA/PGRN-NF-κB-Integrin-α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential.

Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer. However, the mechanisms underlying prostate cancer metastases remain unknown. Prostate cancer cells exhibited discrete adhesion to bone marrow endothelial cells (BMEC), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)-positive prostate cancer cells. The current study sought to characterize the roles of PSCA in the adhesion of prostate cancer cells to BMECs. Cell adhesion was assessed using the adhesion assay and transendothelial migration. The expression and regulation of integrins were evaluated by qRT-PCR, Western blot, promoter-luciferase activity, and chromatin immunoprecipitation (ChIP). Functionally, the potential interacting partners of PSCA in prostate cancer cells were identified by coimmunoprecipitation and mass spectrometry (MS) analysis. The association of PSCA expression with bone metastasis was further analyzed in an in vivo model and prostate cancer patients. We found that overexpression of PSCA enhanced the adhesion capability of prostate cancer cells to BMECs through upregulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in prostate cancer cells. Functional studies showed that downregulation of PGRN and PSCA with siRNAs in prostate cancer cells significantly suppressed the integrin-α4 expression and the adhesion to BMECs in vitro, respectively, which were restorable by exogenous PGRN. Importantly, PSCA depletion significantly reduced tumors' presence in the bone of a mouse model. Furthermore, PSCA expression is elevated in prostate cancer tissue, and significantly associated with increased Gleason score, advanced stage, bone metastasis, and poor prognosis in prostate cancer patients. We conclude that PSCA/PGRN promoted the adhesion of prostate cancer cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases. IMPLICATIONS: The findings presented here suggest PSCA/PGRN as a potential therapeutic target for prostate cancer metastases, especially for bone metastasis.

Shengjing Capsule Improves Spermatogenesis through Upregulating Integrin α6/ß1 in the NOA Rats.

OBJECTIVE: To evaluate the therapeutic effect of Shengjing capsules on nonobstructive azoospermia (NOA) in the rat model. METHODS: Twenty-five male Sprague-Dawley rats were randomly divided into five groups as follows (n=5 per group): normal group, NOA group, and three Shengjing capsule treatment groups (low-dose, medium-dose, and high-dose groups, respectively). HE staining and semen smear were performed to assess sperm quality. The expression levels of PI3K/AKT and integrin α6/ß1 were measured by qRT-PCR and western blot analyses. RESULTS: In the NOA group, almost all of the seminiferous tubules were vacuolated with a thin layer of basal compartment containing some spermatogonial stem cells. The counts of sperms in the NOA group were strongly lower than those of the normal group (P=0.0001). The expression of PI3K/AKT and integrin α6/ß1 was scarcely expressed in the NOA group. All indexes mentioned above were significantly different from those of the medium- and high-dose groups (P=0.001, all). The sperm count of rats treated with Shengjing capsules was significantly higher than that of the NOA group (P=0.0001). The rats of Shengjing capsule groups had more layers of spermatogonial stem cells and spermatocytes, and some had intracavitary sperms. CONCLUSIONS: Shengjing capsules may be a promising therapeutic medicine for NOA. The underlying mechanisms might involve activating SSCs by upregulating the integrin α6/ß1 expression via the PI3K/AKT pathway.