Identification of a basement membrane gene signature for predicting prognosis and estimating the tumor immune microenvironment in prostate cancer.

Basement membrane plays an important role in tumor invasion and metastasis, which is closely related to prognosis. However, the prognostic value and biology of basement membrane genes (BMGs) in prostate cancer (PCa) remain unknown. In the TCGA training set, we used differentially expressed gene analysis, protein-protein interaction networks, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator regression to construct a basement membrane-related risk model (BMRM) and validated its effectiveness in the MSKCC validation set. Furthermore, the accurate nomogram was constructed to improve clinical applicability. Patients with PCa were divided into high-risk and low-risk groups according to the optimal cut-off value of the basement membrane-related risk score (BMRS). It was found that BMRS was significantly associated with RFS, T-stage, Gleason score, and tumor microenvironmental characteristics in PCa patients. Further analysis showed that the model grouping was closely related to tumor immune microenvironment characteristics, immune checkpoint inhibitors, and chemotherapeutic drug sensitivity. In this study, we developed a new BMGs-based prognostic model to determine the prognostic value of BMGs in PCa. Finally, we confirmed that THBS2, a key gene in BMRM, may be an important link in the occurrence and progression of PCa. This study provides a novel perspective to assess the prognosis of PCa patients and provides clues for the selection of future personalized treatment regimens.

Targeted delivery of organic small-molecule photothermal materials with engineered extracellular vesicles for imaging-guided tumor photothermal therapy.

Imaging-guided photothermal therapy (PTT) for cancers recently gathered increasing focus thanks to its precise diagnosis and potent therapeutic effectiveness. Croconaine (CR) dyes demonstrate potential in expanding utility for near infrared (NIR) dyes in bio-imaging/theranostics. However, reports on CR dyes for PTT are scarce most likely due to the short of the efficacious delivery strategies to achieve specific accumulation in diseased tissues to induce PTT. Extracellular vesicles (EVs) are multifunctional nanoparticle systems that function as safe platform for disease theragnostics, which provide potential benefits in extensive biomedical applications. Here, we developed a novel delivery system for photothermal molecules based on a CR dye that exerts photothermal activity through CDH17 nanobody-engineered EVs. The formed CR@E8-EVs showed strong NIR absorption, excellent photothermal performance, good biological compatibility and superb active tumor-targeting capability. The CR@E8-EVs can not only visualize and feature the tumors through CR intrinsic property as a photoacoustic imaging (PAI) agent, but also effectively retard the tumor growth under laser irradiation to perform PTT. It is expected that the engineered EVs will become a novel delivery vehicle of small organic photothermal agents (SOPTAs) in future clinical PTT applications.

Glycine Decarboxylase (GLDC) Plays a Crucial Role in Regulating Energy Metabolism, Invasion, Metastasis and Immune Escape for Prostate Cancer.

Glycine decarboxylase (GLDC) is one of the core enzymes for glycine metabolism, and its biological roles in prostate cancer (PCa) are unclear. First, we found that GLDC plays a central role in glycolysis in 540 TCGA PCa patients. Subsequently, a metabolomic microarray showed that GLDC enhanced aerobic glycolysis in PCa cells, and GLDC and its enzyme activity enhanced glucose uptake, lactate production and lactate dehydrogenase (LDH) activity in PCa cells. Next, we found that GLDC was highly expressed in PCa, was directly regulated by hypoxia-inducible factor (HIF1-α) and regulated downstream LDHA expression. In addition, GLDC and its enzyme activity showed a strong ability to promote the migration and invasion of PCa both in vivo and in vitro. Furthermore, we found that the GLDC-high group had a higher TP53 mutation frequency, lower CD8+ T-cell infiltration, higher immune checkpoint expression, and higher immune exclusion scores than the GLDC-low group. Finally, the GLDC-based prognostic risk model by applying LASSO Cox regression also showed good predictive power for the clinical characteristics and survival in PCa patients. This evidence indicates that GLDC plays crucial roles in glycolytic metabolism, invasion and metastasis, and immune escape in PCa, and it is a potential therapeutic target for prostate cancer.

SETD4 inhibits prostate cancer development by promoting H3K27me3-mediated NUPR1 transcriptional repression and cell cycle arrest.

The suppressor of variegation enhancer of zeste-trithorax (SET) domain methyltransferases have been reported to function as key regulators in multiple tumor types by catalyzing histone lysine methylation. Nevertheless, our understanding on the role of these lysine methyltransferases, including SETD4, in prostate cancer (PCa) remains limited. Hence, the specific role of SETD4 in PCa was investigated in this study. The expression of SETD4 in PCa cells and tissue samples was downregulated in PCa cells and tissue specimens, and decreased SETD4 expression led to inferior clinicopathological characteristics in patients with PCa. knockdown of SETD4 facilitated the proliferation of PCa cells and accelerated cell cycle progression. Mechanistically, SETD4 repressed NUPR1 transcription by methylating H3K27 to generate H3K27me3, subsequently inactivated Akt pathway and impeded the tumorigenesis of PCa. Our results highlight that SETD4 prevents the development of PCa by catalyzing the methylation of H3K27 and suppressing NUPR1 transcription, subsequently inactivating the Akt signaling pathway. The findings suggest the potential application of SETD4 in PCa prognosis and therapeutics.

Current therapy and drug resistance in metastatic castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC), especially metastatic castration-resistant prostate cancer (mCRPC) is one of the most prevalent malignancies and main cause of cancer-related death among men in the world. In addition, it is very difficult for clinical treatment because of the natural or acquired drug resistance of CRPC. Mechanisms of drug resistance are extremely complicated and how to overcome it remains an urgent clinical problem to be solved. Thus, a comprehensive and thorough understanding for mechanisms of drug resistance in mCRPC is indispensable to develop novel and better therapeutic strategies. In this review, we aim to review new insight of the treatment of mCRPC and elucidate mechanisms governing resistance to new drugs: taxanes, androgen receptor signaling inhibitors (ARSIs) and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Most importantly, in order to improve efficacy of these drugs, strategies of overcoming drug resistance are also discussed based on their mechanisms respectively.

Alterations of plasma exosomal proteins and motabolies are associated with the progression of castration-resistant prostate cancer.

BACKGROUND: Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC. METHODS: Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models. RESULTS: Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis. CONCLUSION: Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

Plasma cell subtypes analyzed using artificial intelligence algorithm for predicting biochemical recurrence, immune escape potential, and immunotherapy response of prostate cancer.

Background: Plasma cells as an important component of immune microenvironment plays a crucial role in immune escape and are closely related to immune therapy response. However, its role for prostate cancer is rarely understood. In this study, we intend to investigate the value of a new plasma cell molecular subtype for predicting the biochemical recurrence, immune escape and immunotherapy response in prostate cancer. Methods: Gene expression and clinicopathological data were collected from 481 prostate cancer patients in the Cancer Genome Atlas. Then, the immune characteristics of the patients were analyzed based on plasma cell infiltration fractions. The unsupervised clustering based machine learning algorithm was used to identify the molecular subtypes of the plasma cell. And the characteristic genes of plasma cell subtypes were screened out by three types of machine learning models to establish an artificial neural network for predicting plasma cell subtypes. Finally, the prediction artificial neural network of plasma cell infiltration subtypes was validated in an independent cohort of 449 prostate cancer patients from the Gene Expression Omnibus. Results: The plasma cell fraction in prostate cancer was significantly decreased in tumors with high T stage, high Gleason score and lymph node metastasis. In addition, low plasma cell fraction patients had a higher risk of biochemical recurrence. Based on the differential genes of plasma cells, plasma cell infiltration status of PCa patients were divided into two independent molecular subtypes(subtype 1 and subtype 2). Subtype 1 tends to be immunosuppressive plasma cells infiltrating to the PCa region, with a higher likelihood of biochemical recurrence, more active immune microenvironment, and stronger immune escape potential, leading to a poor response to immunotherapy. Subsequently, 10 characteristic genes of plasma cell subtype were screened out by three machine learning algorithms. Finally, an artificial neural network was constructed by those 10 genes to predict the plasma cell subtype of new patients. This artificial neural network was validated in an independent validation set, and the similar results were gained. Conclusions: Plasma cell infiltration subtypes could provide a potent prognostic predictor for prostate cancer and be an option for potential responders to prostate cancer immunotherapy.

CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling.

BACKGROUND: Circular RNAs (circRNAs) mediate the infiltration of tumor-associated macrophages (TAMs) to facilitate carcinogenesis and development of various types of cancers. However, the role of circRNAs in regulating macrophages in prostate cancer (PCa) remains uncertain. METHODS: Differentially expressed circRNAs in PCa were identified by RNA sequencing. The expression of circSMARCC1 was recognized and evaluated using fluorescence in situ hybridization and quantitative real-time PCR. The oncogenic role of circSMARCC1 in PCa tumor proliferation and metastasis was investigated through a series of in vitro and in vivo assays. Finally, Western blot, biotin-labeled RNA pulldown, luciferase assay, rescue experiments, and co-culture experiments with TAMs were conducted to reveal the mechanistic role of circSMARCC1. RESULTS: CircSMARCC1 was dramatically up-regulated in PCa cells, plasma and tissues. Overexpression of circSMARCC1 promotes tumor proliferation and metastasis both in vitro and in vivo, whereas knockdown of circSMARCC1 exerts the opposite effects. Mechanistically, circSMARCC1 regulates the expression of CC-chemokine ligand 20 (CCL20) via sponging miR-1322 and activate PI3K-Akt signaling pathway involved in the proliferation and epithelial mesenchymal transformation. More importantly, high expression of circSMARCC1 was positively associated with colonization of CD68+/CD163+/CD206+ TAMs in tumor microenvironment. In addition, overexpression of circSMARCC1 facilitates the expression of CD163 in macrophages through the CCL20-CCR6 axis, induces TAMs infiltration and M2 polarization, thereby leading to PCa progression. CONCLUSIONS: CircSMARCC1 up-regulates the chemokine CCL20 secretion by sponging miR-1322, which is involved in the crosstalk between tumor cells and TAMs by targeting CCL20/CCR6 signaling to promote progression of PCa.

The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression.

BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies. METHODS: A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues. RESULTS: Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5. CONCLUSIONS: Our findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.

Abiraterone, Orteronel, Enzalutamide and Docetaxel: Sequential or Combined Therapy?

Objective: To summarize the current therapeutic status using chemotherapeutic agent docetaxel and endocrine therapeutic agents (ARAT, abiraterone, orteronel or enzalutamide) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including sequential therapy and combined therapy, to promote the consensus on the optimal regimen for achieving superior treatment efficacy. Methods: Through literature search in PubMed, articles with the following relevant keywords were collected and anlyzed: CRPC, abiraterone, orteronel and enzalutamide, median survival, overall survival, prostate specific antigen (PSA), PSA response rate and median radiologic progression-free survival. Results: Fifty-eight articles were obtained and analyzed in this review. These articles included androgen axis-targeting agents after docetaxel, docetaxel after androgen axis-targeting agents, Triple sequential and combination therapy, covering four current drugs for mCRPC treatment: docetaxel, abiraterone, orteronel, and enzalutamide. It was found that there may be some cross-resistance between androgen axis-targeting agents, which will reduce the efficacy of subsequent drug treatment. Although neither of the studies of using combination therapy showed serious drug toxicity, the efficacy of sequential therapy was not as good as expected. Most adverse reactions after treatment were reported to be level 1-2. Conclusion: Based on the results of the current studies, abiraterone followed by enzalutamide treatment is the best sequential treatment for most docetaxel-naïve patients. This treatment achieves not only good OS, but also PFS and PSA response rates. In addition, for patients who have previously failed docetaxel treatment, enzalutamide is the best choice as the subsequent treatment.

Identification of UAP1L1 as a critical factor for prostate cancer and underlying molecular mechanism in tumorigenicity.

BACKGROUND: Prostate cancer is the second most common cancer in men, and some new target genes are needed to predict the risk of prostate cancer progression and the treatment. METHODS: In this study, the effects of UAP1L1 (UAP1-like-1) on prostate cancer were investigated by detecting the proliferation, migration, invasion and apoptosis of prostate cancer cells in vitro using MTT, wound healing, Transwell and flow cytometry assay, and the tumor growth in vivo. The downstream genes and pathways of UAP1L1 were explored using Ingenuity Pathway Analysis (IPA), and screened by qRT-PCR and western blot. The effects of CDCA8 on prostate cancer cells were also verified in vitro, which was through detecting the change of proliferation, migration, invasion and apoptosis of prostate cancer cells after CDCA8 knockdown. RESULTS: The results indicated that UAP1L1 promoted the proliferation, migration and invasion of prostate cancer cells, which was inhibited by downregulating CDCA8. Furthermore, the promotion of CDCA8 knockdown on cell apoptosis was reduced when UAP1L1 was simultaneously overexpressed. CONCLUSIONS: In conclusion, the results in this study revealed that UAP1L1 promoted the progression of prostate cancer through the downstream gene CDCA8.

Hsa_circ_0003258 promotes prostate cancer metastasis by complexing with IGF2BP3 and sponging miR-653-5p.

BACKGROUND: More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. METHODS: Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. RESULTS: Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo, while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. CONCLUSIONS: Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

[Progress in the studies of prostate biopsy methods].

Prostate cancer (PCa) is one of the most common malignancies in aged males, ranking the second in the incidence of malignant tumors in men. Early diagnosis is essential, as advanced PCa is quite difficult to be managed, especially when it becomes castration-resistant or neuroendocrine PCa. Currently, the diagnosis of PCa is often based on pathology by prostate biopsy. Many recent studies focus on the impact of different biopsy methods on the diagnosis of the malignancy, but no consensus has been reached hitherto. This review summarizes various prostate biopsy methods and their latest studies.

[L-carnitine-astaxanthin compound nutrients for the treatment of idiopathic oligospermia and asthenozoospermia: A multicenter clinical observation].

OBJECTIVE: To investigate the clinical effects of the L-carnitine-astaxanthin compound nutrients Menglankang (MLK) on idiopathic oligospermia (OS) and asthenospermia (AS). METHODS: This study included 73 cases of OS and 220 cases of AS treated with MLK once a bag, bid, for 3 successive months. Before and at 1, 2 and 3 months after treatment, we obtained and analyzed the semen parameters and sperm DNA fragmentation index (DFI) of the patients. RESULTS: Compared with the baseline, the OS patients showed remarkable increases after 1 and 2 months of treatment in the semen volume (ï¼»3.07 ± 1.47ï¼½ vs ï¼»3.26 ± 1.26ï¼½ and ï¼»3.30 ± 1.28ï¼½ ml), sperm concentration (ï¼»10.96 ± 6.09ï¼½ vs ï¼»16.74 ± 11.15ï¼½ and ï¼»17.56 ± 9.92ï¼½ ×106/ml, P < 0.05), total sperm count (ï¼»29.78 ± 17.48ï¼½ vs ï¼»52.98 ± 32.07ï¼½ and ï¼»57.67 ± 36.98ï¼½ ×106, P < 0.05) and the percentages of progressively motile sperm (PMS) (ï¼»39.8 ± 11.66ï¼½% vs ï¼»45.3 ± 14.03ï¼½% and ï¼»46.42 ± 10.69ï¼½%, P < 0.05) and morphologically normal sperm (MNS) (ï¼»1.71 ± 1.07ï¼½% vs ï¼»1.79 ± 0.91ï¼½% and ï¼»1.84 ± 0.96ï¼½%), and so did the AS patients in PMS (ï¼»19.23 ± 8.32ï¼½% vs ï¼»25.46 ± 13.86ï¼½% and ï¼»27.33 ± 12.88ï¼½%, P < 0.05). After 3 months of medication, the OS patients exhibited even more significant increases in the semen volume (ï¼»3.63 ± 1.39ï¼½ ml) (P < 0.05), sperm concentration (ï¼»20.56 ± 14.7ï¼½ ×106/ml) (P < 0.05), total sperm count (ï¼»66.35 ± 55.91ï¼½ ×106) (P < 0.05), PMS (ï¼»49.24 ± 13.45ï¼½%) (P < 0.05) and MNS (ï¼»2.59 ± 0.93ï¼½%) (P < 0.05), and so did the AS patients in the semen volume (ï¼»3.27 ± 1.42ï¼½ vs ï¼»3.85 ± 1.59ï¼½ ml, P < 0.05), PMS (ï¼»29.11 ± 13.58ï¼½%) (P < 0.05) and NMS (ï¼»2.01 ± 1.14ï¼½% vs ï¼»2.57 ± 1.15ï¼½%, P < 0.05). In comparison with the baseline, the sperm DFI was not significantly improved at 1 month after treatment, but remarkably decreased at 2 and 3 months in the OS patients (ï¼»25.87 ± 13.76ï¼½% vs ï¼»18.66 ± 10.83ï¼½% and ï¼»16.48 ± 11.46ï¼½%, P < 0.05) and the AS patients as well (ï¼»26.40 ± 12.28ï¼½% vs ï¼»19.35 ± 11.54ï¼½% and ï¼»15.32 ± 10.89ï¼½%, P < 0.05). CONCLUSIONS: The L-carnitine-astaxanthin compound nutrients Menglankang can significantly improve the semen quality of the patients with idiopathic oligospermia or asthenospermia.

Sexual Dysfunction in Patients With Urinary Bladder Stones but no Bladder Outlet Obstruction.

Objective: To explore the correlates of sexual dysfunction and lower urinary tract symptoms (LUTS) in male patients with urinary bladder stones and to determine the effect of stone extraction on recovery of sexual function. Materials and Methods: A total of 87 male patients with primary bladder stones were studied from January 2015 to May 2016. All patients underwent pneumatic lithotripsy for bladder stones. Sexual dysfunction was assessed based on sexual function assessment scales. The relationship of bladder stones with sexual dysfunction or LUTS was assessed using a two-sample t-test. Postoperative improvement of sexual function was assessed by repeated measures Analysis of Variance (ANOVA). Results: Forty-one patients had primary bladder stones and 46 had secondary stones from the kidneys. Eighty-three of 87 patients (95%) had sexual dysfunction; 79 patients (91%) had both sexual dysfunction and LUTS. There was a significant association between bladder stones and sexual dysfunction, between sexual dysfunction and LUTS, and between bladder stone and LUTS (p < 0.05). There was no significant association between the course of illness, size and number of bladder stones, or urinary tract infection with sexual function (p > 0.05). In addition, among 83 patients with both bladder stone and sexual dysfunction, 61 patients (73%) had benign prostatic hyperplasia (BPH) and 22 patients (27%) had no BPH. On postoperative evaluation at 3 months, sexual dysfunction scores were significantly improved in 77 patients (88.5%) Conclusion: Patients with bladder stones have a high incidence of sexual dysfunction, particularly those with co-existing LUTS and BPH. About 1/3 patients without BPH had sexual dysfunction and surgical removal of bladder stones significantly improved sexual function and LUTS.

Novel nanomedicines to overcome cancer multidrug resistance.

Chemotherapy remains a powerful tool to eliminate malignant cells. However, the efficacy of chemotherapy is compromised by the frequent emergence of intrinsic and acquired multidrug resistance (MDR). These chemoresistance modalities are based on a multiplicity of molecular mechanisms of drug resistance, including : 1) Impaired drug uptake into cancer cells; 2) Increased expression of ATP-binding cassette efflux transporters; 3) Loss of function of pro-apoptotic factors; 4) Enhanced DNA repair capacity; 5) Qualitative or quantitative alterations of specific cellular targets; 6) Alterations that allow cancer cells to tolerate adverse or stressful conditions; 7) Increased biotransformation or metabolism of anticancer drugs to less active or completely inactive metabolites; and 8) Intracellular and intercellular drug sequestration in well-defined organelles away from the cellular target. Hence, one of the major aims of cancer research is to develop novel strategies to overcome cancer drug resistance. Over the last decades, nanomedicine, which focuses on targeted delivery of therapeutic drugs into tumor tissues using nano-sized formulations, has emerged as a promising tool for cancer treatment. Therefore, nanomedicine has been introduced as a reliable approach to improve treatment efficacy and minimize detrimental adverse effects as well as overcome cancer drug resistance. With rationally designed strategies including passively targeted delivery, actively targeted delivery, delivery of multidrug combinations, as well as multimodal combination therapy, nanomedicine paves the way towards efficacious cancer treatment and hold great promise in overcoming cancer drug resistance. Herein, we review the recent progress of nanomaterials used in medicine, including liposomal nanoparticles, polymeric nanoparticles, inorganic nanoparticles and hybrid nanoparticles, to surmount cancer multidrug resistance. Finally, the future perspectives of the application of nanomedicine to reverse cancer drug resistance will be addressed.

SMARCC1 Suppresses Tumor Progression by Inhibiting the PI3K/AKT Signaling Pathway in Prostate Cancer.

BACKGROUND: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1) protein is a potential tumor suppressor in various cancers. However, its role in prostate cancer (PCa) remains controversial. The aim of this study was to determine the biological function of SMARCC1 in PCa and explore the underlying regulatory mechanisms. METHODS: The expression of SMARCC1 was validated in PCa tissues by immunohistochemistry. Meanwhile, function experiments were used to evaluate the regulatory role on cell proliferation and metastasis in PCa cells with SMARCC1 depletion both in vitro and in vivo. The expression levels of relevant proteins were detected by Western blotting. RESULTS: Our finding showed that SMARCC1 was significantly downregulated in prostate adenocarcinoma, with a higher Gleason score (GS) than that in low GS. The decreased expression of SMARCC1 was significantly correlated with a higher GS and poor prognosis. Additionally, we found that silencing of SMARCC1 dramatically accelerated cell proliferation by promoting cell cycle progression and enhancing cell migration by inducing epithelial mesenchymal transition (EMT). Furthermore, depletion of SMARCC1 facilitated PCa xenograft growth and lung metastasis in murine models. Mechanistically, the loss of SMARCC1 activated the PI3K/AKT pathway in PCa cells. CONCLUSION: SMARCC1 suppresses PCa cell proliferation and metastasis via the PI3K/AKT signaling pathway and is a novel therapeutic target.

Comprehensive signature analysis of drug metabolism differences in the White, Black and Asian prostate cancer patients.

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.