Search

Background: Shizi Sanhua Decoction, a traditional Chinese medicine (TCM) prescription, shows a treatment advantage on male oligospermia. While due to the complexity of the compatibility (multiple herbs composition), the underlying mechanism remains to be deciphered. Methods: Herbs-ingredients-target genes were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SWISSADME database, intersecting with oligospermia-related derived from DisGeNET to obtain co-target genes. The protein-protein interaction (PPI) network of co-target genes was constructed based on the STRING database, and highly condensed sub-networks and top 10 Hub genes were identified with the CytoHubba plug-in. Herbs, ingredients and KEGG enrichment information were projected onto the identified highly condensed subnetwork to build Herbs-ingredients and disease co-target genes sub-network. Results: After integration of herbs-ingredients-target genes (n=453) with disease genes (n=329), 29 cotarget genes were obtained. Among them, PARP1, AR, CYP17A1, ESR1, ABCB1, STS, CFTR, SOAT1, NR5A1, and HIF1A were related to male infertility (WP4673-WikiPathways). Sub-network analysis further revealed the top 10 Hub genes, and the relation with the herbs and ingredients was demonstrated in the sub-network of herbs-ingredients and disease co-target genes. As expected, reproductive- related biological processes (mammary gland epithelium development, GO:0061180; Oocyte meiosis, hsa04114; Progesterone-mediated oocyte maturation, hsa04914) were enriched. Thyroid hormone signaling pathway (hsa04919), Serotonergic synapse (hsa04726), Chemical carcinogenesisreactive oxygen species (hsa05208), and Endocrine resistance (hsa01522) may contribute to the development of male oligospermia. Conclusion: Constructed herbs-ingredients and disease co-target genes sub-network discloses specific bioprocesses and molecular targets of Shizi Sanhua Decoction in oligospermia treatment.

Docetaxel resistance developed in half of castration-resistant prostate cancer (CRPC) patients hinders its long-term clinical application. The current study was designed to investigate the effects of Chinese medicine Zhoushi Qi Ling decoction on the docetaxel resistance of prostate cancer as well as elucidate the underlying molecular mechanism. In our study, Qi Ling significantly decreased viability and colony formation as well as increased apoptosis of docetaxel-resistant (DR) CRPC cells. Qi Ling-treated DR cells exhibited decreased glucose consumption, lactate release and pyruvate production. Moreover, lncRNA SNHG10 was upregulated in DR tissues of CRPC patients and was negatively correlated with the progression-free survival. Bioinformatics analysis indicated miR-1271-5p as the associated miRNA possibly binding with SNHG10. miR-1271-5p up-regulation dramatically decreased the luciferase activity of SNHG10 in DR cells. SNHG10 knockdown sharply increased the expression of miR1271-5p in DR cells. Targetscan predicted TRIM66 as one of the downstream targets of miR-1271-5p. miR-1271-5p up-regulation drastically reduced luciferase activity as well as TRIM66 expression in DR cells. Also, the knockdown of SNHG10 remarkably suppressed the expression of TRIM66 in DR cells. Additionally, Qi Ling treatment reduced SNHG10 and TRIM66, while increased miR1271-5p, in DR cells. In summary, Qi Ling inhibited docetaxel resistance and glycolysis of CRPC possibly via SNHG10/miR-1271-5p/TRIM66 pathway.

A number of traditional Chinese medicines (TCMs) are widely used in prostate cancer treatment in China. The aim of this study was to test the efficacy of a TCM, Zhoushi Qiling Decoction (ZQD), in combination with androgen deprivation therapy (ADT) and explore its underlying mechanism. A total of 151 patients were recruited to receive ADT treatment or ADT+ZQD treatment. The survival of patients who received ADT+ZQD treatment was significantly higher than those who received ADT therapy only. DU145 prostate cancer cells were treated with ZQD (50 mg/mL) for 24 h in vitro and expression levels of an array of miRNAs were examined. Our results suggested that miR-143 demonstrated prominent upregulation in DU145 cells after treatment with ZQD. In patient serum samples, miR-143 expression was also significantly upregulated after ADT+ZQE treatment, which was however absent in patients treated with ADT only. In DU145 cells, ZQD treatment led to a dose-dependent increase in apoptosis, which could be reduced by anti-miR-143 treatment. There was a binding site between miR-143 and B cell CLL/lymphoma-2 (Bcl-2) and ZQD treatment reduced Bcl-2 expression. ZQD treatment led to increased caspase-3 and Bax expression. ZQD treatment could promote apoptosis of prostate cancer cells by promoting miR-143 upregulation, which could be a possible mechanism underlying the inhibitory effect of ZQD in prostate cancer in patient.

The present study aims to investigate the roles of U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) in the resistance to anti-androgen treatment in prostate cancer and its underlying mechanism. U2AF1 and androgen receptor variant 7 (ARV7) knockdown and overexpression were introduced in PC3 and DU145 cells. In addition, a bicalutamide-resistant PC3 (PC3 BR) cell line was also constructed. Cell count, MTT and soft agar colony formation assays were performed to evaluate cell proliferation. qRT-PCR was applied to determine the mRNA levels of U2AF1, ARV7 and Mitogen-Activated Protein Kinase 1 (MAPK1). Western blot was used to determine the MAPK1 protein expression. A negative correlation between ARV7 and U2AF1 in prostate tumor tissues was observed. U2AF1 downregulation was correlated with poor prognosis in prostate cancer patients. U2AF1 exhibited a negative correlation with ARV7 and its downregulation promoted prostate cancer cell proliferation and bicalutamide resistance. The regulatory effects of U2AF1 on ARV7 splicing were associated with MAPK1. U2AF1 affected prostate cancer proliferation and anti-androgen resistance by regulating ARV7 splicing.

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., Tripartite Motif Containing 66 (TRIM66) knockdown suppressed viability and proliferation of prostate cancer cell lines. TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. TRIM66 positively regulated signal transducer and activator of transcription 2 and interleukin‐2 expression. Our study highlights the importance of the TRIM66–signal transducer and activator of transcription 2–interleukin‐2 signaling axis in the tumor biology of prostate cancer.

Tumor-associated macrophages (TAMs) are critical immune cells infiltrated into tumor. In present study, we evaluated the effects of Qi Ling (QL), a traditional Chinese medicine on paclitaxel resistance in prostate cancer cells and explored the underlying mechanisms. We administrated QL to rats and collected the serum from QL-treated rats (QL-serum). We established the co-culture system of TAMs/paclitaxel resistant prostate cancer cells. We treated the TAMs with QL-serum and measured the viability of paclitaxel resistant prostate cancer cells after exposing to paclitaxel. We monitored the expression of M1 and M2 markers, the expression and activation of IL-6/STAT3 signaling pathways in TAMs after QL treatment. We treated TAMs with QL-serum together with interleukin (IL)-6, measured the expression of M1 and M2 markers, and the viability of paclitaxel resistant prostate cancer cells. In co-culture system, QL-serum-treated TAMs decreased the paclitaxel resistance in the human prostate cancer cells. QL-serum treatment significantly up-regulated the expression of M1 markers inducible nitric oxide synthase and tumor necrosis factor α while decreased the expression of M2 markers IL-10 and chemokine (C-C motif) ligand 22. QL-serum suppressed the activation of IL-6/ signal transducer and activator of transcription 3 signaling pathway. All these effects of QL-serum were abolished in the presence of IL-6. Qi Ling re-programmed TAMs and decreases paclitaxel resistance in prostate cancer cells.

To identify novel biomarker(s) in prostate cancer and demonstrate the mechanistic involvements in this disease, RNA-seq was employed to reveal the differentially expressed genes in the blood samples from prostate cancer patients. Relative expression of miR-302b-3p was evaluated using real-time PCR. The potential regulation of RELA by miR-302b-3p was assessed by luciferase reporter assay. Protein levels of NF-κB, Vimentin, N-cadherin and E-cadherin, were quantified using western blotting. Transwell chamber was employed to measure cell migratory and invasive capacity, while cell attachment/detachment assay was performed to evaluated epithelial-mesenchymal transition (EMT)-related behavior. Xenograft tumor model was adopted to determine the anti-tumor activity of miR-302b-3p in vivo. We demonstrated miR-302b-3p was down-regulated in prostate cancer both in vivo and in vitro. We predicted and identified RELA as directly targeted by miR-302b-3p. Ectopic miR-302b-3p expression in PC-3 cells significantly suppressed cell migration, invasion, attachment, detachment capacity, which was accompanied with a decrease in the expression of N-cadherin and Vimentin, and an increase of E-cadherin expression. MiR-302b-3p-proficiency greatly delayed xenograft tumor growth and associated with favorable overall survival. Co-introduction of RELA completely abolished anti-tumor effects of miR-302b-3p, which indicated a potential genetic interaction between RELA/NF-κB and miR-302b-3p. We characterized the aberrant down-regulation of miR-302b-3p in prostate cancer and unraveled a possible involvement of miR-302b-3p/RELA signaling axis in this scenario.

Objective: To investigate the feasibility and effectiveness of Xialiqi capsules in rats with nonbacterial prostatitis. Methods: A total of 90 healthy male SD rats, weighing 200-220 g, were randomly divided into a blank control group (BCG, n=30), a model group (MG, n=30), and an intervention group (IG, n=30). After establishing the model of chronic nonbacterial prostatitis, IG was treated with 50 mg/kg Xialiqi capsules via gavage. The three groups received the same dose of saline via gavage for 7 consecutive days. The differences in leukocytes, phospholipid vesicle density, number of colonies, prostate mass, apparent diffusion coefficient (ADC), degree of inflammatory cell infiltration in the prostate fluid, serum tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, CD3+, CD8+ levels after intervention were compared in the three groups. Results: Compared with the BCG, the number of leukocytes and colonies in the prostate fluid of the MG was elevated, and the density of lipid vesicles was decreased, and the number of leukocytes and colonies in the prostate fluid of the MG significantly decreased and the density of lipid vesicles rebounded after the intervention of Xialiqi capsules (P>0.05). Compared with the BCG, the prostate mass, ADC and the degree of inflammatory cell infiltration were elevated in the MG. There was a significant reversion of the above indices after the intervention of Xialiqi capsules (P

Lobaplatin is the third-generation platinum drug that has been shown promising antitumor activity in preclinical studies and clinical trials for multiple human cancers except prostate cancer. In this study, we investigated the role of lobaplatin on prostate cancer progression and the underlying molecular mechanism. We treated a variety of prostate cancer cell lines with different doses of lobaplatin and examined cell cycle progression, cell apoptosis, cell proliferation, and cell migration. Moreover, we also assessed the in-vivo antitumor activity of lobaplatin using xenograft mouse model. Importantly, we further dissected the underlying molecular mechanism by examining the expression of AR and ERG, as well as their downstream targets. We found that lobaplatin arrested cell cycle progression in G2/M phase and trigged cell apoptosis. Lobaplatin also dramatically inhibited cell proliferation and migration in vitro. Consistently, lobaplatin significantly suppressed tumor growth in xenograft mouse model. Mechanistically, the expression of AR and ERG, as well as their downstream targets, was markedly decreased upon treatment with lobaplatin in prostate cancer cells. Altogether, our results suggest that lobaplatin displayed favorable antitumor activity on prostate cancer both in vitro and in vivo, providing molecular basis and rational for using lobaplatin to combat human prostate cancer.

Prostate cancer chemoresistance is a major contributor to the poor survival of patients. MicroRNAs (miRNAs) play an important role in regulating cancer resistance. Here we aim to explore the role and mechanism of miR-199a in regulating prostate cancer resistance. MiR-199a expressions in human prostate cancer tissues and cell lines were investigated with real-time PCR (RT-PCR). MiR-199a was ectopically overexpressed in PC3 cells, and resistance to paclitaxel (PTX) was evaluated consequently. The interaction between miR-199a and the oncogene Yamaguchi sarcoma viral homolog 1 (YES1) was assessed after miR-199a overexpression. YES1 was ectopically overexpressed, followed by evaluation of PTX resistance. The efficacy of miR-199a as a therapeutic agent was also investigated in vivo. Downregulation of miR-199a was characteristic of prostate cancer, particularly recurrent cancers. MiR-199a was suppressed in PTX-resistant cell line. Overexpression of miR-199a inhibited PTX resistance. YES1 was a target of miR-199a, and overexpression of YES1 reversed the effect of miR-199a in suppressing PTX resistance. In vivo, miR-199a increased tumor PTX sensitivity. The downregulation of miR-199a contributes to PTX resistance in prostate cancer. YES1 mediates the regulation of miR-199a in prostate cancer PTX resistance. This miR-199a replacement therapy has potential to overcome PTX resistance.

This study aimed to understand the molecular mechanism underlying the therapeutic effect of Qi Ling (QL) against androgen-independent prostate cancer.The relative expression of TRIM66 in prostate tumor was interrogated by microarray. Real-time polymerase chain reaction and Western blotting were performed to determine the transcript abundances and protein expressions of TRIM66, HP1γ, AR, c-Myc, and GAPDH. Cell proliferation and apoptosis were analyzed by cell counting kit-8 method and flow cytometry. The regulatory action of c-Myc on TRIM66 was interrogated with luciferase reporter plasmid and the direct binding was demonstrated by chromatin immunoprecipitation. The secretory prostate-specific antigen was quantified by enzyme-linked immunosorbent assay.TRIM66 was aberrantly overexpressed in prostate cancer and associated with unfavorable prognosis. TRIM66/HP1γ/AR was upregulated during the androgen-independent transition in hormone-deprived medium. The TRIM66 level positively linked to cell proliferation and negatively linked to cell apoptosis in androgen-independent prostate cancer cells. QL treatment specifically inhibited c-Myc and therefore directly downregulated TRIM66 via binding to its promoter. Ectopic introduction of TRIM66 significantly reversed the anti-tumor effects of QL against androgen-independent prostate cancer.Our study uncovered the importance of downregulated TRIM66/HP1γ/AR signaling in mediating the anti-tumor properties of QL.Ziel: Ziel der vorliegenden Studie war es, den molekularen Mechanismus zu verstehen, welcher der therapeutischen Wirkung von Qi Ling (QL) auf das androgenunabhängige Prostatakarzinom zugrunde liegt. Methoden: Die relative Expression von TRIM66 in Prostatatumorzellen wurde mittels Microarray analysiert. Mithilfe einer quantitativen Echtzeit-PCR und eines Western Blot wurden die Transkript-Menge und Proteinexpression von TRIM66, HP1γ, AR, c-Myc und GAPDH bestimmt. Zellproliferation und Apoptose wurden mithilfe der Zellzählungsmethode Kit-8 (CCK-8) und Durchflusszytometrie analysiert. Die regulatorische Wirkung von c-Myc auf TRIM66 wurde mithilfe des Luciferase-Reporterplasmids analysiert, und die direkte Bindung wurde per Chromatin-Immunpräzipitation nachgewiesen. Das sekretorische prostataspezifische Antigen wurde mittels enzymgekoppeltem Immunadsorptionstest (ELISA) quantifiziert. Ergebnisse: TRIM66 war bei Prostatakrebs aberrant überexprimiert und mit einer ungünstigen Prognose verbunden. TRIM66/HP1γ/AR wurde im Rahmen der androgenunabhängigen Transition in hormonfreiem Medium hoch reguliert. Das TRIM66-Niveau war positiv mit der Zellproliferation und negativ mit der Apoptose androgenunabhängiger Prostatakrebszellen assoziiert. Die Behandlung mit QL bewirkte eine spezifische Hemmung von c-Myc und über die Bindung an seinen Promotor damit eine Herunterregulierung von TRIM66. Eine ektope Insertion von TRIM66 hob die antitumoralen Wirkungen von QL bei androgenunabhängigem Prostatakarzinom in signifikantem Maße auf. Schlussfolgerung: Unsere Studie offenbarte die Bedeutung einer herunterregulierten TRIM66/HP1γ/AR-Signalübertragung bei der Vermittlung der antitumoralen Eigenschaften von QL.

As the main component of realgar, arsenic sulphide (As4 S4 ) contains antitumour activity by repressing cancer cell proliferation and migration in many tumours. However, the detailed mechanism of these processes is not clear yet. MicroRNAs (miRNAs) can function as tumour suppressor or oncogene based on their target mRNAs in different tumour tissues. Here, we found that As4 S4 could repress the overexpression of microRNA-372 (miR-372) in two prostate cancer cell lines and its overexpression promoted cell proliferation and migration. Large tumour suppressor kinase 2 (LATS2) was confirmed as a direct target of miR-372 using luciferase assays in these two prostate cancer cell lines. Down-regulation of LATS2 could promote prostate cancer cell proliferation and migration just as overexpression of miR-372 did and overexpression of LATS2 could reverse this effect of miR-372. The antitumour activity of As4 S4 and the oncogenic function of miR-372 were further confirmed using a mouse xenograft model. Altogether, our data showed evidence that repressing the overexpression of miR-372 by As4 S4 could inhibit prostate cancer cell proliferation and migration by targeting LATS2. Therefore, miR-372 may be a possible biomarker for the prediction of prostate cancer and As4 S4 may have potential therapeutic function for prostate cancer.

This paper is to characterize the expression status of Fragile X Mental Retardation, Autosomal Homolog 1 (FXR1) in prostate cancer cells and understand its mechanistic involvement in the tumor biology of prostate cancer. The relative expression of FXR1 in prostate cancer cells was determined by real-time polymerase chain reaction and Western blotting. Cell proliferation in FXR1-deficient cells was evaluated by cell counting and MTT assays. The migrative and invasive capacities were measured by transwell assay. The potential regulatory effect of FXR1 on FBXO4 was interrogated using luciferase reporter assay. The direct bind of FXR1 with FBXO4 transcripts was analyzed by RNA immunoprecipitation and RNA pull-down assay. We observed aberrant overexpression of FXR1 in prostate cancer cells at both transcript and protein levels. FXR1 deficiency was associated with inhibited cell proliferation/viability and compromised migration/invasion in prostate cancer cells. Mechanistically, FXR1 negatively regulated FBXO4 transcripts via direct association with its 3′UTR and promoted mRNA degradation. FBXO4 knockdown predominantly rescued the tumor-suppressive phenotype in FXR1-deficient cells. We uncovered the oncogenic role of FXR1 in prostate cancer cells and further demonstrated its dependence on FBXO4. Our data highlight the importance of FXR1-FBXO4 signaling in prostate cancer.

Curcumin is a potent antitumor agent. The objective of this study was to explore the interaction between curcumin and PGK1, an oncogene in the FOXD3/miR-143 axis, in prostate cancer therapy. MiRNA microarray analysis was used to identify miRNAs upregulated by curcumin treatment. MiR-143 was dramatically upregulated by curcumin. Cells were treated with antimiR-143 in combination to curcumin, followed by examining cell viability and migration. Bioinformatics analysis was used to investigate target genes of miR-143. The interaction between miR-143 and PGK1 was evaluated with dual-luciferase assay. Since FOXD3 is important in the regulation of miR-143, we explored whether curcumin regulated FOXD3 expression. FOXD3 was also ectopically overexpressed to investigate its effects on curcumin’s regulation of miR-143. Curcumin treatment significantly upregulated miR-143 and decreased prostate cancer cell proliferation and migration. Those effects were attenuated by anti-miR-143 transfection. Both miR-143 overexpression and curcumin treatment inhibited PGK1 expression and ectopic expression of PGK1 antagonized curcumin’s antitumor effects. FOXD3 was upregulated by miR-143. Ectopic expression of FOXD3 synergized with curcumin in upregulating miR-143 expression. Curcumin inhibits prostate cancer by upregulating miR-143. PGK1 is downregulated by miR-143, and FOXD3 upregulation is essential for the antitumor effect of curcumin.