[Bioinformatics-based analysis of the effect of general Transcription Factor IIH on prognosis of Prostate cancer].

Objective: To investigate the genetic and expression characteristics of transcription factor IIH (TFIIH) in pre-initiationcomplex in prostate cancer (PCa) and its relationship with prostate cancer progression. Methods: Analyzing the expression characteristics and clinical signification of TFIIH subunits about 495 cases of PCa and 52 cases of adjacent cancer in The Cancer Genome Atlas-Prostate adenocarcinoma (TCGA-PRAD) database. PCa microarray chip was used to verify the correlation between the key factor General Transcription Factor IIH Subunit 4 (GTF2H4) in TFIIH and clinical features. Results: The 495 patients with PCa were (61.01±6.82) years old.The mRNA expression of ERCC3、GTF2H4 and MNAT1 were high in PCa tissues with GS≥8(P<0.05). The expression of GTF2H4 and MNAT1 were relevant to the pathological stages(P<0.05). High expression of GTF2H4 has higher biochemical recurrence (BCR) rate in PCa patients(HR=2.47, 95%CI:1.62-3.77, P<0.001), which has better predictive effect of BCR in PCa patients(The 3rd, 5th, and 7th year AUC all>0.7) than other subunits, and it has been verified in four additional databases. Single-factor Cox regression analysis showed that GTF2H4 were risk factors for BCR (HR=2.470, 95%CI:1.620-3.767, P<0.001) and GTF2H5 were protective factors(HR=0.506,95%CI: 0.336-0.762, P=0.001). The results of immunohistochemical staining showed that the protein expression of GTF2H4 was correlated with the clinical features of PCa patients.The differences of the above results were statistically significant. Conclusion: GTF2H4, the key factor of TFIIH, is highly expressed in PCa and indicates a poor prognosis.

[Research status of the innervation of prostate cancer and its potential clinical applications for nerve-targeted therapy].

Nerve fibers are important component in tumor microenvironment (TME) and have been shown to promote the early development of the prostate cancer and metastasis of advanced prostate cancer. Besides, it also activates an angio-metabolic switch, altering the endothelial cell metabolism to trigger angiogenesis. Most studies have showed that nerve infiltration in prostate cancer may be regulated by a variety of nerve growth factors secreted by cancer cells.However, surprisingly, neurons in the TME could also be neural progenitors originating from the subventricular zone. Recently, the effects of tumor-associated neuro-immune signal dysfunction on cancer promotion has gradually become a new focus. Therefore, elucidating the molecular and cellular mechanisms of nerve and its signaling in prostate cancer will help improve the value of clinical application of nerve targeted therapy.

ARRDC3 Inhibits the Progression of Human Prostate Cancer Through ARRDC3-ITGß4 Pathway.

BACKGROUND: Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestins family, which has been identified as a tumor suppressor gene in human breast cancer, but its functions are still not clear in human prostate cancer (PCa). OBJECTIVE: The purpose of the present study was to investigate clinical significance, biological functions and underlying mechanisms of ARRDC3 deregulation in PCa. METHOD: Involvement of ARRDC3 deregulation in malignant phenotypes of PCa was demonstrated by clinical sample evaluation, microarray analysis, and in vitro and in vivo experiments. The mechanisms underlying its regulatory effect on tumor progression were determined. RESULTS: Microarray analysis found that ARRDC3 low expression was significantly associated with high Gleason score in TMA, and the expression level of ARRDC3 was negatively correlated with Gleason score, metastasis and biochemical recurrence in online Taylor Dataset. As revealed by the dataset, Kaplan-Meier analyses revealed that the biochemical recurrence-free survival (BCR-free) time of PCa patients with ARRDC3 high expression was longer than those with ARRDC3 low expression. Additionally, both univariate and multivariate analyses showed that the downregulation of ARRDC3 was an independent prognostic marker for BCR-free survival of patients with PCa. In vitro studies revealed that ARRDC3 could inhibit proliferation, migration and invasion of PCa cell lines. In vivo studies proved that ARRDC3 over-expressing cells formed significantly larger tumor nodules and remarkably speeded up tumor xenografts growth compared with the controls. Moreover, immunohistochemical scores of Ki67 and MMP-9 were significantly lower than those of the control group. Finally, correlation analysis indicated that the expression of ARRDC3 was negatively correlated with ITGß4 in clinical PCa tissues and cell lines. CONCLUSION: Our data revealed that ARRDC3 can serve as a tumor suppressor to inhibit PCa progression and an independent marker to predict the risk of biochemical recurrence and metastasis after radical resection of PCa.

Decreased HoxD10 Expression Promotes a Proliferative and Aggressive Phenotype in Prostate Cancer.

HoxD10 gene plays a critical role in cell proliferation in the process of tumor development. However, the protein expression level and the function of HoxD10 in prostate cancer remain unknown. Using tissue microarray, we demonstrate that the protein expression of HoxD10 is commonly decreased in prostate cancer tissues (n = 92) compared to adjacent benign prostate tissues (n = 77). Functionally, knockdown of HoxD10 resulted in significant promotion of prostate cancer cell proliferation. Moreover, knockdown of HoxD10 strikingly stimulated prostate tumor growth in a mouse xenograft model. We also found a significant association between decreased immunohistochemical staining of HoxD10 expression and higher Gleason score (P = 0.031) and advanced clinical pathological stage (P = 0.011). An analysis of the Taylor database revealed that decreased HoxD10 expression predicted worse biochemical recurrence (BCR)-free survival of PCa patients (P = 0.005) and the multivariate analyses further supported that HoxD10 might be an independent predictor for BCR-free survival (P = 0.027). Collectively, our data suggest that the loss of HoxD10 function is common and may thus result in a progressive phenotype in PCa. HoxD10 may function as a biomarker that differentiates patients with BCR disease from the ones that are not after radical prostatectomy, implicating its potential as a therapeutic target.

Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer.

PURPOSE: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-κB and STAT3 signaling pathways. To better understand the correlation of NF-κB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). METHODS: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. RESULTS: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. CONCLUSIONS: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients' prognosis of PCa, implying their potentials as candidate markers of this cancer.

Persistent ethanol drinking increases liver injury induced by trinitrotoluene exposure: an in-plant case-control study.

On the basis of a general survey conducted in a munitions plant, a case-control study was made on the various risk factors of liver damage induced by trinitrotoluene (TNT) exposure in the plant. One-hundred male cases with occupational TNT liver damage were paired with 100 male controls, one-by-one, for occupation, age and duration (years) of employment. A total of 55 possible risk factors were statistically analysed with a single factor analysis. On the basis of the single analysis, nine factors including drinking, smoking and education were further analysed with a conditional logistic regression model. A calculation was made on the odds ratio (OR) of each factor selected into the model. According to the estimated parameter of the established logistic model, the relative risk of the risk factors could be worked out. Finally, two factors, the amount of ethanol drunk on each occasion and the frequency of drinking every week were selected into the model at the level of a = 0.05. The result showed that these two factors have a dose-response relationship with their OR of occupational TNT liver damage, but there is no connection between smoking and occupational TNT liver damage and no interaction between drinking and smoking. The above results have revealed that people exposed to TNT and with a long history of heavy drinking, have a greater risk of suffering from chronic liver impairment than those that do not drink.