Targeting ADT-Induced Activation of the E3 Ubiquitin Ligase Siah2 to Delay the Occurrence of Castration-Resistant Prostate Cancer.

Siah2 is an E3 ubiquitin ligase that targets androgen receptor (AR) and plays an important role in the development of castration-resistant prostate cancer (CRPC). However, the regulation of Siah2 in prostate cancer (PCa) is largely unknown. In this study, we used AR-dependent and -independent cells lines to investigate the cellular roles of AR and androgen deprivation therapy (ADT) on Siah2 protein levels and E3 ligase activity using Western blotting and co-immunoprecipitation. We also validated our findings using patient samples taken before and after ADT. Finally, we used xenograft tumor models to test the effects of ADT combined with vitamin K3 (Vit K3) on tumor growth in vivo. Our results showed that AR stabilizes Siah2 protein by attenuating its self-ubiquitination and auto-degradation, likely by blocking its E3 ubiquitin ligase activity. Conversely, ADT decreased Siah2 protein expression but enhanced its E3 ligase activity in PCa cells. Notably, the findings that ADT decreasing Siah2 protein expression were verified in a series of paired PCa samples from the same patient. Additionally, we found that ADT-induced Siah2 activation could be abolished by Vit K3. Strikingly, ADT combined with Vit K3 treatment delayed the occurrence of CRPC and dramatically inhibited the growth of tumor xenografts compared with ADT treatment alone. AR is an inhibitor of Siah2 in PCa, and ADT leads to the continuous activation of Siah2, which may contribute to CRPC. Finally, ADT+Vit K3 may be a potential approach to delay the occurrence of CRPC.

Can a second resection be avoided after initial thulium laser endoscopic en bloc resection for non-muscle invasive bladder cancer? A retrospective single-center study of 251 patients.

BACKGROUND: This study aimed to evaluate the efficacy of transurethral thulium laser en bloc resection of the bladder tumor (TmLRBT) in patients with non-muscle invasive bladder cancer (NMIBC) and to investigate whether a second resection can be avoided. METHODS: From June 2012 to June 2018, 251 newly diagnosed patients with NMIBC were enrolled in this retrospective study; all patients received regular administration of pirarubicin after the initial resection. A second transurethral resection (TUR) was performed in patients within 2-6 weeks after the initial TmLRBT in group 1. Patients in group 2 only underwent cystoscopy at 3 months. RESULTS: Second surgery results indicate that recurrence was detected histopathologically in 6/108 and 11/143 patients in group 1 and 2, respectively (P = 0.52); Progression was observed in 2 patients in each group (P = 0.34). The mean follow-up duration was 40.1 months, with no significant difference between the groups (P = 0.32). Recurrence was observed in 23 (21.3%) and 39 (27.3%) patients in groups 1 and 2 during the follow-up, respectively (P = 0.34); disease progression occurred in 4 (3.8%) patients in group 1 compared with 7 (4.0%) in group 2 (P = 0.20). CONCLUSION: Complete removal of tumors can be achieved by TmLRBT. This technique may decrease the number of second TURs.

Identification of key candidate genes and pathways in hepatocellular carcinoma by integrated bioinformatical analysis.

Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms worldwide, however the underlying mechanisms and gene signatures of HCC are unknown. In the present study the profile datasets of four cohorts were integrated to elucidate the pathways and candidate genes of HCC. The expression profiles GSE25097, GSE45267, GSE57957 and GSE62232 were downloaded from the Gene Expression Omnibus database, including 436 HCC and 94 normal liver tissues. A total of 185 differentially expressed genes (DEGs) were identified in HCC, including 92 upregulated genes and 92 downregulated genes. Gene ontology (GO) was performed, which revealed that the upregulated DEGs were primarily enriched in cell division, mitotic nuclear division, mitotic cytokinesis and G1/S transition of the mitotic cell cycle. Pathway enrichment was analyzed based on the Kyoto Encyclopedia of Genes and Genomes database to assess the functional relevance of DEGs. The most significant module was selected from protein-protein interactions and 15 important hub genes were identified. The sub-networks of hub genes were involved in cell division, p53 signaling, and T lymphotropic virus type I infection signaling pathways. In conclusion, the present study revealed that the identified DEG candidate genes may promote the understanding of the cause and molecular mechanisms underlying the development of HCC and that these candidates and signal pathways may be potential targets of clinical therapy for HCC.