RESUMO
OBJECTIVE: Docetaxel remains a main treatment for metastatic castration-resistant prostate cancer (mCRPC); however, the development of docetaxel resistance has been found in some mCRPC patients. The aim of this work is to identify an effective biomarker for predicting therapeutic effectiveness of docetaxel in mCRPC patients. METHODS: We examined DNA polymerase theta (POLQ) expression in The Cancer Genome Atlas (TCGA) database and Tissue microarray. Kaplan-Meier analyses were performed to estimate the prognostic significance of POLQ. A series of functional analyses were conducted in cell lines and xenograft models. Regulated pathways were predicted by Geneset Enrichment Analysis (GSEA) software and further investigated by luciferase reporter and RT-PCR assays. RESULTS: We found that POLQ mRNA levels in CRPC tissues was significantly higher than that of other DNA polymerases in non-CRPC prostate tissues. POLQ upregulation was extensively detected in mCRPC and strongly predicted a poor prognosis. POLQ knockdown enhanced docetaxel sensitivity in a cell-based cytotoxicity assay and promoted the therapeutic effect on the tumor growth of metastatic PC-3M cells in xenograft models. The computational simulation by GSEA software significantly predicted the association between POLQ upregulation and the activation of E2F/G2M checkpoint-related pathways. Moreover, luciferase reporter and RT-PCR assays demonstrated that POLQ knockdown downregulated the transcriptional regulatory activity of E2F and repressed E2F/G2M checkpoint-regulated CDK1 in mCRPC cells. CONCLUSION: Our results suggest that POLQ serves as a predictive factor for poor docetaxel response and provide a novel strategy to enhance the anticancer effects of docetaxel therapy by targeting POLQ in mCRPC patients.
Assuntos
Antineoplásicos/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , Docetaxel/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , DNA Polimerase Dirigida por DNA/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas , DNA Polimerase tetaRESUMO
A field survey was conducted to investigate the presence of Borrelia burgdorferi sensu lato (s.l.) in six counties of Taiwan. Spirochetes were successfully isolated from one rodent ear sample out of 485 rodent ears and 53 live, fed tick (Ixodes granulatus) samples. The spirochetes were confirmed to be B. burgdorferi s.l. by real-time PCR. In addition, 23 of 113 tick samples were tested positive for Borrelia DNA according to real-time PCR. The Borrelia isolate from the rodent and the 23 Borrelia DNA samples from the ticks were identified as B. valaisiana-related genospecies by phylogenetic analysis based on flagellin gene sequences. These findings suggest that the Borrelia valaisiana-related strains are maintained in a zoonotic cycle between tick vectors and reservoir hosts in Taiwan.
