Guangzheng Zhong

Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression

BackgroundMetastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells.MethodsA microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143.ResultsThe expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo.ConclusionsThese data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer.

Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation

WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription; however, its role in bladder cancer remains largely unknown. Our study investigated the role of WDR5 in bladder cancer and demonstrated that WDR5 was upregulated in bladder cancer tissues, and elevated WDR5 protein levels positively correlated with advanced tumor stage and poor survival. Through gain or loss of function, we demonstrated that WDR5 promoted proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro, and tumor growth in vivo. Mechanistically, WDR5 regulated various functions in bladder cancer by mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1, BIRC3 and Nanog by histone H3 lysine 4 trimethylation. Therefore, we have discovered that WDR5 plays an important role in bladder cancer suggesting that WDR5 is a potential biomarker and a promising target in the treatment of bladder cancer.

Adjuvant and Salvage Radiotherapy after Prostatectomy: A Systematic Review and Meta-Analysis

Purpose In men with adverse prognostic factors (APFs) after radical prostatectomy (RP), the most appropriate timing to administer radiotherapy remains a subject for debate. We conducted a systemic review and meta-analysis to evaluate the therapeutic strategies: adjuvant radiotherapy (ART) and salvage radiotherapy (SRT). Materials and Methods We comprehensively searched PubMed, EMBASE, Web of Science and the Cochrane Library and performed the meta-analysis of all randomized controlled trials (RCTs) and retrospective comparative studies assessing the prognostic factors of ART and SRT. Results Between May 1998 and July 2012, 2 matched control studies and 16 retrospective studies including a total of 2629 cases were identified (1404 cases for ART and 1185 cases for SRT). 5-year biochemical failure free survival (BFFS) for ART was longer than that for SRT (Hazard Ratio [HR]: 0.37; 95% CI, 0.30–0.46; p<0.00001, I2 = 0%). 3-year BFFS was significantly longer in the ART (HR: 0.38; 95% CI, 0.28–0.52; p<0.00001, I2 = 0%). Overall survival (OS) was also better in the ART (RR: 0.53; 95% CI, 0.41–0.68; p<0.00001, I2 = 0%), as did disease free survival (DFS) (RR: 0.53; 95% CI, 0.43–0.66; p<0.00001, I2 = 0%). Exploratory subgroup analysis and sensitivity analysis revealed the similar results with original analysis. Conclusion ART therapy offers a safe and efficient alternative to SRT with longer 3-year and 5-year BFFS, better OS and DFS. Our recommendation is to suggest ART for patients with APFs and may reduce the need for SRT. Given the inherent limitations of the included studies, future well-designed RCTs are awaited to confirm and update this analysis.

An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer

The L‐plastin gene is involved in the invasion and metastasis of prostate cancer. However, the molecular mechanisms underlying L‐plastin transcription are unclear. We hypothesize that the occurrence of polymorphic genetic variations in the L‐plastin promoter might affect an individuals susceptibility to prostate cancer. In this study, we identified a single nucleotide polymorphism (SNP) at position −1,687 in the L‐plastin promoter by genotype sequencing. The SNP −1,687 showed different transcriptional activity in the luciferase assay in vitro. The TRANSFAC software was applied to predict the multiple cis‐elements, and luciferase assay was used to further identify the L‐plastin regulatory region. We performed EMSAs, supershift assays and ChIP‐qPCR demonstrated that the transcriptional suppressor NKX3.1 binds to the SNP site of the L‐plastin promoter. SNP −1,687 (T/T) led to an increase in the affinity of NKX3.1 for L‐plastin promoter, resulted in lower levels of L‐plastin RNA and protein expression. Furthermore, we collected and sequenced samples from 640 individuals (372 prostate cancer patients and 268 healthy controls) from 2000 to 2013. The results showed that SNP −1,687 (T/T) occurred more frequently in the healthy individuals than that in the prostate cancer patients compared to SNP −1,687 (C/C). Similarly, SNP −1,687 (T/T) genotype occurred more frequently compared to SNP −1,687 (C/C) genotype in the patients with low and moderately differentiated tumors. In conclusion, SNP −1,687, located in the NKX3.1 binding site within the L‐plastin promoter, might reduce the expression of L‐plastin and potentially decrease the tumorigenesis and progression of prostate cancer. This SNP could be a potential prognostic factor for prostate cancer.

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer–associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer–associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti–VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer.

Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an essential RNA‐ and DNA‐binding protein that regulates diverse biological events, especially DNA transcription. hnRNPK overexpression is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of hnRNPK in bladder cancer are unclear. We investigated hnRNPK expression by immunohistochemistry in 188 patients with bladder cancer, and found that hnRNPK expression levels were significantly increased in bladder cancer tissues and that high‐hnRNPK expression was closely correlated with poor prognosis. Loss‐ and gain‐of‐function assays demonstrated that hnRNPK promoted proliferation, anti‐apoptosis, and chemoresistance in bladder cancer cells in vitro, and hnRNPK knockdown suppressed tumorigenicity in vivo. Mechanistically, hnRNPK regulated various functions in bladder cancer by directly mediating cyclin D1, G0/G1 switch 2 (G0S2), XIAP‐associated factor 1, and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) transcription. In conclusion, we discovered that hnRNPK plays an important role in bladder cancer, suggesting that it is a potential prognostic marker and a promising target for treating bladder cancer.

Downregulation of long noncoding RNA FENDRR predicts poor prognosis in renal cell carcinoma

Long noncoding RNA FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) dysregulation associates with multiple types of human cancer. However, the biological functions of FENDRR in renal cell carcinoma are unresolved. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression level of FENDRR in renal cell carcinoma tissues. An RNA interference assay and ectopic expression experiments were conducted to evaluate the effects of FENDRR on cell proliferation, migration, invasion and colony formation in vitro. RNA immunoprecipitation was conducted to identify proteins associated with FENDRR. It was observed that FENDRR is frequently downregulated in renal cell carcinoma and overexpression of FENDRR attenuated proliferation, migration, invasion and colony growth of renal carcinoma cells. Conversely, knockdown of FENDRR promotes proliferation and invasiveness of renal carcinoma cells. Downregulation of FENDRR associates with poor prognosis of renal cell carcinoma. Mechanistically, it was identified that FENDRR may bind to Polycomb Repressive Complex 2 and lysin methyltransferase 2A histone modifying complexes. In summary, FENDRR acts as an tumor suppressor in renal cell carcinoma and may serve as a candidate target for gene therapy.

Circular RNA, a novel marker for cancer determination (Review)

Circular RNAs are abundant and conserved endogenous RNAs that are formed by exon skipping or back‑splicing events and occur in all forms of life. They have been proven to exhibit tissue‑ or cell‑type specificity and to be able to regulate cell behavior through multiple pathways. In cancer research, numerous studies have indicated that circular RNAs serve as potential biomarkers and therapeutic targets. Furthermore, differential expression of certain circular RNAs clearly predicts the clinical outcomes of cancer patients. Circular RNAs regulate carcinogenesis and cancer progression by acting as a microRNA sponge, coding for proteins and interacting with proteins. The present review mainly focuses on the recent literature regarding the role of circular RNAs in cancer, which may suggest novel strategies for cancer prognosis, diagnosis and clinical treatment.