Yinghao Sun

Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer

Examining plasma RNA is an emerging non-invasive diagnosis technique. However, whether tumour-derived long non-coding RNAs (lncRNAs) in plasma can be used as a novel approach to detect human prostate cancer (PCa) has not yet been established. The study was divided into three parts: (1) the characteristics of PCa-related lncRNA fragments were systematically studied in the plasma or serum of 25 patients; (2) the source of the circulating lncRNA fragments was explored in vitro and in vivo; and (3) the diagnostic performance of metastasis associated in lung adenocarcinoma transcript 1 (MALAT-1) derived (MD) miniRNA was validated in an independent cohort of 192 patients. The expression levels of lncRNAs were measured by quantitative real time polymerase chain reaction (qRT-PCR). The MD-miniRNA copies were calculated using a standard curve in an area under the ROC curve (AUC)-receiver operating characteristic (ROC) analysis. Genome-wide profiling revealed that MALAT-1 and prostate cancer gene 3 (PCA3) are overexpressed in PCa tissues. Plasma lncRNAs probably exist in the form of fragments in a stable form. MD-miniRNA enters cell culture medium at measurable levels, and MD-miniRNA derived from human PCa xenografts actually enters the circulation in vivo and can be measured to distinguish xenografted mice from controls. In addition, plasma MD-miniRNA levels are significantly elevated in PCa patients compared to non-PCa patients (p<0.001). At a cut-off of 867.8 MD-miniRNA copies per microlitre of plasma, the sensitivity is 58.6%, 58.6% and 43.5% and the specificity is 84.8%, 84.8% and 81.6% for discriminating PCa from non-PCa, positive biopsy from negative biopsy and positive biopsy from negative biopsy, respectively. We conclude that MD-miniRNA can be used as a novel plasma-based biomarker for PCa detection and can improve diagnostic accuracy by predicting prostate biopsy outcomes. Further large-scale studies are needed to confirm our findings.

Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4

Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor

OBJECTIVE Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostate cancer (CaP) pathogenesis. MATERIALS AND METHODS In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR. RESULTS We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines. CONCLUSIONS Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.

Impact of hypertension on health-related quality of life in a population-based study in Shanghai, China.

OBJECTIVES The purpose of this study was to examine the relationship between hypertension and health-related quality of life (HRQL) in a general representative Chinese population, and to explore the impacts of comorbidity on people with hypertension. STUDY DESIGN Population-based cross-sectional survey. METHODS A self-administered questionnaire survey including demographic questions and the Mandarin version of 36-item Short Form (SF-36) was conducted in a general population in Shanghai, China. In total, 1034 subjects participated. The SF-36 dimension scores of hypertensive subjects were compared with those of normotensive subjects. Independent association of hypertension with each quality-of-life domain was analysed using a multiple linear regression model, so were the effects of comorbidity on the HRQL of hypertensive subjects. RESULTS Nine hundred and nineteen respondents were included in the analysis, and 16.97% reported hypertension. Respondents with hypertension scored lower than those without hypertension in at least five SF-36 dimensions. The dimension of role limitations due to physical problems was the most affected, whereas the mental health dimension was the least affected. Hypertensive subjects with comorbidity experienced lower SF-36 scores than hypertensive subjects without comorbidity. CONCLUSIONS Hypertension markedly impairs quality of life in terms of both physical and mental health. Comorbidity further deteriorates HRQL among people with hypertension. The findings suggest that people with hypertension represent a vulnerable population, and it is important to prevent and treat comorbidity of hypertension.

Robotic versus Open Partial Nephrectomy: A Systematic Review and Meta-Analysis

Objectives To critically review the currently available evidence of studies comparing robotic partial nephrectomy (RPN) and open partial nephrectomy (OPN). Materials and Methods A comprehensive review of the literature from Pubmed, Web of Science and Scopus was performed in October 2013. All relevant studies comparing RPN with OPN were included for further screening. A cumulative meta-analysis of all comparative studies was performed and publication bias was assessed by a funnel plot. Results Eight studies were included for the analysis, including a total of 3418 patients (757 patients in the robotic group and 2661 patients in the open group). Although RPN procedures had a longer operative time (weighted mean difference [WMD]: 40.89; 95% confidence interval [CI], 14.39–67.40; p = 0.002), patients in this group benefited from a lower perioperative complication rate (19.3% for RPN and 29.5% for OPN; odds ratio [OR]: 0.53; 95%CI, 0.42–0.67; p<0.00001), shorter hospital stay (WMD: −2.78; 95%CI, −3.36 to −1.92; p<0.00001), less estimated blood loss(WMD: −106.83; 95%CI, −176.4 to −37.27; p = 0.003). Transfusions, conversion to radical nephrectomy, ischemia time and estimated GFR change, margin status, and overall cost were comparable between the two techniques. The main limitation of the present meta-analysis is the non-randomization of all included studies. Conclusions RPN appears to be an efficient alternative to OPN with the advantages of a lower rate of perioperative complications, shorter length of hospital stay and less blood loss. Nevertheless, high quality prospective randomized studies with longer follow-up period are needed to confirm these findings.

Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro

Ursolic acid (UA), a pentacyclic triterpenoid compound, has been demonstrated to have an antiproliferative effect in various tumors. We investigated the cell killing effects of UA in the human hormone refractory prostate cancer cell line, PC‐3 cells. Also, the molecular mechanisms underlying its antigrowth effect were explored. We found that UA treatment in vitro can effectively inhibit PC‐3 cell viability in a dose‐dependent manner by inducing apoptosis, demonstrated by annexin V‐FITC/propidium iodide staining. Both extrinsic and intrinsic apoptotic pathways appear to be triggered by UA treatment, because inhibiting activation of both caspase‐8 and ‐9 could prevent UA‐induced apoptosis in PC‐3 cells. The c‐Jun N‐terminal kinase (JNK) was found to be activated, followed by Bcl‐2 phosphorylation and activation of caspase‐9. On the other hand, UA inhibited the Akt pathway, subsequently upregulating the expression of Fas ligand (FasL), which initiates death receptor‐mediated apoptosis in PC‐3 cells. Importantly, experimentally lowering FasL expression by siRNA significantly inhibited UA‐induced caspase‐8 activation and at least partly attenuated the consequent apoptosis, suggesting an involvement of FasL and its regulating pathway in the cell killing effect of UA. UA also inhibited cell invasion by downregulating matrix metalloproteinase‐9 via inhibition of Akt in PC‐3 cells. Although further evaluation of the UA effects in vivo is needed, the present results suggest the potential utility of UA as a novel therapeutic agent in advanced prostate cancer.

bcl-2/bax EXPRESSION AND p53 GENE STATUS IN HUMAN BLADDER CANCER: RELATIONSHIP TO EARLY RECURRENCE WITH INTRAVESICAL CHEMOTHERAPY AFTER RESECTION

PURPOSE Studies have shown that the effects of chemotherapy depend on some biochemical mechanisms to induce apoptosis. Many genes are involved in apoptosis modulation, including p53, bcl-2 and bax. We determined the roles of p53 status and the ratio of bcl-2/bax proteins for predicting the recurrence of bladder superficial transitional cell carcinoma that had been treated with intravesical chemotherapy after resection. MATERIALS AND METHODS We performed Western blot analysis to express bcl-2 and bax proteins, and PCR-SSCP to determine the alteration in the p53 gene in 43 patients with transitional cell carcinoma of the bladder treated with intravesical chemotherapy after tumor resection. RESULTS The expression of bcl-2 or bax did not correlate with histological grade, clinical stage or relapse. In cases of relapse within 1 year after resection bcl-2/bax was greater than and less than 1 in 50 and 11%, respectively (p <0.01). Recurrence within 1 year after the initial operation was also more common in patients with than without p53 gene mutation (64 versus 22%, p <0.05). Furthermore, bcl-2/bax greater than and less than 1 was associated with p53 gene mutation in 38 and 11% of cases, respectively (p <0.05). CONCLUSIONS A bcl-2/bax ratio greater than 1 and p53 gene mutation were closely associated with early relapse in patients with superficial transitional cell carcinoma of the bladder during intravesical chemotherapy after resection. This finding suggests that the relative levels of bcl-2 and bax, and p53 gene status may contribute to drug sensitivity and progression, and help to predict recurrence. Moreover, bcl-2/bax correlated with p53 status, which implies that cross talk among bcl-2, bax and p53 has a role in influencing drug induced apoptosis and regulating resistance to chemotherapy.

Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

Thulium laser resection via a flexible cystoscope for recurrent non‐muscle‐invasive bladder cancer: initial clinical experience

To present our initial experience of thulium laser resection via a flexible cystoscope for recurrent non‐muscle‐invasive bladder cancer (ThuRBT), as transurethral resection for bladder tumour (TURBT) is regarded as the reference standard for treating this disease, but alternative laser resection or ablation is suitable especially for recurrent tumours.