Lin-hui Wang

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.

Coexpression of invasive markers (uPA, CD44) and multiple drug-resistance proteins (MDR1, MRP2) is correlated with epithelial ovarian cancer progression.

Background:Invasion and metastases of cancer cells and the development of resistance to anticancer therapies are the main causes of treatment failure and mortality in cancer patients.Methods:We evaluated invasive markers of urokinase plasminogen activator (uPA) and CD44 and multiple drug-resistance (MDR) markers of MDR1 and MRP2 in four epithelial ovarian cancer (EOC) cell lines, primary tumours (n=120) and matched metastatic lesions (n=40) by immunofluoresence labelling. We correlated uPA and CD44 with MDR markers in primary and metastatic cells using confocal microscope. We also investigated the relationship of the expression of uPA, CD44 and MDR1 with various progression parameters.Results:The coexpression of uPA and CD44 with MDR markers was found in primary and metastatic cells. The overexpression of uPA, CD44 and MDR1 was found in most primary and matched metastatic lesions of EOC, and was significantly associated with tumour stage, grade, residual disease status, relapse and presence of ascites (P<0.05), but not with histology type (P>0.05).Conclusions:Our results suggest that the overexpression of uPA, CD44 and MRD1 is correlated with EOC progression; both uPA and CD44 are related with drug resistance during EOC metastasis and could be useful therapeutically.

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.

Laparoendoscopic Single-site Partial Nephrectomy: A Multi- institutional Outcome Analysis

BACKGROUND Laparoendoscopic single-site surgery (LESS) has been developed in an attempt to further reduce the surgical trauma associated with conventional laparoscopy. Partial nephrectomy (PN) represents a challenging indication for LESS. OBJECTIVE To report a large multi-institutional series of LESS-PN and to analyze the predictors of outcomes after LESS-PN. DESIGN, SETTING, AND PARTICIPANTS Consecutive cases of LESS-PN done between November 2007 and March 2012 at 11 participating institutions were included in this retrospective analysis. INTERVENTION Each group performed LESS-PN according to its own protocols, entry criteria, and techniques. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic data, main perioperative outcome parameters, and perioperative complications were gathered and analyzed. A multivariable analysis was used to assess the factors predicting a short (≤ 20 min) warm ischemia time (WIT), the occurrence of postoperative complication of any grade, and a favorable outcome, arbitrarily defined as a combination of the following events: short WIT plus no perioperative complications plus negative surgical margins plus no conversion to open surgery or standard laparoscopy. RESULTS AND LIMITATIONS A total of 190 cases were included in this analysis. Mean renal tumor size was 2.6, and PADUA score 7.2. Median operative time was 170 min, with median estimated blood loss (EBL) of 150 ml. A clampless technique was adopted in 70 cases (36.8%), and the median WIT was 16.5 min. PADUA score independently predicted length of WIT (low vs high score: odds ratio [OR]: 5.11 [95% confidence interval (CI), 1.50-17.41]; p=0.009; intermediate vs high score: OR: 5.13 [95% CI, 1.56-16.88]; p=0.007). The overall postoperative complication rate was 14.7%. The adoption of a robotic LESS technique versus conventional LESS (OR: 20.92 [95% CI, 2.66-164.64]; p=0.003) and the occurrence of lower (≤ 250 ml) EBL (OR: 3.60 [95% CI, 1.35-9.56]; p=0.010) were found to be independent predictors of no postoperative complications of any grade. A favorable outcome was obtained in 83 cases (43.68%). On multivariate analysis, the only predictive factor of a favorable outcome was the PADUA score (low vs high score: OR: 4.99 [95% CI, 1.98-12.59]; p<0.001). Limitations of the study were the retrospective design and different selection criteria for the participating centers. CONCLUSIONS LESS-PN can be safely and effectively performed by experienced hands, given a high likelihood of a single additional port. Anatomic tumor characteristics as determined by the PADUA score are independent predictors of a favorable surgical outcome. Thus patients presenting tumors with low PADUA scores represent the best candidates for LESS-PN. The application of a robotic platform is likely to reduce the overall risk of postoperative complications.

High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma.

BackgroundChemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The aim of this study was to evaluate the prognostic impact of the expression of the chemokine SDF-1 and its receptors CXCR4 and CXCR7 in patients with renal cell carcinoma.MethodsThe expression of CXCR4, CXCR7 and SDF-1 in specimens from 97 renal cell carcinoma patients was evaluated by immunohistochemistry on a tissue microarray. These results were correlated with the clinicopathological parameters and survival of the patients.ResultsCXCR4 and CXCR7 were expressed in all patients, whereas SDF-1 was expressed in 61 patients (62.9%). No association was observed between the expression of CXCR4, CXCR7 or SDF-1 and the clinical or pathological data except between SDF-1 expression and Fuhrman’s grade (P = 0.015). Patients with high expression of CXCR4, CXCR7 and SDF-1 had shorter overall survival and recurrence-free survival than those with low expression. In a multivariate analysis, the high expression of CXCR4, CXCR7 and SDF-1 correlated with poor overall survival and recurrence-free survival independent of gender, age, AJCC stage, lymph node status, metastasis, histologic variant and Fuhrman’s grade.ConclusionsHigh levels of CXCR4, CXCR7 and SDF-1 were associated with poor overall survival and recurrence-free survival in renal cell carcinoma patients. CXCR4, CXCR7 and SDF-1 may serve as useful prognostic markers and therapeutic targets for renal cell carcinoma.

Pneumatic lithotripsy versus Laser lithotripsy in the endoscopic treatment of ureteral calculi

PURPOSE To compare the efficacy, safety, and features of pneumatic lithotripsy (PL) with those of laser lithotripsy (LL) and present our clinical experience in the endoscopic management of ureteral calculi. PATIENTS AND METHODS From August 1994 to February 2000, 285 consecutive patients underwent endoscopic lithotripsy with either the Swiss Lithoclast pneumatic lithotripter (145 patients) or the Ho:YAG laser lithotripter (140 patients) for the treatment of ureteral calculi. RESULTS In one single session, the overall successful stone fragmentation rate of LL was higher than that of PL (95.7% v 69.7%; P < 0.01). The average time to stone-free status was shorter for LL than for PL (18 days v 31 days; P < 0.01). No major complications were observed in LL, while five ureteral perforations were encountered in PL. CONCLUSIONS Laser lithotripsy has advantages over PL in high efficiency of stone fragmentation and a low complication rate. Laser lithotripsy is a powerful, effective, and safe treatment modality for ureteral calculi.

ATM-mediated KDM2A phosphorylation is required for the DNA damage repair

The ataxia-telangiectasia mutated (ATM) protein is a key signaling molecule that modulates the DNA damage response. However, the exact mechanism by which ATM regulates DNA damage repair has not yet been elucidated. Here, we report that ATM regulates the DNA damage response by phosphorylating lysine-specific demethylase 2A (KDM2A), a histone demethylase that acts at sites of H3K36 dimethylation. ATM interacts with KDM2A, and their interaction significantly increases in response to DNA double-stranded, but not single-stranded, breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage, as demonstrated by a mutagenesis assay and mass spectrometric analysis. Although KDM2A phosphorylation does not alter its own demethylase activity, T632 phosphorylation of KDM2A largely abrogates its chromatin-binding capacity, and H3K36 dimethylation near DNA damage sites is significantly increased. Consequently, enriched H3K36 dimethylation serves as a platform to recruit the MRE11 complex to DNA damage sites by directly interacting with the BRCT2 domain of NBS1, which results in efficient DNA damage repair and enhanced cell survival. Collectively, our study reveals a novel mechanism for ATM in connecting histone modifications with the DNA damage response.

Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling

BackgroundRecent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown.MethodslncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs.ResultsThe microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway.ConclusionsMRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC.

Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic surgery: a systematic review and meta-analysis of observational studies.

PURPOSE To assess the surgical efficacy and potential advantages of laparoendoscopic single-site adrenalectomy (LESS-AD) compared with conventional laparoscopic adrenalectomy (CL-AD) based on published literature. METHODS An online systematic search in electronic databasesM including Pubmed, Embase, and the Cochrane Library, as well as manual bibliography searches were performed. All studies that compared LESS-AD with CL-AD were included. The outcome measures were the patient demographics, tumor size, blood loss, operative time, time to resumption of oral intake, hospital stay, postoperative pain, cosmesis satisfaction score, rates of complication, conversion, and transfusion. A meta-analysis of the results was conducted. RESULTS A total of 443 patients were included: 171 patients in the LESS-AD group and 272 patients in the CL-AD group (nine studies). There was no significant difference between the two groups in any of the demographic parameters expect for lesion size (age: P=0.24; sex: P=0.35; body mass index: P=0.79; laterality: P=0.76; size: P=0.002). There was no significant difference in estimated blood loss, time to oral intake resumption, and length of stay between the two groups. The LESS-AD patients had a significantly lower postoperative visual analog pain score compared with the CL-AD group, but a longer operative time was noted. Both groups had a comparable cosmetic satisfaction score. The two groups had a comparable rate of complication, conversion, and transfusion. CONCLUSIONS In early experience, LESS-AD appears to be a safe and feasible alternative to its conventional laparoscopic counterpart with decreased postoperative pain noted, albeit with a longer operative time. As a promising and emerging minimally invasive technique, however, the current evidence has not verified other potential advantages (ie, cosmesis, recovery time, convalescence, port-related complications, etc.) of LESS-AD.

MicroRNA Expression Profiling in Clear Cell Renal Cell Carcinoma: Identification and Functional Validation of Key miRNAs.

Objective This study aims to profile dysregulated microRNA (miRNA) expression in clear cell renal cell carcinoma (ccRCC) and to identify key regulatory miRNAs in ccRCC. Methods and Results miRNA expression profiles in nine pairs of ccRCC tumor samples at three different stages and the adjacent, non-tumorous tissues were investigated using miRNA arrays. Eleven miRNAs were identified to be commonly dysregulated, including three up-regulated (miR-487a, miR-491-3p and miR-452) and eight down-regulated (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299-3p, miR-29a, miR-429, and miR-532-5p) in tumor tissues as compared with adjacent normal tissues. The 11 miRNAs and their predicted target genes were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and three key miRNAs (miR-199a-5p, miR-22 and miR-429) were identified by microRNA-gene network analysis. Dysregulation of the three key miRNAs were further validated in another cohort of 15 ccRCC samples, and the human kidney carcinoma cell line 786-O, as compared with five normal kidney samples. Further investigation showed that over-expression of miR-199a-5p significantly inhibited the invasion ability of 786-O cells. Luciferase reporter assays indicated that miR-199a-5p regulated expression of TGFBR1 and JunB by directly interacting with their 3’ untranslated regions. Transfection of miR-199a-5p successfully suppressed expression of TGFBR1 and JunB in the human embryonic kidney 293T cells, further confirming the direct regulation of miR-199a-5p on these two genes. Conclusions This study identified 11 commonly dysregulated miRNAs in ccRCC, three of which (miR-199a-5p, miR-22 and miR-429) may represent key miRNAs involved in the pathogenesis of ccRCC. Further studies suggested that miR-199a-5p plays an important role in inhibition of cell invasion of ccRCC cells by suppressing expression of TGFBR1 and JunB.