Yi Ping Zhu

Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy.

miR‐21 has been recognized as an “onco‐microRNA” with the activity of negatively modulating the expression of tumor‐suppressor genes. However, its role in prostate cancer (CaP) has not been well‐documented. We designed this study to assess the potential function of serum miR‐21 in the progression of CaP.

Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells.

AbstractAim:To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.Methods:A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.Results:A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.Conclusion:Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.

Tumor cytoreduction results in better response to androgen ablation-a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer

OBJECTIVES To investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB). MATERIALS AND METHODS Medical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months). RESULTS Age at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P < 0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance. CONCLUSIONS TURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.

Prospectively Packaged Ilioinguinal Lymphadenectomy for Penile Cancer: The Disseminative Pattern of Lymph Node Metastasis

PURPOSE We prospectively evaluated the disseminative pattern of lymph node metastasis in penile cancer cases using packaged lymphadenectomy. In addition, we analyzed prognostic factors of the extent of lymph node metastasis. MATERIALS AND METHODS Packaged inguinal lymphadenectomy was performed in 46 patients. A total of 24 patients with 1 or more positive inguinal lymph nodes underwent packaged iliac lymphadenectomy. Inguinal lymphadenectomy was divided into 3 packages, including medial inguinal, lateral inguinal and Cloquets node packages. Medial and lateral inguinal packages were separated by the lateral surface of the femoral artery and the saphenous vein. Iliac lymphadenectomy was divided into 3 packages, including external iliac, obturator and common iliac packages. Clinicopathological features of the primary tumor and lymph nodes were correlated with the extent of lymph node metastasis. RESULTS Of 92 groin basins 27 cases of inguinal lymphadenectomy and 7 of iliac lymphadenectomy had lymph node metastasis. Medial inguinal and external iliac packages were the most common involved regions in inguinal and iliac lymphadenectomy cases, respectively. No extended lymph node metastasis was observed in the absence of positive lymph nodes in the medial inguinal package. In groin basins with lymph node metastasis in the medial inguinal package extranodal extension was a significant predictor of extended lymph node metastasis. Cloquets node was associated with iliac lymph node metastasis on univariate analysis. However, it was of limited predictive value in patients with 1 or 2 positive inguinal lymph nodes. CONCLUSIONS The medial inguinal package defined in our study was the first involved lymph node region in penile cancer cases. Extranodal extension was an important predictor of extended lymph node metastasis beyond the medial inguinal package.

Long non-coding RNA LOC572558 inhibits bladder cancer cell proliferation and tumor growth by regulating the AKT-MDM2-p53 signaling axis

Long non-coding RNAs (lncRNAs) have been suggested to play important roles in the progression of many cancers such as bladder cancer. However, the detailed mechanism has not been fully understood. We have previously identified a collection of aberrantly expressed lncRNAs in bladder cancer using microarray gene profiling assay. In the current study, we aim to further explore the expression profile and the function of LOC572558, one of the most deregulated lncRNAs in bladder cancer. A large cohort of human bladder cancer tissue samples with benign controls, as well as established human bladder cancer cell lines, has been examined for the expression of LOC572558. The biological functions of LOC572558 were examined by CCK-8 assay, flow cytometry analysis, and wound healing and transwell assays. Using a high-throughput phospho-proteome array, we identified proteins that were ectopic phosphorylated in bladder cancer cells where LOC572558 expression was upregulated. We demonstrated that LOC572558 expression was markedly decreased in bladder cancer tissues and bladder cancer cell lines. Moreover, ectopic expression of LOC572558 inhibited cell proliferation and motility, induced S phase arrest of the cell cycle and promoted cell apoptosis in T24 and 5637 bladder cancer cell lines. We further verified that overexpression of LOC572558 was associated with dephosphorylation of AKT, MDM2 and phosphorylation of p53 protein. Our data clearly demonstrated that LOC572558 is a tumor suppressor and regulates the p53 signaling pathway in bladder cancer. Thus, it may serve as a promising new diagnostic marker and therapeutic target in bladder cancer.

Prostate-specific antigen half-life: A new predictor of progression-free survival and overall survival in Chinese prostate cancer patients

We investigated the potential value of prostate-specific antigen half-life (PSAHL) and decreasing velocity (PSAVd) to predict progression-free survival (PFS) and overall survival (OS) in Chinese patients with prostate cancer. A total of 153 patients treated with hormonal therapy were included in the study. Of these, 78 patients progressed to hormone-refractory prostate cancer (HRPC) and 24 patients died by the end of follow-up. PSAHL was defined as the time during which prostate-specific antigen (PSA) concentration became half of the initial value during the first hormonal therapy. PSAVd reflected the decreasing velocity of PSA during the first hormonal therapy. PFS was defined as the interval from the beginning of hormonal therapy to HRPC. Cox proportional hazards regression analysis was used to evaluate whether PSAHL and PSAVd were significantly associated with PFS and OS. The median PSAHL and PSAVd were 0.50 months and 33.8 ng mL(-1) per month. The median PFS and OS were 22.7 months (95% confidence interval [CI], 22.0-29.6 months) and 43.5 months (95% CI, 37.9-48.4 months), respectively. On univariate and multivariate analysis, long PSAHL (> 0.5 months), metastatic disease, high biopsy Gleason scores (>or= 8) and high nadir PSA (> 0.4 ng mL(-1)) were all found to be significantly associated with short PFS. Long PSAHL, high nadir PSA and short PSA doubling time (PSADT <or= 2.0 months) were significantly associated with short OS. There were no significant relationships between PSAVd and either PFS or OS. Thus, PSAHL is a promising new independent predictor of survival. Patients with long PSAHL were identified as those at high risk for a relatively short PFS and OS.

Narrow-Band Imaging Flexible Cystoscopy in the Detection of Clinically Unconfirmed Positive Urine Cytology

Introduction: The objective of this study was to investigate the value of narrow-band imaging (NBI) cystoscopy in the detection of patients with positive voided urine cytology (VUC) who have no evidence of disease after standard initial investigations. Patients and Methods: Between February 2009 and December 2010, 12 patients with positive or suspicious VUC but no regular endoscopic evidence of cancer were investigated with NBI flexible cystoscopy. All the specimens were biopsied both under NBI and white light imaging (WLI). Random biopsies of bladder and prostatic urethra were performed in cases without suspect lesions. Results: Fourteen NBI cystoscopies were carried out in 12 patients. Non-muscle-invasive bladder cancer was diagnosed in 5 of 12 (42%) patients on the first NBI. One patient had carcinoma in situ diagnosed on repeat NBI 3 months later. The sensitivity and specificity in diagnosing unconfirmed positive VUC was 78 and 91% for NBI vs. 50 and 80% for WLI. Conclusions: NBI cystoscopy significantly improves detection of unconfirmed positive VUC over WLI. It should be carried out early in the investigation of such patients before random biopsies and ureteroscopy.

Prevalence of incidental prostate cancer in patients undergoing radical cystoprostatectomy： data from China and other Asian countries

The purpose of this study is to investigate the frequency of prostate cancer (Pca) discovered incidentally in radical cystoprostatectomy specimens in Asia and to determine the feasibility of prostate-sparing cystectomy (PSC) for Asian patients. Ninety-two male bladder cancer patients who underwent radical cystoprostatectomy at our center between January 2003 and January 2008 were included in this study. The mean age of patients was 67.1 years (range: 32–75 years). Prostate-specific antigen (PSA) levels and digital rectal examination (DRE) results before surgery were obtained retrospectively. Prostates of all patients were embedded and sectioned at 5-mm intervals. The same pathologist examined the prostatic tissues from radical cystoprostatectomy specimens. Finally, a structured literature review was performed using MEDLINE and PUBMED to estimate the occurrence of incidental Pca in Asia. Of the 92 patients, 3 (3.3%) were found to have Pca; in one out of three (33.3%) patients the disease was clinically significant due to a Gleason grade 4 carcinoma. Eight articles were included in our review. The overall incidence of Pca discovered incidentally in radical cystoprostatectomy specimens in Asia was 9.9% (64/642). When age was restricted to < 60 years, only 7 out of 222 (3.2%) patients were found to have synchronous Pca, and none of the cases was clinically significant. The occurrence of Pca in radical cystoprostatectomy specimens in Asia is much lower than that in Western countries. PSC might be feasible for Asian patients under a strict preoperative selection.

Long noncoding RNA expression signatures of bladder cancer revealed by microarray

Dysregulation of long noncoding RNAs (lncRNAs) has been regarded as a primary feature of several human cancers. However, the genome-wide expression and functional significance of lncRNAs in bladder cancer remains unclear. The aim of this study was to identify aberrantly expressed lncRNAs that may play an important role in contributing to bladder cancer pathogenesis. In this study, we described lncRNAs profiles in four pairs of human bladder cancer and matched normal bladder tissues by microarray. We finally determined 3,324 differentially expressed human lncRNAs and 2,120 differentially expressed mRNAs (≥2-fold change). A total of 110 lncRNAs were significantly differentially expressed between the tumor and the control groups (≥8-fold change). Four lncRNAs (TNXA, CTA-134P22.2, CTC-276P9.1 and KRT19P3) were selected for further confirmation of microarray results using quantitative PCR (qPCR), and a strong correlation was identified between the qPCR results and microarray data. We also observed that numerous lncRNA expression levels were significantly correlated with the expression of tens of protein coding genes by construction of the lncRNA-mRNA co-expression network. Kyoto Encyclopedia of Genes and Genomes annotation showed a significant association with p53, bladder cancer, cell cycle and propanoate metabolism pathway gene expression in the bladder cancer group compared with the normal tissue group, indicating that deregulated lncRNAs may act by regulating protein-coding genes in these pathways. We demonstrated the expression profiles of human lncRNAs in bladder cancer by microarray. We identified a collection of aberrantly expressed lncRNAs in bladder cancer compared with matched normal tissue. It is likely that these deregulated lncRNAs play a key or partial role in the development and/or progression of bladder cancer.

Expression of dicer and its related MiRNAs in the progression of prostate cancer

Dicer is aberrantly expressed in several types of malignancies. Cleaved by Dicer, the small noncoding microRNAs (miRNAs) are considered potential tools for the diagnosis and prognosis of cancer. This study investigated the expression of miRNAs thought to target Dicer. Expression of 1,205 human miRNAs and miRNA*s were examined in four patients with prostate cancer (PCa) by miRNA array in which the threshold was set as two-fold. Seventy-three miRNAs and miRNA*s were significantly down-regulated while 10 were up-regulated in PCa tissues compared with matched histologically normal glands. Of these, miR-29b-1, miR-200a, miR-370, and miR-31, which were the most down/up-regulated and closely potentially target to the Dicer 3′ UTR, were investigated further. Tissues of primary tumors and matched normal prostate glands from 185 patients with PCa were collected for further investigation. Dicer mRNA levels were negatively correlated with miR-29b-1 (ρs = −0.177, p = 0.017), miR-200a (ρs = -0.489, p < 0.0001) and miR-31 (ρs = −0.314, p < 0.0001) expression. Compared with adjacent normal glands, PCa tissues showed significantly lower miR-200a and miR-31 expression levels. Furthermore, in metastatic PCa, the expression levels of miR-200a, miR-370, and miR-31 were dramatically higher than in localized PCa. Additionally, elevated expression levels of miR-200a and miR-31 appeared to be associated with castration-resistant PCa. These findings suggest possibilities that miR-200a and miR-31 target Dicer and are involved in the carcinogenesis, migration, and behavior of castration-resistant PCa, indicating that they could be potential biomarkers for monitoring PCa progression.