Tzu-Ping Lin - Academia.edu (original) (raw)

Papers by Tzu-Ping Lin

Molecular cancer research : MCR, Jan 24, 2018

Prostate cancer (PCa) is a prevalent public health problem, especially since non-cutaneous advanc... more Prostate cancer (PCa) is a prevalent public health problem, especially since non-cutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc-interacting protein and transcription factor, in human PCa tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human PCa cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc-targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repre...

Cancer letters, Jan 23, 2018

Long non-coding RNAs (lncRNAs) are emerging as novel diagnostic markers of prostate cancer (PCa) ... more Long non-coding RNAs (lncRNAs) are emerging as novel diagnostic markers of prostate cancer (PCa) and new determinants of castration-resistant PCa (CRPC), an aggressive and metastatic form of PCa. In addition to androgen receptor (AR) signaling, neuroendocrine differentiation (NED) is associated with CRPC. Recent reports demonstrate that the downregulation of repressor element-1 silencing transcription factor (REST) protein is a key step in NED of PCa cells. Here, we report HOTAIR as a novel REST-repressed lncRNA that is upregulated in NED PCa cells and in CRPC. HOTAIR overexpression is sufficient to induce, whereas knockdown of HOTAIR suppressed NED of PCa cells. Gene ontology (GO) analysis of differentially expressed genes under HOTAIR overexpression and in CRPC versus benign prostatic hyperplasia (BPH) suggests that HOTAIR may participate in PCa progression. Taken together, our results provide the first evidence of lncRNA HOTAIR as a driver for NED of PCa cells.

Oncogene, Jan 29, 2018

Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters ... more Monoamine oxidase A (MAOA) is a mitochondrial enzyme, which degrades monoamine neurotransmitters and dietary amines and produces HO. Recent studies have shown increased MAOA expression in prostate cancer (PCa), glioma, and classical Hodgkin lymphoma. However, the biological function of MAOA in cancer development remains unknown. In this study, we investigated the role of MAOA in the development of prostate adenocarcinoma by creating a prostate-specific Pten/MAOA knockout (KO) mouse model, in which MAOA-floxP mouse was crossed with the conditional Pten KO PCa mouse that develops invasive PCa. In contrast to Pten KO mice, age-matched Pten/MAOA KO mice exhibited a significant decrease in both prostate size and the incidence of invasive cancer. We observed a significant decline in AKT phosphorylation and Ki67 expression in Pten/MAOA KO mice, which reduced epithelial cell growth and proliferation. As cancer stem cells (CSCs) are required for tumor initiation and growth, we investigated e...

Journal of the Chinese Medical Association : JCMA, Jan 9, 2017

Patients suffering from renal or ureteral stones can undergo significant discomfort, even when ti... more Patients suffering from renal or ureteral stones can undergo significant discomfort, even when timely diagnosed and treated. The aim of this study was to assess the risk factors and safety of outpatient Extracorporeal Shock Wave Lithotripsy (ESWL) in the management of patients with renal or ureteral stones. In this study, our cohort consisted of 844 outpatients who underwent outpatient ESWL treated between February 2012 and November 2014 at Taipei Veterans General Hospital. Patients who visited the emergency room (ER) within 48 h after Outpatient ESWL were included in this article. This article analyzes the stone size, stone shape (long to short axis ratio), stone location, previous medical management, urinalysis data, complications and treatment received in the emergency department. Among the 844 initial consecutive patients who underwent outpatient ESWL a total of 1095 times, there were 22 (2%) patients who sought help at our emergency room within 48 h after the outpatient ESWL. O...

Journal of the Chinese Medical Association : JCMA, Jan 18, 2017

Prostate cancer (PCa) is not commonly found in men younger than 50 years of age. However, serum p... more Prostate cancer (PCa) is not commonly found in men younger than 50 years of age. However, serum prostate-specific antigen (PSA) concentration has been examined more frequently at a younger age in Asia partially due to an increased awareness of prostate cancer. The purpose of our study was to investigate the efficacy and complication of PSA-triggered transrectal ultrasonography-guided prostate (TRUSP) biopsies. We retrospectively reviewed TRUSP biopsies in young men with elevated PSA concentration in Taipei Veterans General Hospital. We reviewed the cases of patients younger than 50 years of age with elevated PSA concentration (>4.0 ng/mL), who received 12 cores TRUSP biopsies at TPEVGH from January 2008-December 2013. The age, family history, digital rectal examination (DRE) results, PSA concentration, free/total PSA ratio, total prostate volume, PSA density, lower urinary tract symptoms and complications after the procedure were reviewed. The pathologic findings of TRUSP biopsy ...

$Research paper thumbnail of MAOA-a novel decision maker of apoptosis and autophagy in hormone refractory neuroendocrine prostate cancer cells$

Scientific Reports, 2017

Autophagy and apoptosis are two well-controlled mechanisms regulating cell fate. An understanding... more Autophagy and apoptosis are two well-controlled mechanisms regulating cell fate. An understanding of decision-making between these two pathways is in its infancy. Monoamine oxidase A (MAOA) is a mitochondrial enzyme that is well-known in psychiatric research. Emerging reports showed that overexpression MAOA is associated with prostate cancer (PCa). Here, we show that MAOA is involved in mediating neuroendocrine differentiation of PCa cells, a feature associated with hormone-refractory PCa (HRPC), a lethal type of disease. Following recent reports showing that NED of PCa requires downregulation of repressor element-1 silencing transcription factor (REST) and activation of autophagy; we observe that MAOA is a novel direct target gene of REST. Reactive oxygen species (ROS) produced by overexpressed MAOA plays an essential role in inhibiting apoptosis and activating autophagy in NED PCa cells. MAOA inhibitors significantly reduced NED and autophagy activation of PCa cells. Our results here show MAOA as a new decision-maker for activating autophagy and MAOA inhibitors may be useful as a potential therapy for neuroendocrine tumors.

Cancer cell, Mar 13, 2017

Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the under... more Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

Journal of the Chinese Medical Association : JCMA, Jan 23, 2016

The purpose of this study was to evaluate the prostate cancer yield rate of targeted transrectal ... more The purpose of this study was to evaluate the prostate cancer yield rate of targeted transrectal ultrasound (TRUS)-guided biopsy with cognitive magnetic resonance imaging (MRI) registration without concurrent systematic biopsy in patients with previous negative systematic TRUS-guided biopsy results and persistently elevated prostate-specific antigen (PSA) levels. In this prospective study conducted from August 2013 to January 2015, patients with at least one previous negative systematic TRUS-guided biopsy and persistently high PSA (≥4 ng/mL) levels were referred for multiparametric MRI (mpMRI). Those patients with suspicious findings on mpMRI received a subsequent cognitive MRI-TRUS fusion biopsy. The cancer-detection rate, tumor location, and Gleason score were confirmed, and PSA-related data were compared between cancer-yield and noncancer-yield groups. In total, 48 patients were included in this study. MRI was designated to be four and five in 17 patients. Fifteen patients receiv...

Oncotarget, 2014

Prostate cancer (PCa) with neuroendocrine differentiation (NED) is tightly associated with hormon... more Prostate cancer (PCa) with neuroendocrine differentiation (NED) is tightly associated with hormone refractory PCa (HRPC), an aggressive form of cancer that is nearly impossible to treat. Determining the mechanism of the development of NED may yield novel therapeutic strategies for HRPC. Here, we first demonstrate that repressor element-1 silencing transcription factor (REST), a transcriptional repressor of neuronal genes that has been implicated in androgen-deprivation and IL-6 induced NED, is essential for hypoxia-induced NED of PCa cells. Bioinformatics analysis of transcriptome profiles of REST knockdown during hypoxia treatment demonstrated that REST is a master regulator of hypoxia-induced genes. Gene set enrichment analysis (GSEA) of hypoxia and REST knockdown co-upregulated genes revealed their correlation with HRPC. Consistently, gene ontology (GO) analysis showed that REST reduction potential associated with hypoxia-induced tumorigenesis, NE development, and AMPK pathway activation. Emerging reports have revealed that AMPK activation is a potential mechanism for hypoxia-induced autophagy. In line with this, we demonstrate that REST knockdown alone is capable of activating AMPK and autophagy activation is essential for hypoxia-induced NED of PCa cells. Here, making using of in vitro cell-based assay for NED, we reveal a new role for the transcriptional repressor REST in hypoxia-induced NED and characterized a sequential molecular

European Urology Supplements

Urological Science, 2015

Background Few prognostic factors have been proposed for patients with locally advanced renal cel... more Background Few prognostic factors have been proposed for patients with locally advanced renal cell carcinoma (RCC). This study aimed to investigate the possible predictive factors for disease-free survival (DFS) after curative surgery for RCC stage T3 or higher. Methods Patients with locally advanced RCC who underwent cure-intended partial or radical nephrectomy, with or without tumor thrombectomy, at our institution from April 1 st , 2005 to October 31 st , 2013 were retrospectively reviewed. Those undergoing cytoreductive nephrectomy were excluded. Preoperative data, including surgical and pathologic characteristics, were assessed for correlation with DFS. Chi-squared tests, multivariate Cox regression analysis, and Kaplan-Meier survival curve analyses were performed to determine potential predictive factors. A P-value less than 0.05 was considered statistically significant. Results A total of 159 patients were included for analysis. One hundred and nineteen (74.8%) patients remained disease-free during follow-up. Disease recurrence was found in 40 (25.2%) patients, and pathological T stage, capsule penetration, Fuhrman grade, thrombocytosis, and elevated serum alkaline phosphatase and γ-glutamyl transpeptidase levels were significantly associated with disease recurrence on univariate analysis. On multivariate analysis, capsule penetration (hazard ratio [HR] = 2.25, p = 0.038, 95% confidence interval [CI] = 1.05–4.85) and Fuhrman grade 3 or 4 (HR = 8.06, p = 0.003, 95% CI = 2.59–25.02) showed significant associations with DFS. Conclusions In patients with locally advanced RCC, capsule penetration and Fuhrman grade were associated with worse DFS after curative surgery. Urologists should closely monitor patients with capsule penetration and high Fuhrman grades, and adjuvant systemic treatments, other than targeted agents, should be considered.

BMC urology, Jan 9, 2015

Prostate vaporization and enucleation is a novel treatment option for bladder outlet obstruction ... more Prostate vaporization and enucleation is a novel treatment option for bladder outlet obstruction caused by benign prostate enlargement. This surgical technique, however, has not yet been standardized. We present our findings of using a high-power thulium laser to accomplish vapoenucleation of the prostate (ThuVEP). We prospectively collected and analyzed data from 29 patients who underwent ThuVEP between August 2010 and May 2012. The control group included 30 patients who underwent traditional transurethral resection of the prostate (TURP). Operative variables, patient profiles, preoperative and postoperative urine flow rates, prostate volume (measured using transrectal ultrasonography), and the international prostate symptom score (IPSS) were recorded and analyzed using a two-tailed Student's t-test and analysis of variance. The ages (mean ± SD) of the patients were 76.1 ± 9.4 and 72.6 ± 7.4 years (p = 0.28) in the ThuVEP and TURP groups, respectively. The average urinary flow ...

Journal of the American Chemical Society, Jan 18, 2015

Development of anti-cancer agents with high tumor-targeting specificity and efficacy is critical ... more Development of anti-cancer agents with high tumor-targeting specificity and efficacy is critical for modern multidisciplinary cancer research. Monoamine oxidase A (MAOA), a mitochondria-bound enzyme, degrades monoamine neurotransmitters and dietary monoamines. Recent evidence suggests a correlation between increased MAOA expression and prostate cancer (PCa) progression with poor outcomes for patients. MAOA induces epithelial-mesenchymal transition (EMT) and augments hypoxic effects by producing excess reactive oxygen species. Thus, development of MAOA inhibitors which selectively target tumors becomes an important goal in cancer pharmacology. Here we describe the design, synthesis, and in vitro and in vivo evaluation of NMI, a conjugate that combines a near-infrared dye for tumor targeting with the moiety derived from the MAOA inhibitor clorgyline. NMI inhibits MAOA with low micromolar IC50, suppresses PCa cell proliferation and colony formation, and reduces migration and invasion. ...

Journal of the Chinese Medical Association : JCMA, 2003

Chyluria is caused by rupturing of lymphatic varices into the pyelocaliceal system. Although Chyl... more Chyluria is caused by rupturing of lymphatic varices into the pyelocaliceal system. Although Chyluria is rare in western countries, it is not uncommon in Asia. We would like to present the experience of diagnosis, evaluation and treatment of chyluria in Taipei Veterans General Hospital. From 1973 to 1999, a total of 30 patients with chyluria were reviewed. All had the chief complaint of milky white urine passage. They were investigated by multiple workup modalities including computed tomography, intravenous urography, lymphangiography, and cystoscopy. Fifteen cases received 1% silver nitrate instillation and 4 cases underwent nephrolysis either as primary or salvage treatment. Lymphangiography was performed in 24 of the 30 cases and responsible causes of chyluria were noted in 21. They were followed up for at least 12 months in 9 patients treated by intrarenal pelvic instillation of silver nitrate and 3 by nephrolysis, respectively. Recurrence was found in 1 patient (11.1%) receivin...

Urological Science, 2012

Objective: To evaluate interoperator differences in cancer detection and complication rates using... more Objective: To evaluate interoperator differences in cancer detection and complication rates using transrectal ultrasound (TRUS)-guided prostate biopsies. We also analyzed whether there was a correlation between the experience of the operator and the cancer detection rate. Materials and methods: Medical records of 1879 patients who underwent a TRUS-guided prostate biopsy between 2005 and 2009 were retrospectively reviewed. Among them, 1496 patients who underwent a first biopsy without previous prostate surgery were selected for the analysis. Five urology residents performed 327, 351, 218, 332, and 268 biopsies, respectively. Cancer detection rates were analyzed by comparing the initial 20 and 100 patients with the final 20 and 100 patients. Patients were subdivided into two groups: prostate-specific antigen (PSA) of approximately 4e10 and >10 ng/mL. Prostate cancer (CaP) detection and complication rates were compared among operators. Results: Cancer was detected in 541 patients (36%). The operators performed a median of 403 (range: approximately 277e436) transrectal sono-guided prostate biopsies with CaP detection rates of approximately 33.9e42.2% (p ¼ 0.243). Among different operators, we found no differences in cancer detection rates for the initial 100 or final 100 patients, even when separating patients into PSA > 10 ng/ mL and 4 < PSA < 10 ng/mL groups. But significant individual variations in CaP-positive rates (p ¼ 0.046) were observed in the first 20 biopsies for patients with PSA > 10 ng/mL receiving a TRUS biopsy; however, variable PSA levels in different groups of patients may have been responsible for this finding. There were no differences in complication rates among the different operators for the initial 20 and final 20 biopsies or for the initial 50 and final 50 biopsies. Conclusion: No clinically significant differences in CaP detection existed among operators performing TRUS-guided prostate biopsies. Complication rates did not differ among the operators. A TRUS-guided prostate biopsy is a rapidly learned technique and is a good diagnostic tool for CaP detection.