MED19 encodes two unique protein isoforms that confer prostate cancer growth under low androgen through distinct gene expression programs
MED19, a component of the mediator complex and a co-regulator of the androgen receptor (AR), is pivotal in prostate cancer cell proliferation. MED19 has two isoforms: a full-length "canonical" and a shorter "alternative" variant. Specific antibodies were developed to investigate these isoforms. Both exhibit similar expression in normal prostate development and adult prostate tissue, but the canonical isoform is elevated in prostate adenocarcinomas. Overexpression of canonical MED19 in LNCaP cells promotes growth under conditions of androgen deprivation in vitro and in vivo, mirroring earlier findings with alternative MED19-overexpressing LNCaP cells. Interestingly, alternative MED19 cells displayed strong colony formation in clonogenic assays under conditions of androgen deprivation, while canonical MED19 cells did not, suggesting distinct functional roles. These isoforms also modulated gene expression differently. Canonical MED19 triggered genes related to extracellular matrix remodeling while suppressing those involved in androgen-inactivating glucuronidation. In contrast, alternative MED19 elevated genes tied to cell movement and reduced those associated with cell adhesion and differentiation. The ratio of MED19 isoform expression in prostate cancers shifts with the disease stage. Early-stage cancers exhibit higher canonical MED19 expression than alternative MED19, consistent with canonical MED19's ability to promote cell proliferation under androgen deprivation. Conversely, alternative MED19 levels were higher in later-stage metastatic prostate cancer than in canonical MED19, reflecting alternative MED19's capability to enhance cell migration and autonomous cell growth. Our findings suggest that MED19 isoforms play unique roles in prostate cancer progression and highlights MED19 as a potential therapeutic target for both early and late-stage prostate cancer.
PKM2 is essential for bladder cancer growth and maintenance
Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1Î±- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade non-muscle invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1Î±/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target.
Management of the Poorly Functioning Moiety of a Duplex System: A Surgical Intervention Shift From Kidney to Distal Ureters: NYU Case of the Month, January 2019 [Case Report]
Uroplakins play conserved roles in egg fertilization and acquired additional urothelial functions during mammalian divergence
Uroplakin (UP) tetraspanins and their associated proteins are major mammalian urothelial differentiation products that form unique 2D-crystals of 16-nm particles ("urothelial plaques") covering the apical urothelial surface. Although uroplakins are highly expressed only in mouse urothelium and are often referred to as being urothelium-specific, they are also expressed in several nonurothelial cell types in stomach, kidney, prostate, epididymis, testis/sperms and ovary/oocytes. In oocytes, uroplakins co-localize with CD9 on cell surface and multivesicular body-derived exosomes, and the cytoplasmic tail of UPIIIa undergoes a conserved fertilization-dependent, Fyn-mediated tyrosine-phosphorylation that also occurs in Xenopus laevis eggs. Uroplakin knockout and antibody blocking reduce mouse eggs' fertilization rate in in vitro fertilization assays, and UPII/IIIa double-knockout mice have a smaller litter size. Phylogenetic analyses showed that uroplakin sequences underwent significant mammal-specific changes. These results suggest that, by mediating signal transduction and modulating membrane stability that do not require 2D-crystal formation, uroplakins can perform conserved and more ancestral fertilization functions in mouse and frog eggs. Uroplakins acquired the ability to form 2D- crystalline plaques during mammalian divergence enabling them to perform additional functions, including umbrella cell enlargement and the formation of permeability and mechanical barriers, in order to protect/modify the apical surface of the modern-day mammalian urothelium.
Response to commentaries on The American Academy of Pediatrics Workforce Survey for the Section on Urology 2015 [Letter]
The American Academy of Pediatrics Workforce Survey for the Section on Urology 2015
INTRODUCTION: In 2013, the American Academy of Pediatrics (AAP) Division of Workforce and Medical Education Policy assumed the task of organizing the updated AAP Workforce Survey, which was modeled after the Future of Pediatric Education II study. OBJECTIVE: The objective of the present study was to evaluate changes in practice patterns of all pediatric medical and surgical specialists over time, to facilitate advocacy work by the Academy at federal and state levels. STUDY DESIGN: The survey was sent to members of the AAP Section on Urology and the Society for Pediatric Urology between June and November 2014. The survey included general and sub-specialty-specific questions. Data analysis was performed using SPSS 18.0. Descriptive statistics, including frequency distributions and measures of central tendency, were used to summarize all responses. RESULTS: A total of 255 pediatric urologists returned the survey, giving a response rate of 56.4%. The specialty remained vibrant, and members remained content in their career choice. About two-thirds practiced in a full-time clinical setting, and had research, teaching, and/or administrative duties. About 75% reported no change in clinical volume or case complexity, although 50% reported an increase in their referral base. A 50% increase in minor cases and a 43.3% decrease in open cases were reported. Only 13% planned to retire within the next 3-6 years. The current job market for fellows was unrestricted for 51.3%, significantly restricted for location for 23.1%, and restricted with regard to practice type for 25.6%. Overall, 51%, 37%, and 13% of the respondents expressed the opinions that over the next 5 years, too many specialists in pediatric urology were currently being trained, just the right number, and too few, respectively. Medical student interest remained encouraging. DISCUSSION: One of the primary objectives of the survey was to gain insights into whether there was concordance between the number of trainees and the current and future job opportunities. Unfortunately, the main limitations of the survey were the questions on retirement and adding a partner. Since the survey was anonymous, there was a missed opportunity to direct fellows to specific job openings. In addition, every member of a large group may have individually responded, inflating the responses or, in some cases, negating the responses if the partners did not agree. CONCLUSION: Pediatric urologists have an overall sense of contentment of career choice, despite shifts in complex open surgical volume and increasing competition. Surveys that are not anonymous would provide specific geographical manpower needs.
Antenatal hydronephrosis: Here today, gone tomorrow-one way or another: NYU Case of the Month, May 2017
Best of the 2016 Society for Pediatric Urology Fall Congress: Highlights From the 2016 Society for Pediatric Urology Fall Congress, September 9-11, 2016, Dallas, TX
Best of the 2017 AUA Annual Meeting: Highlights From the 2017 American Urological Association Annual Meeting, May 12-16, 2017, Boston, MA
Best of the 2014 Pediatric Urology Fall Congress: Highlights From the 2014 Pediatric Urology Fall Congress, October 24-26, 2014, Miami, FL