title: Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis.
abstract: The conversion of precancerous lesions to full-fledged cancers requires the affected cells to surpass certain rate-limiting steps. We recently showed that activation of HRAS proto-oncogene in urothelial cells of transgenic mice causes simple urothelial hyperplasia (SUH) which is persistent and whose transition to low-grade papillary urothelial carcinoma (UC) must undergo nodular urothelial hyperplasia (NUH). We hypothesized that NUH, which has acquired fibrovascular cores, plays critical roles in mesenchymal-to-epithelial signaling, breaching the barriers of urothelial tumor initiation. Using proteomics involving two-dimensional gel electrophoresis, immunoblotting with pan-phosphotyrosine antibody and MALDI-mass spectrometry, we identified isoform 2 of pyruvate kinase (PKM2) as the major tyrosine-phosphorylated protein switched on during NUH. We extended this finding using specimens from transgenic mice, human UC and UC cell lines, establishing that PKM2, but not its spliced variant PKM1, was over-expressed in low-grade and, more prominently, high-grade UC. In muscle-invasive UC, PKM2 was co-localized with cytokeratins 5 and 14, UC progenitor markers. Specific inhibition of PKM2 by siRNA or shRNA suppressed UC cell proliferation via increased apoptosis, autophagy and unfolded protein response. These results strongly suggest that PKM2 plays an important role in the genesis of low-grade non-invasive and high-grade invasive urothelial carcinomas.
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Haiping
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Mo
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Fenglin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kuo-How
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY 10016, USA.|Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.|Veterans Affairs New York Harbor Healthcare System Manhattan Campus, New York, NY 10010, USA.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D060170:Uroplakin II / Q000502:physiology*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D013963:Thyroid Hormones; D060170:Uroplakin II; D000097810:Thyroid Hormone-Binding Proteins; C000715470:MAS1 protein, human; C554659:Upk2 protein, mouse
keywords: PKM2; bladder cancer; precancerous; tumorigenesis; urothelium