Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis
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Haiping Zhou1,*, Xing Wang1,*, Lan Mo1,*, Yan Liu1, Feng He1, Fenglin Zhang1, Kuo-How Huang1, Xue-Ru Wu1,2,3
1Department of Urology, New York University School of Medicine, New York, NY 10016, USA
2Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
3Veterans Affairs New York Harbor Healthcare System Manhattan Campus, New York, NY 10010, USA
*These authors have contributed equally to this work
Xue-Ru Wu, e-mail: firstname.lastname@example.org
Keywords: bladder cancer, tumorigenesis, precancerous, PKM2, urothelium
Received: September 15, 2015 Accepted: March 02, 2016 Published: March 16, 2016
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.
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