Clear cell renal cell carcinoma (ccRCC) is characterized by stabilization of hypoxia-inducible factor (HIF1), and mutations in von Hippel-Lindau (VHL) gene. Additionally, in about 40% of ccRCC cases the mutation in PBRM1 (POLYBROMO1) gene coding for a non-core subunit of SWI/SNF chromatin remodeling complex was found suggesting potential impairment of this complex function in ccRCC. In this study we assessed the extent to which the core SWI/SNF complex subunit - INI1 (hSNF5/SMARCB1) is affected in ccRCC and whether it has any consequences on the development of this type of cancer. The evaluation of INI1 protein level in samples from 50 patients with diagnosed ccRCC, including three displaying rhabdoid features, showed the INI1 positive staining in rhabdoid cells while the conventional ccRCC cells exhibited reduced INI1 level. This indicated the rhabdoid component of ccRCC as distinct from other known rhabdoid tumors. The reduced INI1 protein level observed in all conventional ccRCC cases used in this study correlated with decreased SMARCB1 gene expression at the transcript level. Consistently, the overexpression of INI1 protein in A498 ccRCC cell line resulted in the elevation of endogenous SMARCB1 transcript level indicating that the INI1-dependent regulatory feedback loop controlling expression of this gene is affected in ccRCC Moreover, the set of INI1 target genes including i.e. CXCL12/CXCR7/CXCR4 chemokine axis was identified to be affected in ccRCC. In summary, we demonstrated that the inactivation of INI1 may be of high importance for ccRCC development and aggressiveness.
American journal of cancer research. 2017 Nov 01*** epublish ***
Elzbieta Sarnowska, Michal Szymanski, Nataliia Rusetska, Marcin Ligaj, Iga Jancewicz, Pawel Cwiek, Marta Skrodzka, Marcin Leszczynski, Joanna Szarkowska, Alicja Chrzan, Malgorzata Stachowiak, Jaroslaw Steciuk, Anna Maassen, Lech Galek, Tomasz Demkow, Janusz A Siedlecki, Tomasz J Sarnowski
Department of Molecular and Translational Oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsaw, Poland., Department of Uro-oncology, M. Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsaw, Poland., Department of Pathology, M. Sklodowska-Curie Memorial Cancer Center and Institute of OncologyWarsaw, Poland., Institute of Biochemistry and Biophysics Polish Academy of SciencesWarsaw, Poland., Department of Urology, Hospital of Ministry of InteriorBialystok, Poland.