Gene expression profile of renal cell carcinomas after neoadjuvant treatment with sunitinib: new pathways revealed
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Tipo de produção
article
Data de publicação
2017
Editora
WICHTIG PUBLISHING
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Citação
INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS, v.32, n.2, p.E210-E217, 2017
Resumo
Background: In renal cell carcinoma (RCC) of the clear cell type, inactivity of the VHL gene induces overexpression of HIF1 alpha and its targets, the tyrosine kinase receptors, promoting RCC development and progression. The discovery of tyrosine kinase inhibitors (TKIs) changed the treatment of these tumors. Other molecular pathways involved in the TKI mechanisms of action have not been described in the literature. The aim of our study was to elucidate alternative mechanisms of action of sunitinib in tumor tissue after neoadjuvant treatment of RCC. Methods: The gene expression profile was accessed using microarray (Affymetrix Human Genome U133 Plus 2.0 platform) and frozen RCC tissues collected from 5 patients with locally advanced non-metastatic tumors who underwent nephrectomy after being treated with 2 cycles of neoadjuvant sunitinib. The results were compared with matched controls comprising 6 patients with no neoadjuvant intervention. Results: There was underexpression of the majority of genes after sunitinib treatment. The lower expression levels of IGFBP1, CCL20, CXCL6 and FGB were confirmed by qRT-PCR in all cases. The downregulation of gene expression leads us to search for methylation as a mechanism of action of the TKI. IGFBP1 was shown to be methylated by methylation-sensitive high-resolution melting technique. Conclusions: The ultimate genetic effects of sunitinib may explain its actions as an antitumor drug that apparently suppresses the expression of important genes related to cell survival, adhesion, invasion and immunomodulation. The methylation of gene promoters was shown to be part of the mechanism of action of this class of drugs.
Palavras-chave
Gene expression, Mechanism of action, Methylation, Renal cell carcinoma, Sunitinib, Tyrosine kinase inhibitor
Referências
- Baeriswyl V, 2009, SEMIN CANCER BIOL, V19, P329, DOI 10.1016/j.semcancer.2009.05.003
- BASHKIN P, 1989, BIOCHEMISTRY-US, V28, P1737, DOI 10.1021/bi00430a047
- Beider K, 2009, PLOS ONE, V4, DOI 10.1371/journal.pone.0005125
- Bergers G, 2000, NAT CELL BIOL, V2, P737
- Brown PD, 1999, APMIS, V107, P174
- Carmeliet P, 2003, NAT MED, V9, P653, DOI 10.1038/nm0603-653
- Chapman DW, 2014, EJNMMI RES, V4, DOI 10.1186/s13550-014-0027-5
- Chen J, 2014, HEPATO-GASTROENTEROL, V61, P518, DOI 10.5754/hge12954
- Cheng XS, 2014, CANCER LETT, V348, P77, DOI 10.1016/j.canlet.2014.03.008
- Choueiri TK, 2015, NEW ENGL J MED, V373, P1814, DOI 10.1056/NEJMoa1510016
- Conway EM, 2001, CARDIOVASC RES, V49, P507, DOI 10.1016/S0008-6363(00)00281-9
- Cross MJ, 2003, TRENDS BIOCHEM SCI, V28, P488, DOI 10.1016/S0968-0004(03)00193-2
- Du DS, 2014, INT J MOL SCI, V15, P6441, DOI 10.3390/ijms15046441
- Escudier B, 2007, LANCET, V370, P2103, DOI 10.1016/S0140-6736(07)61904-7
- Faivre S, 2007, NAT REV DRUG DISCOV, V6, P734, DOI 10.1038/nrd2380
- Fedorko M, 2016, INT J BIOL MARKER, V31, pE26, DOI 10.5301/jbm.5000174
- FOLKMAN J, 1987, SCIENCE, V235, P442, DOI 10.1126/science.2432664
- Gijsbers K, 2005, EXP CELL RES, V303, P331, DOI 10.1016/j.yexer.2004.09.027
- Hanahan D, 2000, CELL, V100, P57, DOI 10.1016/S0092-8674(00)81683-9
- Hanahan D, 2011, CELL, V144, P646, DOI 10.1016/j.cell.2011.02.013
- Ibanez de Caceres I, 2006, CANCER RES, V66, P5021, DOI 10.1158/0008-5472.CAN-05-3365
- Ingber D E, 1987, Prog Clin Biol Res, V249, P273
- Jubb AM, 2006, NAT REV CANCER, V6, P626, DOI 10.1038/nrc1946
- Kim J, 2012, EPIGENETICS-US, V7, P191, DOI 10.4161/epi.7.2.18973
- Kim WY, 2004, J CLIN ONCOL, V22, P4991, DOI 10.1200/JCO.2004.05.061
- Kirshberg S, 2011, PLOS ONE, V6, DOI 10.1371/journal.pone.0024856
- LINEHAN WM, 1995, JAMA-J AM MED ASSOC, V273, P564
- McCawley LJ, 2001, CURR BIOL, V11, pR25, DOI 10.1016/S0960-9822(00)00038-5
- Morimoto AM, 2004, ONCOGENE, V23, P1618, DOI 10.1038/sj.onc.1207268
- Motzer RJ, 2007, NEW ENGL J MED, V356, P115, DOI 10.1056/NEJMoa065044
- Motzer RJ, 2013, NEW ENGL J MED, V369, P722, DOI 10.1056/NEJMoa1303989
- O'Farrell AM, 2003, BLOOD, V101, P3597, DOI 10.1182/blood-2002-07-2307
- Oldham KA, 2012, EUR UROL, V61, P385, DOI 10.1016/j.eururo.2011.10.035
- Perez-Gracia JL, 2009, BRIT J CANCER, V101, P1876, DOI 10.1038/sj.bjc.6605409
- Qiao ZK, 2013, WORLD J SURG ONCOL, V11, DOI 10.1186/1477-7819-11-1
- Rice BW, 2001, J BIOMED OPT, V6, P432, DOI 10.1117/1.1413210
- Rini BI, 2008, J CLIN ONCOL, V26, P5422, DOI 10.1200/JCO.2008.16.9847
- Rubie C, 2010, J TRANSL MED, V8, DOI 10.1186/1479-5876-8-45
- Sato A, 2013, INT J ONCOL, V43, P1441, DOI 10.3892/ijo.2013.2073
- Schlessinger J, 2000, CELL, V103, P211, DOI 10.1016/S0092-8674(00)00114-8
- Schueneman AJ, 2003, CANCER RES, V63, P4009
- Schveigert D, 2013, TUMORI, V99, P523, DOI 10.1700/1361.15105
- Seferovic MD, 2009, ENDOCRINOLOGY, V150, P220, DOI 10.1210/en.2008-0657
- Semenza GL, 2009, SEMIN CANCER BIOL, V19, P12, DOI 10.1016/j.semcancer.2008.11.009
- Sternberg CN, 2010, J CLIN ONCOL, V28, P1061, DOI 10.1200/JCO.2009.23.9764
- Tsaur I, 2011, CANCER BIOMARK, V10, P195, DOI 10.3233/CBM-2012-0247
- Verbeke H, 2011, CANCER LETT, V302, P54, DOI 10.1016/j.canlet.2010.12.013
- Wary Kishore K, 2003, Mol Cancer, V2, P25, DOI 10.1186/1476-4598-2-25
- Wojdacz TK, 2009, EPIGENETICS, V4, P231
- Xiao G, 2015, ONCOTARGET, V6, P14165
- Zlotnik A, 2000, IMMUNITY, V12, P121, DOI 10.1016/S1074-7613(00)80165-X
Coleções
Artigos e Materiais de Revistas Científicas - FM/MCG
Artigos e Materiais de Revistas Científicas - HC/ICESP
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/55
Artigos e Materiais de Revistas Científicas - LIM/60
Artigos e Materiais de Revistas Científicas - ODS/03
Artigos e Materiais de Revistas Científicas - HC/ICESP
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/55
Artigos e Materiais de Revistas Científicas - LIM/60
Artigos e Materiais de Revistas Científicas - ODS/03