Estudio de expresión y prevalencia del transportador MRP4/ABCC4 en cáncer de vesícula biliar y vías biliares en pacientes del noroeste argentino

Carolina Ituarte; Gerardo Arroyo; Cristina Inklemona; Carlos Nuñez; Estela Barros; Rodrigo Maroni; Marcelo Montero Alvi; María Virginia Bürgesser; Oscar Marin; Carlos Davio; Ana Sahores; María May

doi:10.56969/oc.v24i2.38

Autores/as

Carolina Ituarte Hospital Pablo Soria, Jujuy. Intergrupo Latinoamericano de Oncología Gastrointestinal
Gerardo Arroyo Sanatorio El Carmen, Salta, Intergrupo Latinoamericano de Oncología Gastrointestinal
Cristina Inklemona Hospital Pablo Soria, Jujuy, Intergrupo Latinoamericano de Oncología Gastrointestinal
Carlos Nuñez Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires
Estela Barros Hospital Papa Francisco, Salta
Rodrigo Maroni Hospital Papa Francisco, Salta https://orcid.org/0000-0002-7653-9956
Marcelo Montero Alvi Laboratorio de Patología y Citodiagnóstico Oncológico, Salta
María Virginia Bürgesser Centro de Anatomía Patológica, Jujuy
Oscar Marin Hospital Pablo Soria, Jujuy
Carlos Davio Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires https://orcid.org/0000-0002-4650-3784
Ana Sahores Instituto de Investigaciones Farmacológicas https://orcid.org/0000-0001-5439-2677
María May Instituto de Investigaciones Farmacológicas, Universidad de Buenos Aires https://orcid.org/0000-0002-4069-5826

DOI:

https://doi.org/10.56969/oc.v24i2.38

Palabras clave:

MRP4/ABCC4, neoplasias del tracto biliar, inmunohistoquímica, biliary tract neoplasms, immunohistochemistry

Resumen

MRP4/ABCC4 constituye un potencial biomarcador tumoral. No existen estudios acerca de su expresión en cáncer biliar, una neoplasia de alta morbi-mortallidad en el noroeste argentino. Se evalúa la expresión de MRP4 en cáncer biliar y su correlación clínica.

Este es un estudio retrospectivo en 21 muestras de cáncer biliar. La expresión de MRP4 se midió por inmunohistoquímica, considerando el porcentaje de células marcadas en membrana (0-100%) y su intensidad (1-3); el score se obtuvo multiplicando ambos parámetros (0-300). Para simplificar el análisis se consideró baja expresión a los valores comprendidos entre 0 y 100, y alta expresión a valores entre 101 y 300.

Sobre 17 muestras evaluables, 12 presentaron alta expresión (70.6%) y 5 baja expresión (29.4%) para MRP4. La alta expresión se asoció con: 1) una tendencia a menor supervivencia (p=0.1), 2) un 100% de tumores en estadios avanzados, 3) pobre diferenciación histológica, alto grado nuclear y alto índice proliferativo (Ki67).

El cáncer biliar presenta una alta tasa de expresión de MRP4. Se observó una asociación no significativa entre la alta expresión de dicho marcador y menor supervivencia. Estos resultados son coincidentes con ensayos preclínicos en otros tumores donde la sobreexpresión del biomarcador incrementa indicadores de malignidad. Los resultados son alentadores para ampliar el estudio, a fin de establecer el valor pronóstico y/o predictivo de MRP4 en cáncer biliar

Citas

Karim M. Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol 1994; 6: 415-24. DOI: https://doi.org/10.1016/0955-0674(94)90035-3

Taskén K, Aandahl EM. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev 2004; 84:137-67. DOI: https://doi.org/10.1152/physrev.00021.2003

Shayo C, Legnazzi B, Monczor F, et al. The time-course of cyclic AMP signaling is critical for leukemia U-937 cell differentiation. Biochem Biophys Res Commun 2004; 314: 798-804. DOI: https://doi.org/10.1016/j.bbrc.2003.12.166

Schmitt JM, Stork PJ. Cyclic AMP-mediated inhibition of cell growth requires the small G protein Rap1. Mol Cell Biol 2001; 21: 3671-83. DOI: https://doi.org/10.1128/MCB.21.11.3671-3683.2001

Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrugs resistance-associated proteins. J Natl Cancer Inst 2000; 92: 1295-302. DOI: https://doi.org/10.1093/jnci/92.16.1295

Leonard GD, Fojo T, Bates SE. The role of ABC transporter in clinical practice. Oncologist 2003; 8: 411-24. DOI: https://doi.org/10.1634/theoncologist.8-5-411

Sassi Y, Hara Y, Lompré AM, Hulot JS. Multi-drug resistance protein 4 (MRP4/ABCC4) and cyclic nucleotides signaling pathways. Cell Cycle 2009; 8: 962-3. DOI: https://doi.org/10.4161/cc.8.7.8094

Yaneff A, Sahores A, Gómez N, Carozzo A, Shayo C, Davio C1. MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design. Curr Med Chem 2019; 26: 1270-307. DOI: https://doi.org/10.2174/0929867325666171229133259

Russel FG, Koenderink JB, Masereeuw R. Multidrug resistence protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signaling molecules. Trends Pharmacol Sci 2008; 29: 200-7. DOI: https://doi.org/10.1016/j.tips.2008.01.006

Gatti L, Beretta G, Cossa F, Zunino F, Perego P. ABC transporters as potential targets for modulation of drug resistance. Mini Rev Med Chem 2009; 9: 1102-12. DOI: https://doi.org/10.2174/138955709788922656

Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporter in cancer: more than just drug efflux pumps. Nat Rev Cancer 2010; 10: 147-56. DOI: https://doi.org/10.1038/nrc2789

Copsel S, García C, Diez F, et al. Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J Biol Chem 2011; 286: 6979-88. DOI: https://doi.org/10.1074/jbc.M110.166868

Copsel S, Bruzzone A, May M, et al. Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia. Oncotarget 2014; 5: 9308-21. DOI: https://doi.org/10.18632/oncotarget.2425

Sun Y, Shi N, Lu H, et al. ABCC4 copy number variation is associated with susceptibility to esophageal squamous cell carcinoma. Carcinogenesis 2014; 35: 1941-50. DOI: https://doi.org/10.1093/carcin/bgu043

Zhang YH, Wu Q, Xiao XY, Li DW, Wang XP. Silencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell. Cancer Lett 2010; 291: 76-82. DOI: https://doi.org/10.1016/j.canlet.2009.10.003

Yu ZQ, Zhang C, Wang H, et al. Downregulation of ATP- binding cassette subfamily C member 4 increases sensitivity to neoadjuvant radiotherapy for locally advanced rectal carcinoma. Dis Colon Rectum 2013; 56: 600-8. DOI: https://doi.org/10.1097/DCR.0b013e31827c2b80

Zhao X, Guo Y, Yue W, Zhang L, Gu M, Wang Y. ABCC4 is required for cell proliferation and tumorigenesis in non-small cell lung cancer. Onco Targets Ther 2014; 7: 343-51. DOI: https://doi.org/10.2147/OTT.S56029

Bagnoli M, Beretta G, Gatti L, et al. Clinicopathological impact of ABCC1/MRP1 and ABCC4/MRP4 in epithelial ovarian carcinoma. Biomed Res Int 2013; 2013: 143202. DOI: https://doi.org/10.1155/2013/143202

Ho LL, Kench JG, Handelsman DJ, et al. Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer. Prostate 2008; 68: 1421-9. DOI: https://doi.org/10.1002/pros.20809

NorrisMD,SmithJ,TanabeK,etal.Expressionofmultidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. DOI: https://doi.org/10.1158/1535-7163.MCT-04-0161

Mol Cancer Ther 2005; 4: 547-53.

Huynh T, Norris MD, Haber M, Henderson MJ. ABCC4/ MRP4: a MYCN-regulated transporter and potential therapeutic target in neuroblastoma. Front Oncol 2012; 2: 178. DOI: https://doi.org/10.3389/fonc.2012.00178

Zhang Z, Wang J, Shen B, Peng C, Zheng M. The ABCC4 gene is a promising target for pancreatic cancer therapy. Gene 2012; 491: 194-9. DOI: https://doi.org/10.1016/j.gene.2011.09.029

Ferlay J, Ervik M, Lam F, et al (2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. En: https://gco.iarc.fr/today; consultado 6/5/2019.

Arroyo GF, Gentile A, Parada LA. Gallbladder cancer: South American experience. Chin Clin Oncol 2016; 5: 67. DOI: https://doi.org/10.21037/cco.2016.10.01

Macías G, Limardo L, Abriata M. Atlas de mortalidad por cáncer en Argentina 2011-2015, 1a ed, 2017. Buenos Aires: Instituto Nacional del Cáncer.

Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273-81. DOI: https://doi.org/10.1056/NEJMoa0908721

Uribe M, Heinet C, Brito F, Bravo D. Actualización en cáncer de vesícula biliar. Rev Med Clin Condes 2013; 24: 638-43. DOI: https://doi.org/10.1016/S0716-8640(13)70202-5