Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide  

作　　者：María Belén Novoa Díaz Pedro Carriere Graciela Gigola Ariel Osvaldo Zwenger Natalia Calvo Claudia Gentili 

机构地区：[1]Departamento de Biología,Bioquímica y Farmacia,Universidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS),Bahía Blanca 8000,Buenos Aires,Argentina [2]Centro de Estudios Clínicos SAGA,CEC SAGA,Santiago de Chile 8320000,Chile

出　　处：《World Journal of Gastroenterology》2022年第26期3177-3200,共24页世界胃肠病学杂志（英文版）

基　　金：Supported by the Agencia Nacional de Promoción Científica y Tecnológica;No. PICT-2013-1441;Consejo Nacional de Investigaciones Científicas y Técnicas;No. PIP11220150100350;Instituto Nacional del Cáncer Asistencia Financiera Ⅱ;RESOL 493/14, No. 2002-4395-14-1;Instituto Nacional del Cáncer Asistencia Financiera Ⅲ-2016-2017, RESOL-2016-1006-E-APN-MS;No. 2002-3862-16-1 CANCER;Universidad Nacional del Sur;No. PGI:24/B230 and No. PGI:24/B303;Fundación Alberto J. Roemmers of Argentina

摘　　要：BACKGROUND Parathyroid hormone-related peptide(PTHrP)plays a key role in the development and progression of many tumors.We found that in colorectal cancer(CRC)HCT116 cells,the binding of PTHrP to its receptor PTHR type 1(PTHR1)activates events associated with an aggressive phenotype.In HCT116 cell xenografts,PTHrP modulates the expression of molecular markers linked to tumor progression.Empirical evidence suggests that the Met receptor is involved in the development and evolution of CRC.Based on these data,we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC cells.AIM To elucidate the relationship among PTHR1,PTHrP,and Met in CRC models.METHODS For in vitro assays,HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP(1-34)(10-8 M).Where indicated,cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide,the vehicle of the inhibitors.The protein levels were evaluated by Western blot technique.Real-time polymerase chain reaction(RT-qPCR)was carried out to determine the changes in gene expression.Wound healing assay and morpho logical monitoring were performed to evaluate cell migration and changes related to the epithelialmesenchymal transition(EMT),respectively.The number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan(CPT-11),oxaliplatin(OXA),or doxorubicin(DOXO)with or without PTHrP.For in vivo tests,HCT116 cell xenografts on 6-wk-old male N:NIH(S)_nu mice received daily intratumoral injections of PTHrP(40μg/kg)in 100μL phosphate-buffered saline(PBS)or the vehicle(PBS)as a control during 20 d.Humanitarian slaughter was carried out and the tumors were removed,weighed,and fixed in a 4%formaldehyde solution for subsequent treatment by immunoassays.To evaluate the expression of molecular markers in human tumor samples,we studied 23 specimens obtained from CRC patients which were treated at

关 键 词：PTHRP MET receptor tyrosine kinase Parathyroid hormone receptor type 1 Colorectal cancer Drug resistance 

分 类 号：R735.34[医药卫生—肿瘤]