Producción CyT
Physiological Mini Reviews - MOLECULAR BASIS OF ABC TRANSPORTERS REGULATION BY INSULIN-LIKE GROWTH FACTOR 2 MRNA-BINDING PROTEIN 1 (IGF2BP1) IN HEPATOCELLULAR CARCINOMA (HCC).
Congreso
Autoría:
Bucci-Muñoz, María ; Anselmino, Luciano ; GOLA, ALDANA MAGALÍ ; Livore, Verónica Inés ; Mottino, Aldo Domingo ; Rigalli, Juan Pablo ; Ceballos, María Paula ; Ruiz, María LauraFecha:
2023Editorial y Lugar de Edición:
y the Argentinean Physiological Society and the Latin American Association of Physiological SciencesISSN:
1669-5410Resumen *
Introduction: Previously, we showed that IGF2BP1 knockdown (KD) leads to a decrease in ABCB1 and ABCC3 expression (protein and mRNA). Sorafenib (SFB) treatment induced IGF2BP1, ABCB1 and ABCC3 expression and KD of IGF2BP1 prevented the induction of ABCB1 expression, ABCC3 induction was prevented only at the mRNA level. Objective: To study the molecular mechanism of ABC transporter regulation by IGF2BP1 and its influence on SFB chemotherapy. Methods: KD of IGF2BP1 was done by transfection of a siRNA (IGF2BP1 siRNA), scrambled (C siRNA) was used as control, in HepG2 cells. After 24 h of transfection, cells were treated with the transcription inhibitor Actinomycin D (ActD) 5 ug/ml for 6 h. Also, HepG2 cells were pre-treated with ActD 5 ug/ml for 30 min and incubated with SFB 2µM for 48 h. Control cells received DMSO. IGF2BP1, ABCB1 and ABCC3 mRNA levels were measured by Real Time PCR. Data were presented as mean±SEM, N=3-6, p<0.05: * vs. C, # vs CsiRNA, π vs CsiRNA+ActD and ∞ vs SFB+ActD. Statistical analysis was performed using One-Way ANOVA followed by Tukey test. We investigate the impact of combined expression variations of IGF2BP1, ABCC3, and ABCB1 on the survival probability of a cohort of patients with HCC, we accessed gene-level RNA-seq read counts from The Cancer Genome Atlas Liver HCC dataset (N=368). Results: mRNA levels of ABCB1 and ABCC3 decreased after KD of IGF2BP1 (55±3%#; 55±6%#, respectively) and in presence of ActD mRNA levels of transporters still down regulated respect to CsiRNA+ActD (ABCB1:62±4%π; ABCC3:29±2%π). SFB increased mRNA levels of IGF2BP1, ABCB1 and ABCC3 (160±3*%, 210±4%*,132±8%*; respectively) and ActD was not able to prevent it (100±3%∞,100±2%∞,76±4%∞; respectively). Bioinformatic studies showed that patients with the lowest probability of survival are those with high expression of all three genes and those with high expression of IGF2BP1 and ABCB1, but low expression of ABCC3. Conclusion: ABCC3 and ABCB1 are modulated by IGF2BP1 in a post-transcriptional manner under both constitutive expression and under induction by SFB. Overexpression of IGF2BP1 and ABC transporters is associated with a poor prognosis of survival in HCC. Información suministrada por el agente en SIGEVAPalabras Clave
IGF2BP1HCCMrp3Pgp