<p>The Hedgehog signal transducer <em>Smoothened</em> and microRNA-326: pathogenesis and regulation of drug resistance in pediatric B-cell acute lymphoblastic leukemia</p>

Abstract

Purpose Multidrug resistance (MDR) and the subsequent disease relapse are the major causes of childhood acute lymphoblastic leukemia (ALL) related death. The Hedgehog (Hh) signaling pathway can contribute to cancer MDR. In the current study, Smoothened ( Smo ) was selected as the experimental target due to its importance in the Hh pathway in order to evaluate its probable role in pediatric B-ALL drug resistance. Patients and methods The study included 27 pediatric B-ALL and 16 control bone marrow samples. Quantitative RT-PCR was used to investigate the expression levels of Smo and miR-326 as the key players of the Hh pathway. Western blot analysis was performed. The presence of minimal residual disease was studied using PCR-SSCP. The association between Smo expression and drug resistance was analyzed statistically. Results Results showed a significant increase in the Smo expression levels in drug-resistant patients in comparison with drug-sensitive children with B-ALL ( P =0.0128, AUC=0.82). A considerable negative association between miR-326 and Smo expression levels was identified ( r =−0.624, P =0.002). A binomial test confirmed the regulatory role of miR-326 on the translational repression of Smo ( P =0.031). Statistics showed no association between Smo and ABCA2 expression levels. However, a significant positive correlation was observed between the Smo and ABCA3 transcripts in the resistant ALL children ( r =0.607, P =0.016). Conclusion Data revealed the possible oncogenic impact of Smo on leukemogenesis and drug resistance in pediatric B-ALL. Upregulation of Smo was introduced, for the first time, as a prognostic factor for drug resistance in childhood B-ALL. To the best of our knowledge, this is the first study that shows a positive correlation between Smo and ABCA3 expression levels in pediatric B-ALL, explaining a possible mechanism for the development of drug resistance in this cancer. Moreover, the current project revealed a negative modulatory effect of miR-326 on the expression levels of Smo .

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…Furthermore, our group has recently identified that overexpression of Smo at the protein level following the downregulation of miR-326 is related to MDR in pediatric B-ALL. Our results revealed a positive correlation between Smo and ABCA3 transcripts in these children (133).…”

MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools

“…[i] Sample issues: Sixteen publications in this systematic review had considerably small sample sizes (30 or less; 26%) [ 36 , 40 , 41 , 46 , 48 , 49 , 58 , 64 , 68 , 69 , 77 , 78 , 80 , 82 , 84 , 86 ]. Larger sample sizes are required to achieve sufficient statistical power and allow for solid conclusions to be drawn.…”

“…In terms of prognosis and drug sensitivity, study of matched samples before and after therapy is strongly encouraged. Newly diagnosed children with ALL, as well as relapsed and remitted cases, were detected together in five case–control studies included in the present review [ 32 , 41 , 43 , 46 , 54 ].…”

The role of miRNAs as a big master regulator of signaling pathways involved in lymphoblastic leukemia

“…intermediate (Farahani et al, 2015). Further, a recent study showed that miR-326 could target the SMO oncogene and suppress the HH signal pathway in the MDR of B-ALL children (Sheybani et al, 2019).…”