MiR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST

Background: mirnas are involved in osteosarcoma (os) chemoresistance,and twist reportedly enhances cisplatin-induced os cell apoptosis by inhibiting multiple signaling pathways. in this study,we profiled mirnas differentially expressed in chemoresistant os,with a focus to identify mirnas that regulate twist expression and os chemoresistance. methods. os patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (chemoresistant),and those who showed ≥90% tumor necrosis were defined as good responders (control). mirna microarray analysis was carried out with a discovery cohort (n = 12) of age-,sex- and tumor stage-matched chemoresistant and control os patients. results: among the up-regulated mirnas in chemoresistant os samples,mir-33a was verified to down-regulate twist expression,which was supported by an inverse mirna-33a/twist expression trend in the validation cohort (n = 70),target-sequence-specific inhibition of twist-3′ untranslated region-luciferase reporter activity by mir-33a,and alteration of twist expression by overexpression or inhibition of mir-33a in human os cell lines. in saos-2 cells treated with cisplatin,inhibition of mir-33a by antagomir-33a markedly increased cell apoptosis,which was enhanced by overexpression of twist. the apoptosis-inducing effect of twist overexpression was reversed by overexpression of mir-33a. in mg-63 cells,overexpression of mir-33a significantly decreased cisplatin-induced cell apoptosis,which was enhanced by knockdown of twist. antagomir-33a significantly increased cisplatin-induced cell apoptosis,which was reversed by knockdown of twist. conclusions: we have demonstrated in this study that mir-33a is up-regulated in chemoresistant os and that the mir-33a level is negatively correlated with the twist protein level in os. our in vitro data indicate that mir-33a promotes os cell resistance to cisplatin by down-regulating twist; on the other hand,inhibition of mir-33a by antagomir-33a enhances cisplatin-induced apoptosis in os cells by up-regulating twist expression. the findings suggest that inhibition of mir-33a/twist signaling could be a potential new strategy to enhance neoadjuvant chemotherapy for os. © 2014 zhou et al.; licensee biomed central ltd.