Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is asso...Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is associated with platinum-based chemotherapy resistance.High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients.Mechanistically,TBCE silencing significantly affects cytoskeleton rearrangement,which in turn increases cisplatin-induced cycle arrest and apoptosis.To develop these findings into potential therapeutic drugs,endosomal pH-responsive nanoparticles(NPs)were developed to simultaneously encapsulate TBCE siRNA and cisplatin(DDP)to reverse this phenomena.NPs(siTBCE+DDP)concurrently silenced TBCE expression,increased cell sensitivity to platinum treatment,and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft(PDX)models.Taken together,NP-mediated delivery and the co-treatment of siTBCE+DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.展开更多
基金supported by grants from the National Natural Science Foundation of China (81874226 and 81803020)the “Three Million for Three Years” Project of the High-Level Talent Special Funding Scheme of Sun Yat-sen Memorial Hospitalthe Guangdong Natural Science Foundation (2016A030313834and 2017A030313871,China)
文摘Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is associated with platinum-based chemotherapy resistance.High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients.Mechanistically,TBCE silencing significantly affects cytoskeleton rearrangement,which in turn increases cisplatin-induced cycle arrest and apoptosis.To develop these findings into potential therapeutic drugs,endosomal pH-responsive nanoparticles(NPs)were developed to simultaneously encapsulate TBCE siRNA and cisplatin(DDP)to reverse this phenomena.NPs(siTBCE+DDP)concurrently silenced TBCE expression,increased cell sensitivity to platinum treatment,and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft(PDX)models.Taken together,NP-mediated delivery and the co-treatment of siTBCE+DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.
