Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas.
Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas.
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DOI：
10.1038/srep28953
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发表时间：
2016-06-30
影响因子：
4.6
通讯作者：
Fujiwara T
中科院分区：
文献类型：
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作者：
Osaki S;Tazawa H;Hasei J;Yamakawa Y;Omori T;Sugiu K;Komatsubara T;Fujiwara T;Sasaki T;Kunisada T;Yoshida A;Urata Y;Kagawa S;Ozaki T;Fujiwara T
骨肉瘤是一种罕见的恶性骨肿瘤。它通常对化疗难治，这导致其预后不良。骨肉瘤耐药性的逆转是改善骨肉瘤患者预后的主要临床挑战。我们开发了一种肿瘤特异性的可复制溶瘤腺病毒OBP-301（端粒溶素），并使用人骨肉瘤细胞系和异种移植肿瘤模型评估了其与化疗药物（顺铂和阿霉素）的协同作用。从诱导细胞凋亡的角度探讨OBP-301化疗增敏作用的分子机制。OBP-301抑制抗凋亡骨髓细胞白血病1（MCL 1）表达，这反过来又导致人骨肉瘤细胞的化疗增敏。siRNA介导的MCL 1表达的敲低使人骨肉瘤细胞对常见的化疗药物敏感。我们还发现，通过病毒诱导的转录因子E2 F-1激活靶向MCL 1的microRNA-29的上调对于增强骨肉瘤细胞中化疗诱导的凋亡至关重要。端粒酶特异性溶瘤腺病毒协同化疗药物抑制人骨肉瘤细胞活力。在骨肉瘤异种移植肿瘤模型中，与单药治疗相比，联合治疗还显著抑制肿瘤生长。我们的数据表明，复制型病毒介导的肿瘤特异性MCL 1消融可能是一种有前途的策略，以减轻骨肉瘤患者的化疗耐药性。
Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.