High mobility group box 1-mediated autophagy promotes neuroblastoma cell chemoresistance
High mobility group box 1-mediated autophagy promotes neuroblastoma cell chemoresistance
复制标题
DOI：
10.3892/or.2015.4278
复制
发表时间：
2015-12-01
期刊：
影响因子：
4.2
通讯作者：
Qian, Jihong
中科院分区：
文献类型：
--
作者：
Wang, Li;Zhang, Huiping;Qian, Jihong
神经母细胞瘤是儿童最常见的肿瘤之一。不幸的是，生存结果仍然不令人满意，因为NB通常发展为多药耐药。近年来的研究表明，高迁移率族蛋白1（HMGB 1）介导的自噬促进了骨肉瘤、肺腺癌和卵巢癌的化疗耐药性，但其在NB中的确切分子机制尚不清楚。在本研究中，我们研究了HMGB 1在NB对抗癌药物产生耐药性中的作用。抗癌药物，包括阿霉素，顺铂和依托泊苷各自诱导HMGB 1上调，促进细胞溶质HMGB 1易位和人NB细胞自噬活性的升高。RNA干扰介导的HMGB 1敲低恢复NB细胞的化疗敏感性。HMGB 1可促进NB细胞的增殖和侵袭能力。HMGB 1通过诱导Beclin-l介导的自噬（一种已知赋予耐药性的细胞内自卫机制）来增强耐药性。此外，我们发现HMGB 1促进自噬进展并减少阿霉素诱导的氧化应激。因此，通过其作为自噬调节剂的作用，HMGB 1是化疗耐药性和肿瘤发生的关键因素，它可能是提高NB治疗效果的新靶点。
Neuroblastoma (NB) is one of the most common tumors in childhood. Unfortunately, the survival outcomes remain unsatisfactory since NB commonly develops multidrug resistance. Recent studies have demonstrated that the high mobility group box 1 (HMGB1)-mediated autophagy promotes chemoresistance in osteosarcoma, lung adenocarcinoma and ovarian cancer, but the exact molecular mechanism underlying HMGB1-mediated autophagy in NB has not been clearly defined. In the present study, we investigated the role of HMGB1 in the development of resistance to anticancer agents in NB. Anticancer agents including doxorubicin, cisplatin and etoposide each induced HMGB1 upregulation, promoted cytosolic HMGB1 translocation and the elevation of autophagic activity in human NB cells. RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of NB cells. Furthermore, mechanistic investigation revealed that HMGB1 promoted the proliferative activity and invasive potential of NB cells. HMGB1 enhanced drug resistance by inducing Beclin-l-mediated autophagy, an intracellular self-defense mechanism known to confer drug resistance. In addition, we found that HMGB1 facilitated autophagic progression and reduced oxidative stress induced by doxorubicin. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance and tumorigenesis, and it may be a novel target for improving the efficacy of NB therapy.