SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway
SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway
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SALL4通过ATM/Chk2/p53途径诱导鼻咽癌放射抗性
DOI：
10.1002/cam4.2056
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发表时间：
2019-04-01
期刊：
影响因子：
4
通讯作者：
Hu, Guoqing
中科院分区：
文献类型：
--
作者：
Nie, Xin;Guo, Ergang;Hu, Guoqing
放射治疗是鼻咽癌的主要治疗手段，但其疗效受到鼻咽癌固有和获得性放射抵抗的限制。因此，破译新的分子靶点和途径对于提高NPC的放射敏感性至关重要。SALL 4是各种癌症发展和预后的重要因素，但其在放射抗性中的作用仍然难以捉摸。本研究旨在探讨SALL 4表达与鼻咽癌放射抵抗的关系。SALL 4的表达与鼻咽癌的T分期密切相关。在体外和体内，抑制SALL 4降低增殖并使细胞对辐射敏感。此外，SALL 4沉默增加了CNE 2和CNE 2 R细胞中辐射诱导的DNA损伤、凋亡和G2/M期阻滞。此外，SALL 4的敲低损害了p-ATM、p-Chk 2、p-p53和抗凋亡蛋白Bcl-2的表达，而促凋亡蛋白则上调。这些结果表明SALL 4可能通过ATM/Chk 2/p53途径及其下游凋亡相关蛋白诱导辐射抗性。以SALL 4为靶点可能为放射抵抗的鼻咽癌患者开发新的放射增敏治疗药物提供新的途径。
Radiotherapy is the mainstay and primary curative treatment modality in nasopharyngeal carcinoma (NPC), whose efficacy is limited by the development of intrinsic and acquired radioresistance. Thus, deciphering new molecular targets and pathways is essential for enhancing the radiosensitivity of NPC. SALL4 is a vital factor in the development and prognosis of various cancers, but its role in radioresistance remains elusive. This study aimed to explore the association of SALL4 expression with radioresistance of NPC. It was revealed that SALL4 expression was closely correlated with advanced T classification of NPC patients. Inhibition of SALL4 reduced proliferation and sensitized cells to radiation both in vitro and in vivo. Furthermore, SALL4 silencing increased radiation‐induced DNA damage, apoptosis, and G2/M arrest in CNE2 and CNE2R cells. Moreover, knockdown of SALL4 impaired the expression of p‐ATM, p‐Chk2, p‐p53, and anti‐apoptosis protein Bcl‐2, while pro‐apoptosis protein was upregulated. These findings indicate that SALL4 could induce radioresistance via ATM/Chk2/p53 pathway and its downstream proteins related to apoptosis. Targeting SALL4 might be a promising approach for the development of novel radiosensitizing therapeutic agents for radioresistant NPC patients.