Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation
Long noncoding RNA FOXD2-AS1 enhances chemotherapeutic resistance of laryngeal squamous cell carcinoma via STAT3 activation
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长非编码RNA FOXD2-AS1通过STAT3激活增强喉鳞状细胞癌的化疗耐药性
DOI：
10.1038/s41419-020-2232-7
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发表时间：
2020-01-20
影响因子：
9
通讯作者：
Zhang, Siyi
中科院分区：
文献类型：
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作者：
Li, Rui;Chen, Shuwei;Zhang, Siyi
喉鳞状细胞癌(LSCC)是常见的头颈部肿瘤。尽管最近喉癌的管理有所改善，但患者的化疗耐药性仍然是一个挑战。在本研究中，我们发现长的非编码RNA FOXD2-AS1通过增加喉癌的干性来调节喉癌的治疗耐药。喉癌化疗耐药患者FOXD2-AS1的表达高于化疗敏感患者，提示预后不良。功能获得或丧失实验表明，上调的FOXD2-AS1维持了癌症的干性，降低了对化疗的反应，而FOXD2-AS1的下调则有相反的效果。FOXD2-AS1作为STAT3和PRMT5的支架，促进STAT3的转录活性，这对于维持肿瘤的干性和促进化疗耐药是必不可少的。短发夹状RNA干扰FOXD2-AS1可挽救LSCC的化疗敏感性。因此，FOXD2-AS1促进喉癌化疗耐药，是STAT3的上游激活剂，使FOXD2-AS1成为提高喉癌患者化疗效果的潜在治疗靶点。
Laryngeal squamous cell carcinoma (LSCC) is a common head and neck cancer. Despite recently improved management of LSCC, chemotherapy resistance of patients remains a challenge. In this study, we identified that long noncoding RNA FOXD2-AS1 regulates LSCC therapeutic resistance by augmenting LSCC stemness. LSCC chemotherapy-resistant patients showed increased FOXD2-AS1 expression compared with that in chemotherapy-sensitive patients, which predicted poor prognosis. Gain- or loss-of-function experiments showed that upregulated FOXD2-AS1 maintained cancer stemness, reducing the response to chemotherapy, while FOXD2-AS1 downregulation had the opposite effects. FOXD2-AS1 acted as a scaffold for STAT3 and PRMT5, promoting STAT3 transcriptional activity, which is essential to maintain cancer stemness and promote chemotherapeutic resistance. Interfering with FOXD2-AS1 using short hairpin RNA rescued LSCC’s chemotherapeutic sensitivity. Thus, FOXD2-AS1 promotes LSCC chemotherapeutic resistance and is an upstream activator of STAT3, making FOXD2-AS1 a potential therapeutic target to improve the chemotherapy effect in LSCC patients.