HIF1A-AS2 induces osimertinib resistance in lung adenocarcinoma patients by regulating the miR-146b-5p/IL-6/STAT3 axis.
HIF1A-AS2 induces osimertinib resistance in lung adenocarcinoma patients by regulating the miR-146b-5p/IL-6/STAT3 axis.
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HIF1A-AS2通过调节miR-146b-5p/IL-6/STAT3轴诱导肺腺癌患者对奥希替尼耐药
DOI：
10.1016/j.omtn.2021.09.003
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Si J;Ma Y;Lv C;Hong Y;Tan H;Yang Y
尽管表皮生长因子受体酪氨酸激酶抑制剂（TKI）在肺腺癌（LUAD）患者中显示出疗效，但TKI耐药性不可避免地发展，限制了长期结果。因此，迫切需要解决LUAD的耐药性问题。长链非编码RNA（lncRNA）HIF 1A-AS 2可能是各种肿瘤类型进展中的关键介质。我们研究了HIF 1A-AS 2在改变肺腺癌的肿瘤恶化和奥希替尼耐药中的功能。使用临床样本，我们发现HIF 1A-AS 2在LUAD标本中上调，预测总生存率和无病生存率较差。HIF 1A-AS 2沉默可抑制LUAD细胞的增殖、迁移和肿瘤发生，以及奥希替尼在体外和体内对肿瘤细胞的治疗功效。RNA沉淀分析、蛋白质印迹、荧光素酶分析和拯救实验表明，HIF 1A-AS 2吸收microRNA-146 b-5 p（miR-146 b-5 p），促进白细胞介素-6（IL-6）表达，激活IL-6/STAT 3通路，并导致LUAD进展。miR-146 b-5 p和IL-6水平与LUAD患者的预后相关。我们的研究结果表明，HIF 1A-AS 2通过靶向miR-146 b-5 p/IL-6/STAT 3轴在腺癌细胞中作为致癌因子发挥作用，并且可能是生存的预后指标。此外，它可能是提高奥希替尼在LUAD患者中疗效的潜在治疗靶点。EGFR-TKI在肺腺癌（LUAD）患者中表现出显著的治疗疗效。然而，TKI的耐药性不可避免地发展。该研究表明，HIF 1A-AS 2通过靶向miR-146 b-5 p/IL-6/STAT 3轴作为致癌因子发挥作用，可能是提高奥希替尼在LUAD患者中疗效的潜在治疗靶点。
Although epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) show efficacy in lung adenocarcinoma (LUAD) patients, TKI resistance inevitably develops, limiting long-term results. Thus, there is an urgent need to address drug resistance in LUAD. Long non-coding RNA (lncRNA) HIF1A-AS2 could be a critical mediator in the progression of various tumor types. We examined the function of HIF1A-AS2 in modifying tumor aggravation and osimertinib resistance in lung adenocarcinoma. Using clinical samples, we showed that HIF1A-AS2 was upregulated in LUAD specimens, predicting poorer overall survival and disease-free survival. HIF1A-AS2 silencing inhibited the proliferation, migration, and tumorigenesis of LUAD cells and therapeutic efficacy of osimertinib against tumor cells in vitro and in vivo. RNA precipitation assays, western blotting, luciferase assays, and rescue experiments demonstrated that HIF1A-AS2 sponged microRNA-146b-5p (miR-146b-5p), promoting interleukin-6 (IL-6) expression, activating the IL-6/STAT3 pathway, and leading to LUAD progression. miR-146b-5p and IL-6 levels were correlated with the prognosis of LUAD patients. Our results indicated that HIF1A-AS2 functions as an oncogenic factor in adenocarcinoma cells by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a prognostic indicator of survival. Moreover, it can be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients. EGFR-TKIs have exhibited notable therapeutic efficacy in lung adenocarcinoma (LUAD) patients. However, TKIs resistance inevitably develops. The study indicates that HIF1A-AS2 functions as an oncogenic factor by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients.
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影响因子：
8.8
作者：
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影响因子：
64.5
作者：
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