HIF1A-AS2 induces osimertinib resistance in lung adenocarcinoma patients by regulating the miR-146b-5p/IL-6/STAT3 axis

Abstract

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.

Keywords

• HIF1A-AS2
• miR-146b-5p
• IL-6
• osimertinib resistance
• lung cancer