LncRNA APCDD1L-AS1 induces icotinib resistance by inhibition of EGFR autophagic degradation via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis in lung adenocarcinoma

Abstract

Background Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer. Methods Molecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance. Results A novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib-resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib. Conclusion APCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients.

Identification of a Ferroptosis-Related LncRNA Signature as a Novel Prognosis Model for Lung Adenocarcinoma

“…Ferroptosis is an iron-dependent cell death program that has been shown to be involved in the development of tumors and the response to antitumor treatment (14,19,41). In addition, many lncRNAs are known to participate in malignant tumor progression and tumor resistance, and become new biomarkers and therapeutic targets for cancer diagnosis and treatment (42)(43)(44). Many lncRNAs can affect the ferroptosis of cancer cell and tumor immunity (45)(46)(47), being promising to become tumor markers with clinical value.…”

“…SLC7A11, the target gene of lncRNA, is a key gene of ferroptosis that can be downregulated by XAV939 (an NSCLC inhibitor), which inhibits the development of NSCLC through a ferroptosis mediated pathway (49). Jie Wu et al found that lncRNA APCDC1L-AS can induce LUAD resistance to icotinib (a kind of TLIs) by inhibiting autophagic degradation of EGFR (44). The lncRNA P53RRA in the cytoplasm affects some metabolic gene transcription and promotes ferroptosis by activating P53 (45).…”

“…Jie Wu et al. found that lncRNA APCDC1L-AS can induce LUAD resistance to icotinib (a kind of TLIs) by inhibiting autophagic degradation of EGFR ( 44 ). The lncRNA P53RRA in the cytoplasm affects some metabolic gene transcription and promotes ferroptosis by activating P53 ( 45 ).…”

Exosomal-mediated transfer of APCDD1L-AS1 induces 5-fluorouracil resistance in oral squamous cell carcinoma via miR-1224-5p/nuclear receptor binding SET domain protein 2 (NSD2) axis

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Wu (2021) Exosomal-mediated transfer of APCDD1L-AS1 induces 5-fluorouracil resistance in oral squamous cell carcinoma via miR-1224-5p/nuclear receptor binding SET domain protein 2 (NSD2)

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“…However, with the deepening of the research, it has been confirmed that lncRNAs are crucial to biological development and disease occurrence, including mediating cell proliferation, differentiation, apoptosis, autophagy, drug resistance, etc. (Bhat et al, 2020;Huang et al, 2021;Wu et al, 2021). Of special note, lncRNAs also affect the proliferation and migration of VSMCs and then participate in vascular diseases.…”