BACKGROUND
Osimertinib resistance is a major challenge in the treatment of EGFR-mutated lung adenocarcinoma (LUAD), and the role of LINC00511 in this process remains unclear.
METHODS
We analyzed LINC00511 expression, patient prognosis, and its correlation with EIF2AK3 (encoding PERK) in LUAD using the GEPIA2 database, and further validated its circulating levels in patient peripheral blood by RT-qPCR. In vitro experiments, we constructed osimertinib-resistant H1650-OS and H1975-OS cell lines and regulated the expression of LINC00511 using genetic means. We evaluated the effects on resistance through functional experiments and used Western blot to detect PERK/Nrf2 and ER stress (ERS)-related proteins. Finally, we established a xenograft model to validate the in vitro findings in vivo.
RESULTS
The results showed that elevated LINC00511 levels in patients with osimertinib resistance, and positively correlated with PERK. Knockdown of LINC00511 could block the activation of the PERK/Nrf2 axis, inducing ERS. In vivo experiments confirmed that silencing LINC00511 enhances the inhibitory effect of osimertinib on osimertinib-resistant LUAD. Mechanistically, LINC00511 inhibits ERS through the PERK-Nrf2 pathway, thereby driving resistance.
CONCLUSION
These findings provide clinical evidence for the early diagnosis and risk stratification of Osimertinib resistance, and suggest that targeting the LINC00511-PERK-Nrf2 axis may become a novel therapeutic strategy for restoring drug sensitivity, offering potential targets for the development of intelligent diagnostic and therapeutic nanomaterials.
Qingyang Lei, Jing Peng, Na Li et al.· Cellular Signalling· 0 citations
BACKGROUND
Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a major cause of cancer-related mortality. Despite advances in targeted therapies, tumor heterogeneity and acquired resistance frequently undermine clinical outcomes. This study aimed to identify novel oncogenic drivers and underlying mechanisms in LUAD.
METHODS
We examined cellular retinoic acid-binding protein 2 (CRABP2) expression in human LUAD specimens and evaluated its functional role through in vitro assays (cell proliferation, migration, invasion, and apoptosis) and in vivo xenograft tumor growth. Mechanistic exploration involved RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and immunoblotting for the nuclear factor kappa B (NF-κB) signaling components, along with rescue experiments to dissect the pathway dependency.
RESULTS
CRABP2 was identified as a candidate oncogene in LUAD. Functional assays confirmed that CRABP2 promoted proliferation, migration, and invasion, suppressed apoptosis, and accelerated xenograft tumor growth. Mechanistically, CRABP2 potentiated retinoic acid (RA) signaling and activated the NF-κB pathway, as evidenced by enhanced inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) phosphorylation, subsequent NF-κB inhibitor alpha (IκBα) phosphorylation, and nuclear translocation of total and phosphorylated p65. Rescue experiments revealed that CRABP2‑induced NF-κB activation is RA-dependent and that this activation mediates the oncogenic effects of CRABP2.
CONCLUSIONS
Our findings establish a CRABP2/RA/NF‑κB axis that drives LUAD progression, highlighting this pathway as a potential therapeutic target for intervention in LUAD.
Xi-Rui Zhu, Biao Fan, Qingyang Lei et al.· Frontiers in Bioscience· 0 citations
