Characterization of an endoplasmic reticulum stress-associated lncRNA prognostic signature and the tumor-suppressive role of RP11-295G20.2 knockdown in lung adenocarcinoma

Endoplasmic reticulum stress (ERS) is commonly induced by accumulating misfolded or unfolded proteins in tumor microenvironment. Long non-coding RNAs (lncRNAs) play important roles in ERS response and lung adenocarcinoma (LUAD) progression. However, the role of ERS-related lncRNAs in LUAD remains unknown. In this study, we aimed to identify ERS-associated lncRNAs with prognostic value in LUAD and characterize their clinical implications. Cox and least absolute shrinkage and selection operator regression analyses identified nine ERS-related lncRNAs with independent prognostic abilities, including five protective factors (CROCCP2, KIAA0125, LINC0996, RPARP-AS1 and TBX5-AS1) and four risk factors (LINC0857, LINC116, RP11-21L23.2 and RP11-295G20.2). We developed an ERS-related lncRNA risk prediction model in predicting overall survival of LUAD patients, which classified TCGA cohorts into high-risk (HS) and low-risk (LS) groups. Comprehensive bioinformatic analyses revealed HS patients featured with late-stage tumors, greater mutation burdens, weaker anti-tumor immunity/responses, and lower sensitivity to targeted drugs compared to LS patients, contributing to tumor progression and a poor prognosis. Functional enrichment analysis implicated these ERS-related lncRNAs in cell migration, cell death, and immunity. Furthermore, expression of the most significantly upregulated risk lncRNA, RP11-295G20.2, was validated at the mRNA level using clinical LUAD samples. Knockdown of RP11-295G20.2 obviously reduced ERS and suppressed proliferation, invasion, and migration of LUAD cells. This novel ERS-related lncRNA signature provides a new biomarker for prognostic prediction, and ERS-associated RP11-295G20.2 serves as a potential therapeutic target in LUAD.