Vape-Associated lncRNA Transcript 1 (VALT1) Amplifies the Tumorigenic Effects of e-Cigarette Vapor in Lung Epithelial Cells

TL;DR

This study identifies a new long noncoding RNA, VALT1, that is increased by e-cigarette vapor and promotes cancer-like behaviors in lung cells.

Contribution

VALT1 is a novel e-cigarette vapor-responsive lncRNA that enhances tumorigenic effects in lung epithelial cells.

Findings

VALT1 expression increases with e-cigarette vapor exposure and promotes cell proliferation and survival.

VALT1 overexpression mimics e-cigarette-induced cancer-like effects, including ROS detoxification and migration.

VALT1 knockdown reduces these tumorigenic effects in lung epithelial cells.

Abstract

Background/Objectives: Lung cancer remains a major global health burden, largely driven by cigarette use. Although electronic cigarettes (e-cigarettes) are viewed as safer alternatives due to their reduced chemical load, growing evidence shows their vapor can disrupt cellular transcriptomes, including long noncoding RNAs (lncRNAs). In this study, we examined the regulation and function of vape-associated lncRNA transcript 1 (VALT1), a novel transcript upregulated in the oral transcriptomes of e-cigarette users and similarly elevated in non-small-cell lung cancer (NSCLC) tumors. Methods: Publicly available RNA-seq datasets were analyzed, and VALT1 was identified as an e-cigarette-responsive lncRNA. Its dose-dependent induction by e-cigarette smoke extract (eCSE) and cytoplasmic localization were confirmed via RT-qPCR. Its effects on cancer-associated phenotypes including proliferation, ROS detoxification, resistance to apoptosis, migration, cytoskeletal disorganization, and nuclear remodeling were assessed through overexpression and siRNA-mediated knockdown in A549 and BEAS-2B cells. Results: Acute eCSE exposure induced a biphasic, dose-dependent increase in VALT1 expression, accompanied by enhanced proliferation, ROS detoxification, apoptosis resistance, migration, cytoskeletal disorganization, and nuclear remodeling in A549 cells. VALT1 overexpression reproduced these phenotypes in both cell lines without eCSE treatment, whereas knockdown attenuated them. VALT1 promoted survival under cytotoxic stress in A549 but not BEAS-2B cells. Conclusions: These findings support an active role for VALT1 as an e-cigarette vapor-upregulated transcript that contributes to its phenotypic readout and enhances cellular survival under extracellular chemical stress—thereby aggravating tumorigenic phenotypes even in the absence of mutations that contribute to malignant transformation.

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