ADH1B regulates tumor stemness by activating the cAMP/PKA/CREB1 signaling axis to inhibit recurrence and metastasis of lung adenocarcinoma

Abstract

Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of cases. Despite advancements in diagnostics and therapies, tumor metastasis and drug-resistant recurrence present significant clinical challenges. This study evaluates the prognostic role of ADH1B in lung adenocarcinoma (LUAD) metastasis and recurrence. Analysis of tissue samples from 46 LUAD patients revealed that lower ADH1B expression correlates with increased metastasis and poorer overall survival. Kaplan-Meier survival analysis demonstrated that elevated ADH1B levels are significantly associated with longer overall survival and recurrence-free survival. In vitro experiments indicated that ADH1B overexpression inhibits proliferation, migration, and invasion in A549 and H1299 cell lines. Additionally, ADH1B expression was negatively correlated with tumor stemness markers, indicating its role in suppressing stem cell characteristics. Mechanistically, ADH1B activates the cAMP/PKA/CREB1 signaling pathway, enhancing SOX1 expression and inhibiting the ERK pathway, which contributes to reduced tumor stemness. In vivo studies confirmed that ADH1B overexpression decreases stem cell populations and tumor growth in xenograft models. Our findings suggest that ADH1B functions as a critical regulator of LUAD progression, with its low expression acting as a marker of poor prognosis while promoting metastasis and tumor stemness. This research identifies ADH1B as a potential therapeutic target, offering novel strategies to address the challenges of metastasis and recurrence in LUAD.