ARPC1B promotes gastric cancer tumorigenesis via IGF2BP3-mediated stabilization of HK2 mRNA and glycolytic reprogramming.

Abstract

Background: Cancer cells improve survival through metabolic reprogramming, predominantly shifting to glycolysis. Actin-related protein 2/3 complex subunit 1B (ARPC1B) is abnormally overexpressed in multiple malignancies and significantly associated with the poor prognosis of patients. However, the role of ARPC1B in gastric cancer (GC) remains poorly characterized.

Methods: ARPC1B expression in GC and its association with clinicopathological features were assessed using bioinformatics (TCGA, GEPIA), western blotting, and immunohistochemical staining. The functional impact of ARPC1B on glycolysis (ECAR, OCR, glucose uptake, lactate/ATP production) and tumorigenesis (proliferation, migration, invasion, in vivo xenografts) was evaluated following ARPC1B knockdown or overexpression. ARPC1B-IGF2BP3 interaction was validated by co-immunoprecipitation and confocal microscopy. IGF2BP3-dependent stabilization of hexokinase 2 (HK2) mRNA was examined via RNA immunoprecipitation and actinomycin D assays.

Results: ARPC1B was significantly upregulated in GC tissues and cell lines, with elevated expression correlating positively with advanced tumor stage and pathological grade. ARPC1B depletion suppressed glycolytic activity (reduced ECAR, increased OCR, glucose consumption, lactate/ATP production), inhibited proliferation, migration, and invasion in vitro, and attenuated tumor growth and metastasis in vivo. Mechanistically, ARPC1B bound to IGF2BP3, impeding its degradation and ubiquitination, thereby enhancing HK2 mRNA stability. Consequently, ARPC1B increased HK2 protein expression, while HK2 overexpression rescued the anti-glycolytic and anti-tumorigenic effects of ARPC1B knockdown.

Conclusion: ARPC1B drives GC progression by stabilizing HK2 mRNA through IGF2BP3 binding, thereby potentiating glycolytic reprogramming to facilitate tumor growth and metastasis. Targeting the ARPC1B-IGF2BP3-HK2 axis may represent a novel therapeutic strategy for GC.