INHBA Promotes the Progression of Gastric Cancer by Activating MAPK Signaling Pathway via Targeting ITGA6.

[OBJECTIVES] Gastric cancer (GC) is among the most prevalent malignancies worldwide, ranking as the fifth most common cancer and the fifth leading cause of cancer-related mortality. This study intends to investigate how Inhibin subunit beta A (INHBA) promotes the progression of GC by activating the mitogen-activated protein kinase (MAPK) signaling pathway via targeting Integrin alpha-6 (ITGA6).

[METHODS] Quantitative reverse transcription-Polymerase Chain Reaction (qRT-PCR) and Immunohistochemistry (IHC) were utilised to validate the expression levels of INHBA in GC, which were subsequently correlated with the clinicopathological factors and outcomes. Cellular and animal studies were conducted to ascertain the role of INHBA in GC. RNA-sequencing (RNA-seq) and bioinformatics analysis were used to screen for the downstream target and pathway of INHBA, with Co-immunoprecipitation (Co-IP), Co-Immunofluorescent (Co-IF), Western blot (WB) and Rescue experiments validating their mechanisms of action in GC.

[RESULTS] IHC and qRT-PCR analysis confirmed that GC tissues exhibited higher INHBA expression than adjacent noncancerous tissues. This elevated INHBA expression was found to be significantly associated with the incidence of tumor lesions, lymph node metastasis, and progression to higher TNM stages. Functional experiments showed that INHBA promoted GC cell proliferation and enhanced their migration and invasion while inhibiting apoptosis. Animal studies results indicated that INHBA overexpression promoted tumor growth and increased tumor weight and volume. Through a series of experiments, including RNA-seq, Co-IP, Co-IF, WB, and rescue assays, this study demonstrated that INHBA promotes GC progression by targeting ITGA6 to regulate the MAPK signaling pathway.

[CONCLUSIONS] INHBA/ITGA6/MAPK axis can provide new insights into GC therapy. Targeted INHBA inhibition holds promise as a therapeutic approach for GC treatment.