Paracrine activin B-NF-κB signaling shapes an inflammatory tumor microenvironment in gastric cancer via fibroblast reprogramming

Abstract

Background Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. Methods The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. Results Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1β. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. Conclusions GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.

Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment

“…The highly complex and heterogeneous TME, formed by the recruitment of non-cancerous host cells and remodeling of the vasculature and extracellular matrix (ECM), including collagen, hyaluronan, laminin, and fibronectin, is regulated by cancer cells (Jahanban-Esfahlan et al 2017 ; Jahanban-Esfahlan et al 2018 ; Lee TW and Lee 2022 ). Critical networks for intercellular communication in the TME encompass various cell-to-cell interactions, including paracrine signaling, through the production of cytokines, growth factors, and chemokines (Shi et al 2019 ; Song et al 2020 ; Jin Y et al 2023 ). Adhesion molecules, such as integrins, selectins, and cadherins, regulate tumor growth and suppression through signal transduction by promoting cell-to-cell interactions and cell–ECM adhesion (Kechagia et al 2019 ; Yeini et al 2021 ; Hwang et al 2023 ).…”