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Cellular and Molecular Biology

INHBA, regulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating the PI3K/AKT pathway in gastric cancer

British Journal of Cancer (2026)Cite this article

Subjects

Abstract

Background

Gastric cancer (GC) is one of the most common malignant tumors with poor overall survival (OS). The mechanism underlying the progression of GC needs to be investigated in depth.

Methods

Differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) and Gene Expression Omnibus (GEO) datasets in GC. The function of INHBA in GC was investigated in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and western blot assays were performed to identify the target transcription factors. Immune cell infiltration was assessed using CIBERSORT algorithms. M2 macrophage polarization induced by INHBA was detected in vitro. The expression levels of downstream target genes of INHBA were measured at mRNA and protein levels.

Results

INHBA was upregulated in GC cells, and high expression of INHBA was associated with poor OS. INHBA was able to promote GC cell migration, invasion, and tumor metastasis and growth. INHBA expression was upregulated by the transcription factor C/EBPβ. Moreover, INHBA in GC cells mediated M2 macrophage polarization. Of note, our data showed that INHBA activated PI3K/AKT pathway and formed a PI3K/AKT/TGF-β positive feedback loop to promote tumor progression.

Conclusions

High INHBA expression predicts poor survival of GC patients. INHBA, upregulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating PI3K/AKT pathway in GC. INHBA may be a potential therapeutic target for GC.

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Fig. 1: A predictive model was constructed with the DEGs in GC and the association between INHBA expression and clinicopathological features.
Fig. 2: INHBA promoted the invasion, metastasis and tumor growth ability of gastric cancer.
Fig. 3: INHBA expression was upregulated by transcription factor C/EBPβ.
Fig. 4: INHBA in gastric cancer induced M2 macrophage polarization.
Fig. 5: INHBA activated PI3K/AKT pathway.

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Data availability

NGS data have been deposited to Gene Expression Omnibus under accession code GSE277561. The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD057014 and PXD057073. All other remaining data are available within the Article and Supplementary Files, or available from the authors upon request.

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Acknowledgements

We thank LetPub (www.letpub.com.cn) for its linguistic assistance during the preparation of this manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81902463), Natural Science Foundation of Shandong Province (ZR2023MH024) and the China Postdoctoral Science Foundation (No., 2020M682197).

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Authors and Affiliations

  1. Department of Pathology, Qilu Hospital, Shandong University, Jinan, China

    Duan-Bo Shi, Jun-Yi He, Ran-Ran Ma & Peng Gao

  2. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medicine, Shandong University, Jinan, Shandong, China

    Duan-Bo Shi, Yong-Chao Qin, Sen Liu, Rui-nan Zhao, Ran-Ran Ma & Peng Gao

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  1. Duan-Bo Shi
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Contributions

PG and DBS performed the conception and design of this manuscript. DBS, JYH and RRM collected clinical tumor samples. DBS, YCQ, SL, RNZ, JYH and RRM performed in vitro data analysis and interpretation, DBS performed in vivo data analysis and interpretation. PG and DBS performed the manuscript writing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ran-Ran Ma or Peng Gao.

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The authors declare no competing interests.

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Informed consent was obtained from all patients, and the patients’ privacy has been fully protected. All of the animal experiments were conducted in accordance with the Guidelines for Animal Health and Use (Ministry of Science and Technology, China, 2006). The study was approved by the Research Ethics Committee of Qilu Hospital and performed in accordance with the Declaration of Helsinki.

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Shi, DB., Qin, YC., Liu, S. et al. INHBA, regulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating the PI3K/AKT pathway in gastric cancer. Br J Cancer (2026). https://doi.org/10.1038/s41416-025-03326-5

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