Tumor-derived C4BPA promotes macrophage M2-like polarization through C5a -C5aR1-STAT3 axis and drives gastric cancer progression.
[BACKGROUND] C4b-binding protein α (C4BPA) is a soluble complement regulator reported to be altered in several malignancies, but its role in gastric cancer (GC) biology and tumor-immune crosstalk rema
APA
Zhang Z, Xie Y, et al. (2026). Tumor-derived C4BPA promotes macrophage M2-like polarization through C5a -C5aR1-STAT3 axis and drives gastric cancer progression.. International immunopharmacology, 168(Pt 1), 115830. https://doi.org/10.1016/j.intimp.2025.115830
MLA
Zhang Z, et al.. "Tumor-derived C4BPA promotes macrophage M2-like polarization through C5a -C5aR1-STAT3 axis and drives gastric cancer progression.." International immunopharmacology, vol. 168, no. Pt 1, 2026, pp. 115830.
PMID
41237697
Abstract
[BACKGROUND] C4b-binding protein α (C4BPA) is a soluble complement regulator reported to be altered in several malignancies, but its role in gastric cancer (GC) biology and tumor-immune crosstalk remains unclear.
[METHODS] We generated C4BPA knockdown and overexpression GC cell lines, assessing proliferation, migration, and invasion in vitro. Furthermore, patient-derived GC organoids were engineered to overexpress C4BPA to assess its impact on organoid growth and size. In vivo tumor growth was evaluated in a subcutaneous mouse xenograft model. Mechanistic studies measured Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation and complement expression in tumor cells. We performed co-culture experiments with THP-1-derived macrophages to assess macrophage STAT3 activation and M2 marker expression.
[RESULTS] C4BPA knockdown markedly suppressed GC cell proliferation and reduced migration and invasion in vitro, whereas C4BPA overexpression produced the opposite effects. Consistently, C4BPA overexpression in patient-derived GC organoids resulted in faster growth and larger organoid size. Tumors formed by C4BPA-depleted cells grew substantially slower in mice. Mechanistically, C4BPA loss reduced phosphorylation of JAK2 and STAT3 in tumor cells and decreased production of C3a and C5a. Co-culture of C4BPA-deficient tumor cells with macrophages led to attenuated macrophage STAT3 signaling and downregulation of M2 polarization markers. Recombinant human C5a dose-dependently increased macrophage p-STAT3 through C5a receptor 1 (C5aR1) and restored M2 marker expression in the shC4BPA co-culture condition.
[CONCLUSIONS] C4BPA promotes gastric tumor cell proliferation and motility and shapes a pro-tumoral M2 macrophage phenotype. These data nominate the C4BPA → C5a → C5aR1 → STAT3 axis as a candidate immunomodulatory pathway in GC and suggest C4BPA as a potential therapeutic target.
[METHODS] We generated C4BPA knockdown and overexpression GC cell lines, assessing proliferation, migration, and invasion in vitro. Furthermore, patient-derived GC organoids were engineered to overexpress C4BPA to assess its impact on organoid growth and size. In vivo tumor growth was evaluated in a subcutaneous mouse xenograft model. Mechanistic studies measured Janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation and complement expression in tumor cells. We performed co-culture experiments with THP-1-derived macrophages to assess macrophage STAT3 activation and M2 marker expression.
[RESULTS] C4BPA knockdown markedly suppressed GC cell proliferation and reduced migration and invasion in vitro, whereas C4BPA overexpression produced the opposite effects. Consistently, C4BPA overexpression in patient-derived GC organoids resulted in faster growth and larger organoid size. Tumors formed by C4BPA-depleted cells grew substantially slower in mice. Mechanistically, C4BPA loss reduced phosphorylation of JAK2 and STAT3 in tumor cells and decreased production of C3a and C5a. Co-culture of C4BPA-deficient tumor cells with macrophages led to attenuated macrophage STAT3 signaling and downregulation of M2 polarization markers. Recombinant human C5a dose-dependently increased macrophage p-STAT3 through C5a receptor 1 (C5aR1) and restored M2 marker expression in the shC4BPA co-culture condition.
[CONCLUSIONS] C4BPA promotes gastric tumor cell proliferation and motility and shapes a pro-tumoral M2 macrophage phenotype. These data nominate the C4BPA → C5a → C5aR1 → STAT3 axis as a candidate immunomodulatory pathway in GC and suggest C4BPA as a potential therapeutic target.
MeSH Terms
Humans; Stomach Neoplasms; STAT3 Transcription Factor; Animals; Receptor, Anaphylatoxin C5a; Mice; Complement C5a; Macrophages; Cell Line, Tumor; Cell Proliferation; Janus Kinase 2; Cell Movement; Disease Progression; Signal Transduction
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