SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway

• Published in: Journal of cellular and molecular medicine Vol. 28; no. 10; pp. e18397 - n/a
• Main Authors: Jiang, Guangchun, Xu, Shuo, Mai, Xiaobin, Tu, Juan, Wang, Le, Wang, Lijing, Zhan, Yaping, Wang, Yan, Zhang, Qianqian, Zheng, Lingyun, Li, Jiangchao, Tang, Pei, Qi, Cuiling
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-05-2024; John Wiley and Sons Inc
• Subjects: Acute phase proteins; Amyloid; Amyloid P component; Animals; Antibodies; Breast cancer; CAF; Cancer therapies; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell culture; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chemokines; CXCL12; CXCL12 protein; CXCR4 protein; Disease Progression; Fibroblasts; Gene Deletion; Hepatocytes; Humans; Insulinoma; Insulinoma - genetics; Insulinoma - pathology; insulinoma growth; insulinoma metastasis; Kinases; Ligands; Malignancy; malignant insulinoma; MAP Kinase Signaling System; Medical research; Metastases; Metastasis; Mice; Mice, Knockout; Neuroendocrine tumors; Original; p38 Mitogen-Activated Protein Kinases - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pentraxins; Proteins; Pulmonary fibrosis; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; SAP; SAP protein; Signal transduction; Tumors; United States > US; China; CAF; malignant insulinoma; CXCL12; SAP; insulinoma growth; insulinoma metastasis
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.18397

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute‐phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1‐Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1‐Tag2;SAP−/− mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C‐X‐C motif chemokine ligand 12 (CXCL12) secreted by cancer‐associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.