PRELP inhibits colorectal cancer progression by suppressing epithelial-mesenchymal transition and angiogenesis via the inactivation of the FGF1/PI3K/AKT pathway

• Published in: Apoptosis (London) Vol. 30; no. 1; pp. 16 - 34
• Main Authors: Li, Xiaoqing, Jiang, Zhongxiang, Li, Junfeng, Yang, Kun, He, Jin, Deng, Qianxi, Xu, Shuman, Jiang, Zhihang, Liu, Fuqiang, Jiang, Zheng
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2025; Springer; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Animal models; Animals; Apoptosis; Bevacizumab; Bevacizumab - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell adhesion; Cell Biology; Cell culture; Cell Line, Tumor; Cell migration; Cell Movement; Cell proliferation; Cell Proliferation - drug effects; Cholecystokinin; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Deactivation; Development and progression; Disease Progression; Effectiveness; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Extracellular matrix; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibroblast growth factor 1; Fibroblast Growth Factor 1 - genetics; Fibroblast Growth Factor 1 - metabolism; Fibroblast growth factors; Gene Expression Regulation, Neoplastic; Growth factors; Humans; Immunofluorescence; In vivo methods and tests; Leucine; Male; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Monoclonal antibodies; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Oncology; Phenotypes; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proteoglycans; Proteoglycans - genetics; Proteoglycans - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; RNA; Signal Transduction - drug effects; Stem cells; TOR protein; Tumor cell lines; Tumors; Virology; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Epithelial-mesenchymal transition; Angiogenesis; PRELP; FGF1; Colorectal cancer
• ISSN: 1360-8185; 1573-675X; 1573-675X
• DOI: 10.1007/s10495-024-02015-7

Proline/arginine-rich end and leucine-rich protein (PRELP) is identified as a small proteoglycan in the extracellular matrix that has been tightly associated with cell adhesion. At present, the role of PRELP in colorectal cancer (CRC) remains largely unknown. PRELP expression in human CRC tissue samples was analyzed by qRT-PCR and immunochemistry. CCK-8, colony formation, transwell, and tube formation assays were utilized to determine the influences of PRELP on the malignant phenotypes of CRC cells. Mouse xenograft and tumor metastasis models were constructed to further validate the function of PRELP. Furthermore, we investigated the efficacy of PRELP combined with bevacizumab treatment in a mouse xenograft model of CRC. Additionally, RNA-seq was performed to analyze the potential signaling pathways regulated by PRELP. Immunofluorescence staining and coimmunoprecipitation were conducted to confirm the interaction between PRELP and fibroblast growth factor 1 (FGF1). In this study, we found that PRELP exerted a tumor-suppressive effect on CRC. The expression level of PRELP was significantly reduced in CRC tissues and cell lines. Both in vivo and in vitro experiments confirmed that PRELP inhibited CRC cell proliferation, promoted apoptosis, and suppressed migration and invasion via a reduction in the epithelial-mesenchymal transition and attenuated angiogenesis, thereby dampening tumor progression. In addition, PRELP markedly potentiated the efficacy of bevacizumab in a mouse xenograft model. Mechanistically, PRELP bound to FGF1 and reduced the stability of the FGF1 protein, accompanied by an increase in its degradation, which subsequently inactivated the PI3K/AKT/mTOR pathway, thereby leading to reduction in tumor angiogenesis and metastasis. Our study for the first time unveiled the tumor-suppressive role of PRELP in CRC and provided a potential effective strategy for the treatment of CRC.