Li Xiaoqing, Jiang Zhongxiang, Li Junfeng, Yang Kun, He Jin, Deng Qianxi, Xu Shuman, Jiang Zhihang, Liu Fuqiang, Jiang Zheng
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Apoptosis. 2025 Feb;30(1-2):16-34. doi: 10.1007/s10495-024-02015-7. Epub 2024 Sep 6.
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.
富含脯氨酸/精氨酸的末端和富含亮氨酸的蛋白质（PRELP）被鉴定为细胞外基质中的一种小蛋白聚糖，它与细胞黏附紧密相关。目前，PRELP在结直肠癌（CRC）中的作用仍 largely未知。通过qRT-PCR和免疫化学分析了人CRC组织样本中PRELP的表达。利用CCK-8、集落形成、Transwell和管形成试验来确定PRELP对CRC细胞恶性表型的影响。构建小鼠异种移植和肿瘤转移模型以进一步验证PRELP的功能。此外，我们在CRC小鼠异种移植模型中研究了PRELP联合贝伐单抗治疗的疗效。另外，进行RNA测序以分析受PRELP调节的潜在信号通路。进行免疫荧光染色和免疫共沉淀以证实PRELP与成纤维细胞生长因子1（FGF1）之间的相互作用。在本研究中，我们发现PRELP对CRC发挥肿瘤抑制作用。CRC组织和细胞系中PRELP的表达水平显著降低。体内和体外实验均证实，PRELP通过减少上皮-间质转化和减弱血管生成来抑制CRC细胞增殖、促进凋亡并抑制迁移和侵袭，从而抑制肿瘤进展。此外，PRELP在小鼠异种移植模型中显著增强了贝伐单抗的疗效。机制上，PRELP与FGF1结合并降低FGF1蛋白的稳定性，同时增加其降解，随后使PI3K/AKT/mTOR通路失活，从而导致肿瘤血管生成和转移减少。我们的研究首次揭示了PRELP在CRC中的肿瘤抑制作用，并为CRC的治疗提供了一种潜在的有效策略。
