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

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Apoptosis Pub Date : 2024-09-06 DOI:10.1007/s10495-024-02015-7
Xiaoqing Li, Zhongxiang Jiang, Junfeng Li, Kun Yang, Jin He, Qianxi Deng, Shuman Xu, Zhihang Jiang, Fuqiang Liu, Zheng Jiang
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Abstract

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.

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PRELP 通过抑制 FGF1/PI3K/AKT 通路,抑制上皮-间质转化和血管生成,从而抑制结直肠癌的进展。
富脯氨酸/精氨酸末端和富亮氨酸蛋白(PRELP)是细胞外基质中的一种小型蛋白多糖,与细胞粘附密切相关。目前,PRELP 在结直肠癌(CRC)中的作用在很大程度上仍然未知。本研究采用 qRT-PCR 和免疫化学方法分析了人 CRC 组织样本中 PRELP 的表达。利用 CCK-8、集落形成、transwell 和试管形成试验确定 PRELP 对 CRC 细胞恶性表型的影响。为了进一步验证 PRELP 的功能,我们构建了小鼠异种移植和肿瘤转移模型。此外,我们还研究了 PRELP 与贝伐珠单抗联合治疗 CRC 小鼠异种移植模型的疗效。此外,我们还进行了RNA-seq分析,以分析PRELP调控的潜在信号通路。免疫荧光染色和共沉淀证实了PRELP与成纤维细胞生长因子1(FGF1)之间的相互作用。本研究发现,PRELP 对 CRC 有抑制肿瘤的作用。在 CRC 组织和细胞系中,PRELP 的表达水平明显降低。体内和体外实验均证实,PRELP 可抑制 CRC 细胞增殖、促进细胞凋亡,并通过减少上皮-间质转化和减弱血管生成抑制细胞迁移和侵袭,从而抑制肿瘤进展。此外,在小鼠异种移植模型中,PRELP 还能显著增强贝伐珠单抗的疗效。从机理上讲,PRELP 与 FGF1 结合,降低了 FGF1 蛋白的稳定性,同时增加了其降解,进而使 PI3K/AKT/mTOR 通路失活,从而导致肿瘤血管生成和转移的减少。我们的研究首次揭示了PRELP在CRC中的抑瘤作用,并为治疗CRC提供了一种潜在的有效策略。
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来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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