CN-121992102-A - Application of IGFBP7 in colorectal cancer diagnosis and treatment

Abstract

The invention relates to the use of IGFBP7 in clinical diagnosis of colorectal cancer and as a drug target. Studies in accordance with the present invention demonstrate that the amount of IGFBP7 secreted by tumor endothelial cells is continuously reduced during inflammation-associated colorectal neoplasia. Functional analysis demonstrated that endothelial-derived IGFBP7 was secreted into the tumor microenvironment and exerted an anti-angiogenic effect. In addition, CRC cells are able to actively ingest vesicles containing IGFBP 7. IGFBP7 inhibits proliferation and migration of tumor cells by inhibiting EGR1 expression, thereby down-regulating TGF- β1 signaling pathway activity. Notably, this study identified that vesicle-associated membrane protein associated protein a (VAPA) is a key factor in mediating transport of IGFBP7 vesicles to lysosomes, VAPA promoted degradation of IGFBP7, thereby impairing its cancer suppression function. Endothelial cell-derived IGFBP7 inhibits the progression of CRC via the EGR1/TGF- β1 pathway, whereas VAPA-mediated lysosomal degradation limits its cancer-inhibiting effect. These findings underscore that endothelial cell-derived IGFBP7 is a very promising therapeutic target in the colorectal cancer field.

Inventors

• ZHOU WENTING
• WANG RUI
• PENG ZHIHAI

Assignees

• 厦门大学附属翔安医院

Dates

Publication Date

20260508

Application Date

20260210

Claims (8)

1. Use of igfbp7 as biomarker in the preparation of a colorectal cancer diagnostic kit.
2. Use of igfbp7 as biomarker in the preparation of a kit for prognosis and staging of colorectal cancer.
3. 3. The use of a reagent for detecting the content of IGFBP7 gene or protein in the preparation of a colorectal cancer diagnostic kit.
4. 4. Use of a reagent for detecting IGFBP7 gene or protein content in the preparation of a colorectal cancer prognosis and staging kit.
5. Use of IGFBP7 or an IGFBP7 promoter for the preparation of a medicament for the treatment of colorectal cancer.
6. Use of IGFBP7 or an IGFBP7 promoter for the preparation of a medicament for preventing recurrent metastasis and for treating resistance to colorectal cancer.
7. 7. A pharmaceutical composition for the treatment of colorectal cancer, comprising IGFBP7 in combination with an anti-VEGF antibody.
8. 8. Use of a pharmaceutical composition according to claim 7 for the preparation of a medicament for the treatment of colorectal cancer.

Description

Application of IGFBP7 in colorectal cancer diagnosis and treatment Technical Field The invention belongs to the field of disease diagnosis and drug targets, and particularly relates to application of IGFBP7 in clinical diagnosis of colorectal cancer and serving as a drug target. Background Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and the Tumor Microenvironment (TME) significantly affects disease progression and treatment response. Tumor endothelial cells play a critical role in the initiation, progression and metastasis of CRC, but their specific mechanism of action has not yet been fully elucidated. The IGFBP family contains a variety of structurally similar proteins that regulate biological processes such as proliferation and growth of cells by binding to insulin-like growth factors (IGFs) and modulating their bioavailability. Insulin-like growth factor binding protein 7 (Insulin-like growth factor binding protein, IGFBP 7) has been shown to be involved in a variety of physiological and pathological processes as a key member of the IGFBP family. It was not only identified as a urinary biomarker of acute kidney injury (PMID: 35752325), but its down-regulation of expression was reported to improve symptoms of heart failure (PMID: 38991046). In addition, IGFBP7 regulates immune cell-endothelial cell interactions in inflammatory diseases such as psoriasis (PMID: 36917196). However, there is currently no report of the relationship of IGFBP7 to colorectal cancer. Disclosure of Invention The invention aims at overcoming the defects in the prior art and providing the application of IGFBP7 in clinical diagnosis of colorectal cancer and as a drug target. In a first aspect, the invention provides the use of IGFBP7 as a biomarker in the preparation of a kit for diagnosis of colorectal cancer. In a second aspect, the invention provides the use of IGFBP7 as a biomarker in the preparation of a kit for prognosis and staging of colorectal cancer. In a third aspect, the invention provides the use of a reagent for detecting IGFBP7 gene or protein content in the preparation of a kit for diagnosing colorectal cancer. In a fourth aspect, the invention provides the use of a reagent for detecting IGFBP7 gene or protein content in the preparation of a kit for prognosis and staging of colorectal cancer. In a fifth aspect, the invention provides the use of IGFBP7 or an IGFBP7 promoter in the manufacture of a medicament for treating colorectal cancer. In a sixth aspect, the invention provides the use of IGFBP7 or an IGFBP7 promoter in the manufacture of a medicament for preventing recurrent metastasis and for treating resistance to colorectal cancer. In a seventh aspect, the invention provides a pharmaceutical composition for the treatment of colorectal cancer, said pharmaceutical composition comprising IGFBP7 in combination with an anti-VEGF antibody. In an eighth aspect, the invention provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of colorectal cancer. The invention has the advantages that. Endothelial cell-derived IGFBP7 is used as a biomarker for prognosis and staging of colorectal cancer, and is based on a multi-dimensional evidence chain such as scRNA-seq, nuGEN sequencing after CD31+ endothelial cell sorting, RNAscope/IHC/flow and the like, research shows that IGFBP7 is highly expressed in normal vascular endothelial cells, but is significantly reduced in tumor-related endothelial cells, and is progressively reduced from adenoma to adenocarcinoma, which means that the change is not a generalized tumor expression difference, but has a cell type-specific tumor microenvironment endothelial remodeling event, and forms a new recognition framework different from 'tumor cell-derived IGFBP 7'. The dynamic regulation law of stage dependence of endothelial IGFBP7 in the process of driving cancer is revealed, namely, in an AOM/DSS colitis-related CRC model, the disease process is subdivided into acute inflammation (T1), chronic inflammation (T2), early tumorigenesis (T3) and tumor progression (T4), and the endothelial IGFBP7 is proved to rise in the inflammatory stage, be down-regulated from T3 and be significantly reduced in T4, and simultaneously changes in opposite directions with the up-regulation of pro-angiogenesis and TGF-beta channel genes, and the expression mode of 'time axis + stage specificity' provides new molecular evidence for understanding a key window of inflammation-cancer transformation. Establishing the paracrine transport mode of IGFBP7 with 'endothelial secretion-tumor endocytosis', namely researching the contradiction phenomenon that the transcription level is almost zero but the intracellular protein is detectable, combining with the evidence that the culture supernatant of endothelial cells is enriched, the Golgi inhibitor is sensitive and the exosome inhibitor is insensitive, the tumor cell protein is increased and mRNA