ANGPTL3 promotes colorectal carcinoma progression and metastasis through regulating COL1A2 transcription via interacting with integrin αVβ3.

Distant metastasis constitutes the predominant determinant of adverse prognosis and mortality in colorectal cancer (CRC), with hepatic dissemination representing the most prevalent metastatic pattern and primary contributor to CRC-related deaths. The pathogenesis of colorectal liver metastases (CRLM) involves a multistep cascade modulated by intricate tumor-host interactions, yet the molecular drivers remain incompletely elucidated. Through comparative transcriptomic profiling of matched primary tumors (PT) and liver metastases (LM) in CRC patients, we identified angiopoietin-like protein 3 (ANGPTL3) as a metastasis-associated molecular signature showing significant upregulation in LM tissues correlating with aggressive clinicopathological features. Functional characterization revealed that ANGPTL3 overexpression orchestrated pro-metastatic reprogramming, potentiating in vitro proliferation, migration, and invasion capacities, while concurrently driving subcutaneous tumorigenesis and hepatic colonization in vivo. Conversely, ANGPTL3 silencing markedly attenuated these malignant phenotypes. Mechanistic investigations revealed that ANGPTL3 binds to integrin αVβ3 via its FLD domain, inducing ITGB3 phosphorylation at Y773 and activating the downstream FAK/Src-JAK2/STAT3 axis. This cascade culminates in the transcriptional upregulation of the core extracellular matrix (ECM) component COL1A2, resulting in aberrant collagen deposition and ECM remodeling. The remodeled microenvironment in turn facilitates epithelial-mesenchymal transition (EMT) and angiogenesis, thereby promoting CRC progression and metastasis. Our findings thus delineate the ANGPTL3-integrin αVβ3-STAT3-COL1A2 axis as a central driver of CRC metastasis, nominating ANGPTL3 as both prognostic biomarker for metastatic risk stratification and therapeutic target amenable to molecular intervention in CRC management.