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PRL-3 as a metastasis-associated phosphatase in colorectal cancer: Mechanisms and therapeutic strategies
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DOI：10.1007/s10585-025-10385-8.png)
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Abstract
En 中文
Metastasis remains the leading cause of mortality in colorectal cancer (CRC), and understanding the molecular drivers of this process is central to developing improved interventions. Phosphatase of regenerating liver-3 (PRL-3; PTP4A3) has emerged as a metastasis-associated phosphatase with selective expression in advanced CRC and nearly universal presence in liver metastases. Structurally, PRL-3 is a dual-specificity phosphatase with a conserved catalytic domain and a C-terminal prenylation motif that directs it to cellular membranes. Functionally, PRL-3 disrupts polarity, remodels the cytoskeleton, and interacts with magnesium transporters to influence ion homeostasis. In malignancy, it integrates into the signaling pathways of epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated b cells/interleukin-6/signal transducer and activator of transcription 3 (NF-κB/IL-6/STAT3). This integration promotes epithelial–mesenchymal transition, matrix degradation, survival in the circulation, colonization of distant organs, angiogenesis, and immune evasion. Clinically, high PRL-3 expression correlates with advanced disease staging, recurrence, and poor survival, underscoring its prognostic value. Therapeutic strategies targeting PRL-3—including small-molecule allosteric inhibitors, RNA interference, CRISPR-based editing, and the first-in-class antibody PRL3-zumab—demonstrate promising preclinical activity, with early clinical translation underway. This review highlights PRL-3 as a structural, functional, and translationally relevant driver of metastasis and considers its potential as a biomarker and therapeutic target in CRC and beyond. This review highlights the metastatic role of phosphatase of regenerating liver-3 (PRL-3) in colorectal cancer, where it drives proliferation, invasion, and metastasis through diverse signaling networks. We discuss PRL-3’s molecular biology, its integration into pathways such as EGFR, PI3K/AKT, and NF-κB/STAT3, and its strong association with liver metastasis and poor prognosis. Emerging therapeutic approaches, including small-molecule inhibitors, monoclonal antibodies, and gene-editing strategies, underscore PRL-3’s promise as a predictive biomarker and therapeutic target in advanced colorectal cancer.
Keywords:
PRL-3 (PTP4A3)
Colorectal cancer
Metastasis
Oncogenic signaling
Therapeutic targeting
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