Proteomics Reveals Cell-Surface Urokinase Plasminogen Activator Receptor (uPAR) Expression Impacts Most Hallmarks of Cancer

Seong Beom Ahn, Abidali Mohamedali, Dana Pascovici, Subash Adhikari, Samridhi Sharma, Edouard C Nice, Mark S Baker
Proteomics 2019 August 11, : e1900026
While metastasis is the primary cause of colorectal cancer (CRC) mortality, the molecular mechanisms underpinning it remains elusive. Metastasis is propagated through driver oncogene/suppressor gene mutations, accompanied by passenger mutations and underlying genomic instability. To understand cancer biology, a unifying framework called the hallmarks of cancer (HoCs) had been developed, which organizes cell biological alterations under ten key hallmarks. Underlying these HoCs, genome instability generates mutational diversity that is amplified by inflammation. Recognizing how critical cancer cell-surface proteins influence these HoCs has been proposed to accelerate precision medicine therapeutic development. Here, we asked if a moderate decrease in expression (↓43%) of HCT116 cell line urokinase plasminogen activator receptor (uPAR) negates HoCs driven by its KRAS and PIK3CA mutational background found in CRC. Comprehensive proteomics (whole cell lysis with two membrane protein enrichments) coupled with Ingenuity Pathway Analysis (IPA) demonstrated that uPAR negates essential pathways across the HoC spectrum, particularly those associated with metastasis, resisting cell death and sustaining proliferation, and parallels Cancer Hallmarks Analytics Tool analysis. Decreasing uPAR predominantly alters metastasis-related and uPAR-interactome protein expression (e.g., EGFR, caveolin, vitronectin, integrin β4). Collectively, we demonstrate that uPAR is a lynchpin protein capable of regulating several HoC pathways in a classical CRC mutational background. This article is protected by copyright. All rights reserved.


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