Proteomics reveals cell‐surface urokinase plasminogen activator receptor expression impacts most hallmarks of cancer

Seong Beom Ahn, Abidali Mohamedali, Dana Pascovici, Subash Adhikari, Samridhi Sharma, Edouard C. Nice, Mark S. Baker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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) has 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 have been proposed to accelerate precision medicine therapeutic development. A moderate decrease (43%↓) in HCT116 cell surface urokinase plasminogen activator receptor (uPAR) expression mitigates against many HoCs driven by these cell's KRAS and PIK3CA mutational signature. Comprehensive proteomics (whole cell lysis with two membrane protein enrichments) coupled with ingenuity pathway analysis (IPA) demonstrates 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, it is demonstrated that uPAR is a lynchpin protein capable of regulating several HoC pathways in a classical CRC mutational background.

Original languageEnglish
Article number1900026
Pages (from-to)1-13
Number of pages13
JournalProteomics
Volume19
Issue number21-22
DOIs
Publication statusPublished - Nov 2019

Keywords

  • colorectal cancer
  • hallmarks of cancer
  • membrane protein extraction
  • uPAR

Cite this