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Biglycan as a potential regulator of tumorgenicity and immunogenicity in K-RAS-transformed cells

Karthikeyan Subbarayan1, Chiara Massa1, Sandra Leisz1

  • 1Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany.

Oncoimmunology
|May 9, 2022
PubMed

Insights

Biglycan (BGN) expression is inversely linked to K-RAS mutations in colorectal cancer, impacting tumor growth and immune evasion. Restoring BGN may offer a new therapeutic strategy for K-RAS-associated malignancies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Biglycan (BGN), an extracellular matrix component, is crucial in physiological and pathological processes.
  • Reduced BGN expression correlates with diminished immunogenicity in HER-2/neu-overexpressing cells.
  • Investigating BGN's role in K-RAS-driven cancers is essential.

Purpose of the Study:

  • To determine if oncogene-driven networks suppress BGN expression.
  • To analyze BGN expression and function in K-RAS-mutated colorectal carcinoma (CRC) models and patient data.
  • To explore the therapeutic potential of BGN restoration in K-RAS-associated malignancies.

Main Methods:

  • Analysis of BGN expression in murine and human BGNlow/BGNhigh K-RAS(G12V)-transformed models.
  • Comparison of BGN levels in CRC tissues versus normal colon epithelial cells.
  • Functional assays including cell growth, migration, and tumor formation after BGN transfection.
  • RNA-sequencing to assess changes in antigen processing and MHC class I expression.
  • Evaluation of tumor-infiltrating lymphocytes in BGN-manipulated models.

Main Results:

  • K-RAS-mutated CRC tissues exhibit significantly lower BGN mRNA and protein levels compared to normal cells, correlating with reduced patient survival.
  • Restoration of BGN in BGNlow K-RAS-expressing cells led to decreased cell growth and migration.
  • Increased surface expression of MHC class I antigens was observed upon BGN restoration, linked to enhanced antigen processing machinery.
  • BGNhigh K-RAS-transformed fibroblasts showed reduced tumor formation, increased MHC class I expression, and a higher frequency of tumor-infiltrating lymphocytes.

Conclusions:

  • A novel inverse relationship between BGN and K-RAS expression is identified in K-RAS-overexpressing models and CRC.
  • Altered BGN expression impacts tumor growth, immunogenicity, and patient outcomes in CRC.
  • Reversion of BGN represents a potential therapeutic strategy for K-RAS-driven cancers.
Keywords:
Immune escapeK-RASMHC class Icolorectal carcinomaextracellular matrix proteinoncogeneproteoglycan

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