Journal
ONCOIMMUNOLOGY
Volume 11, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2022.2069214
Keywords
Immune escape; oncogene; K-RAS; colorectal carcinoma; proteoglycan; MHC class I; extracellular matrix protein
Categories
Funding
- Wilhelm Sander-Stiftung [2019.076.1]
- DFG (Deutsche Forschungsgemeinschaft) [Se581/34-1]
- Deutsche Krebshilfe
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The extracellular matrix component biglycan (BGN) is reduced in K-RAS-associated malignancies, leading to altered growth properties, reduced immunogenicity, and worse patients' outcome.
The extracellular matrix component biglycan (BGN) plays an essential role in various physiological and pathophysiological processes. A deficient BGN expression associated with reduced immunogenicity was found in HER-2/neu-overexpressing cells. To determine whether BGN is suppressed by oncogene-driven regulatory networks, the expression and function of BGN was analyzed in murine and human BGN(low)/BGN(high) K-RAS(G12V)-transformed model systems as well as in different patients' datasets of colorectal carcinoma (CRC) lesions. K-RAS-mutated CRC tissues expressed low BGN mRNA and protein levels when compared to normal colon epithelial cells, which was associated with a reduced patients' survival. Transfection of BGN in murine and human BGN(low) K-RAS-expressing cells resulted in a reduced growth and migration of BGN(high) vs BGN(low) K-RAS cells. In addition, increased MHC class I surface antigens as a consequence of an enhanced antigen processing machinery component expression was found upon restoration of BGN, which was confirmed by RNA-sequencing of BGN(low) vs. BGN(high) K-RAS models. Furthermore, a reduced tumor formation of BGN(high) versus BGN(low) K-RAS-transformed fibroblasts associated with an enhanced MHC class I expression and an increased frequency of tumor-infiltrating lymphocytes in tumor lesions was found. Our data provide for the first time an inverse link between BGN and K-RAS expression in murine and human K-RAS-overexpressing models and CRC lesions associated with altered growth properties, reduced immunogenicity and worse patients' outcome. Therefore, reversion of BGN might be a novel therapeutic option for K-RAS-associated malignancies.
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