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

Karthikeyan Subbarayan, Chiara Massa, Sandra Leisz, André Steven, Daniel Bethmann, Katharina Biehl, Claudia Wickenhauser, Barbara Seliger

Oncoimmunology 2022

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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 BGNlow/BGNhigh K-RASG12V-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 BGNlow K-RAS-expressing cells resulted in a reduced growth and migration of BGNhigh vs BGNlow 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 BGNlow vs. BGNhigh K-RAS models. Furthermore, a reduced tumor formation of BGNhigh versus BGNlow 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. © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

Citation

Karthikeyan Subbarayan, Chiara Massa, Sandra Leisz, André Steven, Daniel Bethmann, Katharina Biehl, Claudia Wickenhauser, Barbara Seliger. Biglycan as a potential regulator of tumorgenicity and immunogenicity in K-RAS-transformed cells. Oncoimmunology. 2022;11(1):2069214