Biglycan 作为 K-RAS 转化细胞中致瘤性和免疫原性的潜在调节因子

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.