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

Abstract

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.

Keywords: Immune escape; K-RAS; MHC class I; colorectal carcinoma; extracellular matrix protein; oncogene; proteoglycan.

Figure 1.

Increased correlation and clinical relevance of K-RAS and BGN expression in CRC lesions.

Figure 2.

Basal and restored BGN expression in CRC and K-RAS-transformed fibroblasts.

Figure 3.

BGN-mediated induction of MHC class I APM component expression in K-RAS model systems and altered NK cell responses.

Figure 3.

Continued.

Figure 4.

Distinct gene expression profiles of BGN^low vs. BGN^high K-RAS-overexpressing SW480 cells.

Figure 5.

Influence of BGN expression on the growth properties of K-RAS-transformed fibroblasts.

Figure 6.

Reduced in vivo tumor growth and enhanced immune cell infiltration of BGN^high compared to BGN^low K-RAS-transformed fibroblasts in immune competent mice.