Background PRELP (proline arginine-rich end leucine-rich repeat protein; also Prolargin), a small leucine-rich proteoglycan, functions as a molecule anchoring basement membranes to connective tissues via the interaction with collagens and heparin. PRELP facilitates the binding of cells to glycosaminoglycans as an important regulator of cell adhesion and thus displays pathophysiological features. Melanoma is an immunogenic tumor, whose relationship with immune cells resident in the microenvironment significantly influences cancer cell proliferation, progression and metastasis. Evasion from immune surveillance is a hallmark of melanoma progression. While our laboratory reported that the proteoglycan biglycan (BGN) was enhancing MHC class I in tumor cells,1 the role of PRELP in tumor immunology has not been studied.
Methods The murine metastatic melanoma cell line B16F10, characterized by a reduced expression of MHC class I surface antigens was chosen for this study. B16F10 cells were transiently transfected with PRELP as well as co-transfected with BGN. Expression of antigen processing machinery (APM) components and PRELP was determined by qPCR and MHC class I surface expression by flow cytometry. Promoter activity of APM components was analysed by luciferase reporter assays. XTT assays were used to determine cell proliferation. The association of PRELP and MHC class I was studied by bioinformatics in a mixed melanoma dataset of 83 samples.2
Results Over-expression of PRELP in B16F10 cells enhanced the expression of MHC class I surface antigens, which was due to a PRELP-mediated transcriptional upregulation of components of the MHC class I APM components TAP1, TAP2 and TAPBP as determined by qPCR and promoter assay in PRELP transfectants versus mock controls. Furthermore, MHC class I surface expression was even more pronounced upon BGN co-transfection with PRELP. PRELP overexpression was able to inhibit the proliferation of the B16F10 cells. Bioinformatics analyses demonstrated a positive correlation of PRELP with HLA-A , -B and -C alleles in human melanoma.
Conclusions Our findings demonstrated that overexpression of PRELP correlates with higher MHC class I expression and inhibits cell proliferation. For the first time, co-transfections of the two proteoglycans PRELP and BGN had a synergistic effect on upregulating MHC class I expression. Therefore, PRELP can serve as a novel therapeutic strategy that deserves further investigation.
Acknowledgements The project is supported by Wilhelm-Sander-Stiftung (No: 2019.076.1) and by a Roux grant (FKZ: PK37) of the Medical Faculty of the Martin-Luther-University Halle-Wittenberg.
Subbarayan K, Leisz S, Wickenhauser C, Bethmann D, Massa C, Steven A, Seliger B. Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells. Oncoimmunology 2018;7:e1373233.
Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP, Wagner SN, Ramaswamy S, Mesirov JP, Hynes RO. Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Molecular Cancer Research 2008;6:760-769.
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