Versican Promotes Tumor Progression, Metastasis and Predicts Poor Prognosis in Renal Carcinoma

Abstract

The proteoglycan versican (VCAN) promotes tumor progression and enhances metastasis in several cancers; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Recent evidence suggests that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC. Thus, we investigated whether VCAN expression is associated with the pathogenesis of ccRCC. VCAN expression was analyzed using three RCC and normal kidney cell lines as well as a clinical cohort of 84 matched ccRCC and normal renal tissues. Functional analyses on growth and progression properties were performed using VCAN depleted ccRCC cells. Microarray expression profiling was employed to investigate the target genes and biological pathways involved in VCAN-mediated ccRCC carcinogenesis. ccRCC had elevated VCAN expression in comparison with normal kidney in both cell lines and clinical specimens. The elevated expression of VCAN was significantly correlated with metastasis (P<0.001) and worse 5-year overall survival after radical nephrectomy (P=0.014). In vitro, VCAN knockdown significantly decreased cell proliferation and increased apoptosis in Caki-2 and 786-O cells, and this was associated with alteration of several TNF signaling-related genes such as TNF-α, BID, and BAK. Furthermore, VCAN depletion markedly decreased cell migration and invasion which correlated with reduction of MMP7 and CXCR4. These results demonstrate that VCAN promotes ccRCC tumorigenesis and metastasis and thus, is an attractive target for novel diagnostic, prognostic and therapeutic strategies.

Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis

“…Versican is a large CS proteoglycan and has the ability to modulate tumour progression in different Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 carcinomas including breast, gastric, renal, ovarian clear cell carcinoma and osteosarcoma [123][124][125][126][127].…”

Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages

“…A recent study demonstrated that macrophages co-cultured with versican deficient mesothelioma cells acquired a more pro-inflammatory phenotype with increased phagocytic activity 62 . Versican is an ECM component that is upregulated in cancers [63][64][65] , and it has been suggested to have immunosuppressive functions 66,67 . Other studies have identified the ECM component hyaluronan as being capable of stimulating TAMs to acquire an immunosuppressive M2like phenotype 68,69 .…”

VCAN gene expression and its association with tumor stage and lymph node metastasis in colorectal cancer patients

“…Studies on pancreatic cancer show the greatly increased in versican expression is associated with the malignancy of the tumor [10]. VCAN influences on metastatic phenotype in renal carcinoma [18] and human bladder cancer cell lines [19]. A study on VCAN protein indicates there is an associate between the protein levels with disease recurrence in CRC [11].…”