Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) resulting from the hereditary loss of the von Hippel-Lindau (VHL) tumor suppressor gene is the leading cause of death in VHL patients due to the deleterious effects of the metastatic tumor(s). VHL functions in the destruction of the alpha subunits of the heterodimeric transcription factor, hypoxia-inducible factor (HIF-1a and HIF-2a), in normoxic conditions. When VHL function is lost, HIF-a protein is stabilized, and target hypoxia-inducible genes are transcribed. The process of tumor invasion and metastasis involves the destruction of the extracellular matrix, which is accomplished primarily by the matrix metalloproteinase (MMP) family of enzymes. Here, we describe a connection between the loss of VHL tumor suppressor function and the upregulation of membrane type-1 MMP (MT1-MMP) gene expression and protein. Specifically, MT1-MMP is upregulated in VHLÀ/À RCC cells through an increase in gene transcription, which is mediated by the cooperative effects of the transcription factors, HIF-2 and Sp1. Further, we identify a functional HIF-binding site in the proximal promoter of MT1-MMP. To our knowledge, this is the first report to show direct regulation of MT1-MMP by HIF-2 and to provide a direct link between the loss of VHL tumor suppressor function and an increase in MMP gene and protein expression.

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

“…A study in renal carcinoma cells deficient in the tumor suppressor von Hippel Lindau (VHL) protein and expressing high levels of endogenous HIF-2a showed induction of MT1-MMP expression at the transcriptional level (Petrella et al, 2005). Moreover, two putative HIF-binding sites have been found in the MT1-MMP promoter.…”

Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction

“…In contrast to HIF-2α-induced modulation of MMP1, MMP3, MMP9, MMP12, MMP13 and ADAMTS4, promoter activity and expression of MMP2, MMP14, MMP15 and ADAMTS5 were not affected by HIF-2α, despite the existence of HIF-2α binding sites. The features of the 5′-flanking regions of MMP2, MMP14 and MMP15 are distinct from those of other MMPs, including the absence of a TATA box and the 12-O-tetradecanoylphorbol-13-acetate response element (TRE) sequence and the presence of Sp1 binding sites [35][36][37][38] . The promoter structure of ADAMTS4 also differs from that of ADAMTS5, with a high frequency of interferon regulatory factor binding sites in ADAMTS5 (ref.…”

Membrane-Type I Matrix Metalloproteinase-Dependent Regulation of Rheumatoid Arthritis Synoviocyte Function

“…Given the multiplicity of cytokines, growth factors, matrix degradation products, and lipid mediators found within the proinflammatory environment that characterizes RA (1-4), it will likely prove difficult to identify a dominant MT1-MMP regulator (50). Indeed less "classical" inflammatory mediators such as hypoxia, HIF-2b, Wnt family members, or epigenetic changes in DNA methylation may well serve as dominant players in the control of MT1-MMP expression or activity in RA (64)(65)(66)(67)(68)(69). Nevertheless, given the expression of MT1-MMP within RA synoviocytes at sites of tissue damage in vivo, its pathophysiologically relevant functional properties, and the recent development of MT1-MMP-specific inhibitors (70), the proteinase could serve as an important target for therapeutic intervention.…”