c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase

Abstract

The progression and negative outcome of a variety of human carcinomas is intimately associated with aberrant activity of the c-Met oncogene. The underlying cause of this dysregulation, however, remains a subject of discussion, as the majority of cancer patients do not present with activating mutations in c-Met receptor itself. Here we show that the oncogenic protease matriptase is ubiquitously co-expressed with the c-Met in human squamous cell carcinomas and amplifies migratory and proliferative responses of primary epithelial cells to the cognate ligand for c-Met, proHGF/SF, through c-Met and Gab1 signaling. Furthermore, the selective genetic ablation of c-Met from matriptase-expressing keratinocytes completely negates the oncogenic potential of matriptase. In addition, matriptase-dependent carcinoma formation could be blocked by the pharmacologic inhibition of the Akt-mTor pathway. Our data identify matriptase as an initiator of c-Met-Akt-mTor-dependent signaling axis in tumors and reveal mTor activation as an essential component of matriptase/c-Met-induced carcinogenesis. The study provides a specific example of how epithelial transformation can be promoted by epigenetic acquisition of the capacity to convert a widely available paracrine growth factor precursor to its signaling competent state.

Imaging a functional tumorigenic biomarker in the transformed epithelium

“…The role that matriptase, which is expressed on the surface of cancerous epithelial cells, plays in cancer is unclear; however, matriptase has been shown to cleave a number of cancerpromoting substrates from growth factors to basement membrane proteins (8,9). In addition to adenocarcinomas, studies have implicated matriptase in the initiation of oncogenic activity in squamous cell carcinoma models (10). Matriptase is expressed in a range of normal human tissue types with high transcript levels found in the colon, rectum, and pancreas (11).…”

“…Matriptase is expressed in a range of normal human tissue types with high transcript levels found in the colon, rectum, and pancreas (11). In healthy tissue, matriptase is responsible for regulating barrier formation in the skin, intestines, and during embryonic development (10,12,13). The proteolytic activity of matriptase is closely regulated by its cognate macromolecular inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1) (8).…”

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

“…Three major macromolecular substrates of matriptase have been identified: hepatocyte growth factor, protease-activated receptor 2 (PAR-2), and urokinase-type plasminogen activator (6). Through the cleavage of these substrates, matriptase triggers specific responses, including cell proliferation, migration, inflammatory cytokine production, inflammatory cell recruitment, hyperplasia, and fibrosis (8,9). These responses are crucial in fibrotic diseases (10,11), but the role of matriptase in fibrotic disorders has thus far never been explored.…”

Coagulation signaling to epithelia

“…Calreticulin associates with the "eat me" signal phosphatidyl serine on the cell surface of apoptotic, but not viable, cells to promote internalization. 9 Although the mechanism by which calreticulin redistributes from ER to the plasma membrane is not known, it is plausible that KDEL-deficient calreticulin, as identified by Theocharides et al, would fail to reach the cell surface, thereby depriving the apoptotic neutrophil one of the determinants that drive its removal by macrophages, and leaving the uningested cell to undergo necrosis and promote inflammation. Such a scenario occurs in the setting of cyclin-dependent kinase deficiency, whereby apoptotic smooth muscle cells lack surface calreticulin and resist efferocytosis by local macrophages.…”

“…Tumorexpressed matriptase activation by coagulation proteases could contribute to facilitating the activation of pro-HGF, pro-uPA, and potentially other matriptase substrates alongside PAR2 and fibrin downstream of TF to promote tumor growth and dissemination. 9,10 Future investigations of PAR2 activation by the TF-dependent FVII/Xa/matriptase pathway are warranted in order to extend these findings to human pathology.…”