vogel, lotte – University of Copenhagen

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Department of Cellular and Molecular Medicine > icmm-staff > vogel, lotte

Lotte Katrine Vogel

associate professor

e-mail: vogel@sund.ku.dk
telephone: (+45) 35 33 55 52
mobile: (+45) 30 56 43 96 
room: 33.5.30

Research
Is a cure for cancer within reach?

Research in mice has shown that over-expression of the serine protease, matriptase, single-handed causes tumors with high efficiency [1]. Matriptase is located on the basolateral plasma membrane of all epithelial cells [2,3] and all epithelial cell derived cancers [4], and catalyzes the conversion of signal molecules, leading to the activation of signal transduction pathways [5,6]. Matriptase is kept under strict control by HAI-1 and HAI-2 under normal conditions [7,8]. In contrast, seventy percent of mice overexpressing matriptase in the skin developed squamous cell carcinomas, whereas mice overexpressing both matriptase and either HAI-1 [1] or HAI-2 [9]  had a malignant cancer incidence resembling wild type mice. Similar results were obtained from another mouse study, where the tumorigenicity and metastatic capability of human prostate cancer cells were studied [10]. It was shown that the expression of HAI-2 diminishes during prostate cancer progression and furthermore that the tumorigenicity and metastatic capability of the prostate cancer cells was reduced, when HAI-2 expression was increased [10]. Whereas, the way by which HAI-1 and HAI-2 control matriptase remains unclear, it clearly demonstrates that HAI-1 and HAI-2 are able to control the potent oncogenic potential of matriptase.

Even more importantly, mice with already established tumors, caused by up-regulation of the matriptase expression and application of a carcinogen to the skin, showed a markedly impaired malignant progression and regression of individual tumors upon the induction of HAI-2 expression [9]. This suggests that HAI-2 and possibly also HAI-1 may provide a way to cure cancer if supplied at the right time and place.  

Matriptase, prostasin (the non-enzymatic co-activator of matriptase [3]), HAI-1 and HAI-2 are all synthesized on the rough endoplasmic reticulum. Matriptase [11], prostasin [11] and HAI-1 [12] are transported along the secretory pathway to the plasma membrane [13], whereas HAI-2 is a resident endoplasmic reticulum-protein [14]. Based on this it is our hypothesis that the anti-oncogenic action of HAI-1 and HAI-2 takes place in the endoplasmic reticulum since this is the only subcellular localization shared between HAI-1 and HAI-2. Furthermore, based on the homology between HAI-1 and HAI-2 [15] and redundancy in functions [16,17], we also expect the anti-oncogenic feature to be shared by the two.  

The goal of the Vogel laboratory is to provide a basic understanding of the interplay between matriptase, prostasin, HAI-1 and HAI-2 in order to use this knowledge to design treatment(s) for cancer patients.

Reference List 

    1.    List K, Szabo R, Molinolo A, Sriuranpong V, Redeye V et al. (2005) Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev 19: 1934-1950. 19/16/1934 [pii];10.1101/gad.1300705 [doi].

    2.    List K, Szabo R, Molinolo A, Nielsen BS, Bugge TH (2006) Delineation of matriptase protein expression by enzymatic gene trapping suggests diverging roles in barrier function, hair formation, and squamous cell carcinogenesis. Am J Pathol 168: 1513-1525. S0002-9440(10)62174-8 [pii];10.2353/ajpath.2006.051071 [doi].

    3.    Friis S, Godiksen S, Bornholdt J, Selzer-Plon J, Rasmussen HB et al. (2011) Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase. J Biol Chem 286: 5793-5802. M110.186874 [pii];10.1074/jbc.M110.186874 [doi].

    4.    List K (2009) Matriptase: a culprit in cancer? Future Oncol 5: 97-104. 10.2217/14796694.5.1.97 [doi].

    5.    Szabo R, Rasmussen AL, Moyer AB, Kosa P, Schafer JM et al. (2011) c-Met-induced epithelial carcinogenesis is initiated by the serine protease matriptase. Oncogene 30: 2003-2016. onc2010586 [pii];10.1038/onc.2010.586 [doi].

    6.    Sales KU, Friis S, Konkel JE, Godiksen S, Hatakeyama M et al. (2014) Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis. Oncogene . onc2013563 [pii];10.1038/onc.2013.563 [doi].

    7.    Szabo R, Molinolo A, List K, Bugge TH (2007) Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development. Oncogene 26: 1546-1556. 1209966 [pii];10.1038/sj.onc.1209966 [doi].

    8.    Szabo R, Hobson JP, Christoph K, Kosa P, List K et al. (2009) Regulation of cell surface protease matriptase by HAI2 is essential for placental development, neural tube closure and embryonic survival in mice. Development 136: 2653-2663. 136/15/2653 [pii];10.1242/dev.038430 [doi].

    9.    Sales KU, Friis S, Abusleme L, Moutsopoulos NM, Bugge TH (2014) Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors. Oncogene 0. onc2014391 [pii];10.1038/onc.2014.391 [doi].

  10.    Tsai CH, Teng CH, Tu YT, Cheng TS, Wu SR et al. (2014) HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 33: 4643-4652. onc2013412 [pii];10.1038/onc.2013.412 [doi].

  11.    Friis S, Godiksen S, Bornholdt J, Selzer-Plon J, Rasmussen HB et al. (2011) Transport via the transcytotic pathway makes prostasin available as a substrate for matriptase. J Biol Chem 286: 5793-5802. M110.186874 [pii];10.1074/jbc.M110.186874 [doi].

  12.    Godiksen S, Selzer-Plon J, Pedersen EDK, Abell K, Rasmussen HB et al. (2008) Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary. Biochemical Journal 413: 251-259.

  13.    Godiksen S, Selzer-Plon J, Pedersen ED, Abell K, Rasmussen HB et al. (2008) Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary. Biochem J 413: 251-259. BJ20071496 [pii];10.1042/BJ20071496 [doi].

  14.    Larsen BR, Steffensen SD, Nielsen NV, Friis S, Godiksen S et al. (2013) Hepatocyte growth factor activator inhibitor-2 prevents shedding of matriptase. Exp Cell Res 319: 918-929. S0014-4827(13)00011-6 [pii];10.1016/j.yexcr.2013.01.008 [doi].

  15.    Szabo R, Hobson JP, List K, Molinolo A, Lin CY et al. (2008) Potent inhibition and global co-localization implicate the transmembrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity. J Biol Chem 283: 29495-29504. M801970200 [pii];10.1074/jbc.M801970200 [doi].

  16.    Szabo R, Molinolo A, List K, Bugge TH (2007) Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development. Oncogene 26: 1546-1556.

  17.    Larsen BR, Steffensen SD, Nielsen NV, Friis S, Godiksen S et al. (2013) Hepatocyte growth factor activator inhibitor-2 prevents shedding of matriptase. Exp Cell Res 319: 918-929. S0014-4827(13)00011-6 [pii];10.1016/j.yexcr.2013.01.008 [doi].