Matrix Metalloproteinases
Principal Investigator:
Professor Veli-Matti Kähäri, MD, PhD.
Address: Department of Dermatology, University of Turku, and Turku University Central Hospital, P.O.B 52, FI-20521 Turku. Tel: +358-2-3131600; fax:+358-2-3337229; e-mail:veli-matti.kahari@utu.fi
Research Group:
Risto Ala-Aho, PhD, post-doctoral fellow
Niina Hieta, MD, PhD, specialist in dermatology and allergology
Janne Kallio, MSc, graduate student
Atte Kivisaari, MD, graduate student, resident
Pilvi Tiilikka, MD, graduate student, resident
Mervi Toriseva, MSc, graduate student
Juho Joutsa, BM, MD/PhD student
Johanna Markola, project engineer
Sari Pitkänen, technician
Description of the Project:
The aim of the project is to elucidate the role and regulation of matrix metalloproteinases (MMPs) in tissue repair and fibrosis, and in tumor growth and invasion, especially in malignant melanoma and in non-melanoma skin cancer. Elucidation of the role of MMPs in the growth and invasion of cancer cells is likely to be feasible in development of diagnostic and prognostic indicators for progression of cutaneous cancer. Furthermore, understanding the mechanisms regulating proteolytic capacity of normal and malignant cells is also important in development of specific therapeutic modalities for preventing tumor growth and metastasis.
Selected Publications:
Ahonen M, Baker AH, Kähäri V-M. (1998) Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 58:2310-2315.
Ravanti L, Heino J, López-Otín C, Kähäri V-M. (1999) Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem 74:2446-2455.
Ravanti L, Häkkinen L, Larjava H, Saarialho-Kere U, Foschi M, Han J, Kähäri V-M (1999) Transforming growth factor-b induces collagenase-3 expression by human gingival fibroblasts via p38 mitogen-activated protein kinase. J Biol Chem 274:37292-37300.
Johansson N, Ala-aho R, Uitto V-J, Grénman R, Fusenig NE, López-Otín C, Kähäri V-M. (2000) Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci 113:227-235.
Ala-aho R, Johansson N, Grénman R, Fusenig NE, López-Otín C, Kähäri V-M. (2000) Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-g is associated with activation of extracellular signal-regulated kinase1,2 and STAT1. Oncogene 19:248-257.
Reunanen N, Foschi M, Han J, Kähäri V-M. (2000) Activation of extracellular signal-regulated kinase-1/2 inhibits type I collagen expression in human skin fibroblasts. J Biol Chem 275: 34634-34639
Westermarck J, Li S, Jaakkola P, Kallunki T, Grénman R, Kähäri V-M. (2000) Activation of fibroblast collagenase-1 expression by tumor cells of squamous cell carcinomas is mediated by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase-2. Cancer Res 60:7156-7162
Ravanti L, Toriseva M, Penttinen R, Crombleholme T, Foschi M, Han J, Kähäri V-M. Human collagenase-3 expression by fetal skin fibroblasts is induced by transforming growth factor-b via p38 mitogen-activated protein kinase. FASEB J 2001;15:1098-100.
Ala-aho R, Grénman R, Seth P, Kähäri V-M. (2002) Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. Oncogene 21:1187-95
Ahonen M, Ala-aho R, Baker AH, George SJ, Grénman R, Saarialho-Kere U, Kähäri V-M. (2002) Antitumor activity and by-stander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. Mol Ther 6: 705-715.
Reunanen N, Li S-P, Ahonen M, Foschi M, Han J, Kähäri V-M. (2002) Activation of p38a MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization. J Biol Chem 277:32360-8.
Leivonen S, Chantry A, Häkkinen L, Han J, Kähäri V-M. (2002) Smad3 mediates transforming growth factor-b-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts. Evidence for cross-talk between Smad3 and p38 signaling pathways. J Biol Chem 277:46338–46.
Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, Kähäri V-M. (2003) Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene 22:2121-34.
Hieta N, Impola U, López-Otín C, Saarialho-Kere U, Kähäri V-M. (2003) Matrix metalloproteinase-19 expression in cutaneous wound healing and in cultured dermal fibroblasts J Invest Dermatol 121:997-1004.
Ala-aho R, Ahonen M, George SJ, Heikkilä J, Grénman R, Kallajoki M, Kähäri V-M. (2004). Targeted inhibition of human collagenase-3 (MMP-13) expression by antisense ribozyme inhibits squamous cell carcinoma growth in vivo. Oncogene 23:5111-5123.
Leivonen S-K, Häkkinen L, Liu D, Kähäri V-M. (2005) Smad3 and extracellular signal- regulated kinase 1/2 coordinately mediate transforming growth factor-b-induced expression of connective tissue growth factor in human fibroblasts J Invest Dermatol 124:1162-1169
Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kähäri V-M, Pyrhönen S. (2005) High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11:5158-5166
Leivonen S-K, Ala-aho R, Koli K, Grénman R, Peltonen J, Kähäri V-M. (2006) Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 25:2588-2600
Toriseva MJ, Ala-aho R, Karvinen J, Baker AH, Marjomäki VS, Heino J, Kähäri V-M. (2007) Collagenase-3 (MMP-13) enhances remodeling of three-dimensional collagen and promotes survival of human skin fibroblasts. J Invest Dermatol 127:49-59.
Junttila MR, Ala-aho R, Jokilehto T, Peltonen J, Kallajoki M, Grénman R, Jaakkola P, Westermarck J, Kähäri V-M. (2007) p38a and p38d mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 26:5267-5279.
Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu S-L, Lin S, Chan EKL, Wang X-J, Grénman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J (2007) CIP2A inhibits PP2A in human malignancies. Cell 130: 51-62.
Kivisaari AK, Kallajoki M, Mirtti T, McGrath JA, Bauer JW, Weber F, Königová R, Sawamura D, Sato-Matsumura KC, Shimizu H,Csikós M, Sinemus K, Beckert W,and Kähäri V.-M. (2007) Transformation specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas. Brit J Derm 158:778-85.
International collaboration:
The group has several on-going international collaborations, which have resulted in joint publications. The group is a partner in EU FP6 Integrated project CANCERDEGRADOME funded for the period 2004-2008