Genomes and Genes
Gene Symbol: Mmp13
Description: matrix metallopeptidase 13
Alias: Clg, MMP-13, Mmp1, collagenase 3, collagenase-1, interstitial collagenase, matrix metalloproteinase 13
- Yamagata K, Li X, Ikegaki S, Oneyama C, Okada M, Nishita M, et al. Dissection of Wnt5a-Ror2 signaling leading to matrix metalloproteinase (MMP-13) expression. J Biol Chem. 2012;287:1588-99 pubmed publisher..Moreover, we provide evidence suggesting that Wnt5a-Ror2 signaling might also be required for expression of MMP-13 gene during the development of the cartilaginous tissue. ..
- Tarin C, Gomez M, Calvo E, Lopez J, Zaragoza C. Endothelial nitric oxide deficiency reduces MMP-13-mediated cleavage of ICAM-1 in vascular endothelium: a role in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29:27-32 pubmed publisher..Taking together, these results point toward MMP-13 as a mechanism for the NO-mediated protection of atherosclerosis. ..
- Casey L, Lan Y, Cho E, Maltby K, Gridley T, Jiang R. Jag2-Notch1 signaling regulates oral epithelial differentiation and palate development. Dev Dyn. 2006;235:1830-44 pubmed
- Deguchi J, Aikawa E, Libby P, Vachon J, Inada M, Krane S, et al. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation. 2005;112:2708-15 pubmed..These data support the hypothesis that MMP-13/collagenase-3 plays a vital role in the regulation and organization of collagen in atherosclerotic plaques. ..
- Ortega N, Behonick D, Colnot C, Cooper D, Werb Z. Galectin-3 is a downstream regulator of matrix metalloproteinase-9 function during endochondral bone formation. Mol Biol Cell. 2005;16:3028-39 pubmed..Thus, the disruption of growth plate homeostasis in Mmp-9 null mice links galectin-3 and MMP-9 in the regulation of the clearance of late chondrocytes through regulation of their terminal differentiation. ..
- Inada M, Yasui T, Nomura S, Miyake S, Deguchi K, Himeno M, et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn. 1999;214:279-90 pubmed..However, osteopontin, bone sialoprotein, and collagenase 3 were not expressed at all, indicating that they are directly regulated by Cbfa1 in the terminal hypertrophic ..
- Ferguson C, Alpern E, Miclau T, Helms J. Does adult fracture repair recapitulate embryonic skeletal formation?. Mech Dev. 1999;87:57-66 pubmed..matrix remodeling and vascular invasion including vascular endothelial growth factor (VEGF) and matrix metalloproteinase 13 (mmp13)...
- Wu N, Opalenik S, Liu J, Jansen E, Giro M, Davidson J. Real-time visualization of MMP-13 promoter activity in transgenic mice. Matrix Biol. 2002;21:149-61 pubmed..These results suggested that MMP-13 participated in the wound healing of acute wounds, and it was a significant factor in long-term remodeling of wound connective tissue in rodent skin. ..
- Behonick D, Xing Z, Lieu S, Buckley J, Lotz J, Marcucio R, et al. Role of matrix metalloproteinase 13 in both endochondral and intramembranous ossification during skeletal regeneration. PLoS ONE. 2007;2:e1150 pubmedExtracellular matrix (ECM) remodeling is important during bone development and repair. Because matrix metalloproteinase 13 (MMP13, collagenase-3) plays a role in long bone development, we have examined its role during adult skeletal ..
- Zigrino P, Kuhn I, Bauerle T, Zamek J, Fox J, Neumann S, et al. Stromal expression of MMP-13 is required for melanoma invasion and metastasis. J Invest Dermatol. 2009;129:2686-93 pubmed publisher..These data suggest an important role of MMP-13 in tumor growth and an unexpected role in organ-specific metastasis of melanoma cells. ..
- Fallowfield J, Mizuno M, Kendall T, Constandinou C, Benyon R, Duffield J, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178:5288-95 pubmed..SAMs are the source of matrix metalloproteinase (MMP) 13 (collagenase 3), considered to be the primary interstitial collagenase in rodents...
- Jimenez M, Balbin M, Lopez J, Alvarez J, Komori T, Lopez Otin C. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol Cell Biol. 1999;19:4431-42 pubmedb>Collagenase 3 (MMP-13) is a recently identified member of the matrix metalloproteinase (MMP) gene family that is expressed at high levels in diverse human carcinomas and in articular cartilage from arthritic patients...
- Tu X, Joeng K, Nakayama K, Nakayama K, Rajagopal J, Carroll T, et al. Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell. 2007;12:113-27 pubmed..Together, these results reveal a Wnt-dependent osteogenic mechanism, and they provide a potential target pathway for designing therapeutics to promote bone formation. ..
- Lederle W, Hartenstein B, Meides A, Kunzelmann H, Werb Z, Angel P, et al. MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma. Carcinogenesis. 2010;31:1175-84 pubmed publisherMatrix metalloproteinases (MMPs) such as MMP13 promote tumour growth and progression by mediating extracellular matrix (ECM) reorganization and regulating the biological activity of cytokines...
- Little C, Barai A, Burkhardt D, Smith S, Fosang A, Werb Z, et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 2009;60:3723-33 pubmed publisherTo investigate the role of matrix metalloproteinase 13 (MMP-13; collagenase 3) in osteoarthritis (OA).
- Jin J, Tan M, Warner D, Darling D, Higashi Y, Gridley T, et al. Mesenchymal cell remodeling during mouse secondary palate reorientation. Dev Dyn. 2010;239:2110-7 pubmed publisher..Because palate elevation represents a classic example of embryonic tissue re-orientation, our findings here may also shed light on the process of tissue re-orientation in general. ..
- Lafleur M, Drew A, de Sousa E, Blick T, Bills M, Walker E, et al. Upregulation of matrix metalloproteinases (MMPs) in breast cancer xenografts: a major induction of stromal MMP-13. Int J Cancer. 2005;114:544-54 pubmed..These xenografts are a valuable means for examining in vivo production of MMPs and suggest that MMP-13 and MT1-MMP will be relevant targets for inhibiting breast cancer progression. ..
- Zhou Z, Apte S, Soininen R, Cao R, Baaklini G, Rauser R, et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci U S A. 2000;97:4052-7 pubmed..In tissues from null mice, activation of latent matrix metalloproteinase 2 was deficient, suggesting that MT1-MMP is essential for its activation in vivo. ..
- Hartenstein B, Dittrich B, Stickens D, Heyer B, Vu T, Teurich S, et al. Epidermal development and wound healing in matrix metalloproteinase 13-deficient mice. J Invest Dermatol. 2006;126:486-96 pubmed..Here, we employed mmp13 knockout mice to elucidate the function of MMP13 in embryonic skin development, skin homeostasis, and cutaneous ..
- Koziel L, Kunath M, Kelly O, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004;6:801-13 pubmed..Finally, we propose that the development of exostoses in the human Hereditary Multiple Exostoses syndrome can be attributed to activation of Ihh signaling...
- Westermarck J, Kahari V. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999;13:781-92 pubmed
- Yang C, Hsieh H, Yao C, Hsiao L, Tseng C, Wu C. Protein kinase C-delta transactivates platelet-derived growth factor receptor-alpha in mechanical strain-induced collagenase 3 (matrix metalloproteinase-13) expression by osteoblast-like cells. J Biol Chem. 2009;284:26040-50 pubmed publisherMatrix metalloproteinase-13 (MMP-13, or collagenase 3) has been shown to degrade intact collagen and to participate in situations where rapid and effective remodeling of collagenous ECM is required...
- Morris Wiman J, Du Y, Brinkley L. Occurrence and temporal variation in matrix metalloproteinases and their inhibitors during murine secondary palatal morphogenesis. J Craniofac Genet Dev Biol. 1999;19:201-12 pubmed..The results of this study demonstrate that MMPs 2, 3, 7, 9 and 13 and TIMPs 1 and 2 and their messages are present during the course of palatal shelf remodelling and that their expression is temporally regulated. ..
- Lecomte J, Louis K, Detry B, Blacher S, Lambert V, Bekaert S, et al. Bone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization. Cell Mol Life Sci. 2011;68:677-86 pubmed publisherIn this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the ..
- Chin J, Werb Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. Development. 1997;124:1519-30 pubmed..Our data suggest that matrix metalloproteinases play a pivotal role in the morphogenesis of structures derived from epithelium (oral sulcus), cranial paraxial mesoderm (tongue) and cranial neural crest (Meckel's cartilage). ..
- Gack S, Vallon R, Schmidt J, Grigoriadis A, Tuckermann J, Schenkel J, et al. Expression of interstitial collagenase during skeletal development of the mouse is restricted to osteoblast-like cells and hypertrophic chondrocytes. Cell Growth Differ. 1995;6:759-67 pubmedWe determined the expression pattern of the matrix metalloproteinase interstitial collagenase (MMP-1) during mouse embryo development using in situ hybridization and immunohistochemistry. Localized MMP-1 mRNA was first detected at 14...
- Blackburn J, Rhodes C, Coon C, Brinckerhoff C. RNA interference inhibition of matrix metalloproteinase-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis. Cancer Res. 2007;67:10849-58 pubmed..ERK signaling drives the production of the interstitial collagenase matrix metalloproteinase-1 (MMP-1), which is expressed specifically by invasive melanomas...
- Madlener M, Parks W, Werner S. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res. 1998;242:201-10 pubmed..These observations imply an additional role of macrophage-related proteolysis, independent of its classical roles during earlier, inflammatory phases of cutaneous wound repair...
- Fukuda H, Mochizuki S, Abe H, Okano H, Hara Miyauchi C, Okano H, et al. Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production. Br J Cancer. 2011;105:1615-24 pubmed publisher..Our results suggest that MMP-13 is overproduced by endothelial cells in the lungs with melanoma cells and has a protective role in lung metastasis by local generation of endostatin. ..
- Colnot C, Helms J. A molecular analysis of matrix remodeling and angiogenesis during long bone development. Mech Dev. 2001;100:245-50 pubmed..Here, we have produced a 'molecular map' of the initial vascularization of the developing skeleton that provides a framework in which to interpret a wide range of fetal skeletal malformations, disruptions, and dysplasias. ..
- Green K, Almholt K, Ploug M, Rønø B, Castellino F, Johnsen M, et al. Profibrinolytic effects of metalloproteinases during skin wound healing in the absence of plasminogen. J Invest Dermatol. 2008;128:2092-101 pubmed publisher..Furthermore, these in vivo data reveal that galardin-sensitive metalloproteinases mediate compensatory fibrinolysis to facilitate wound healing in the absence of plasmin. ..
- Colnot C, Lu C, Hu D, Helms J. Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev Biol. 2004;269:55-69 pubmed..Collectively, these studies clarify further the contributions of the cartilage, perichondrium, and vascular endothelium to long bone development. ..
- Shukla A, Barrett T, Nakayama K, Nakayama K, Mossman B, Lounsbury K. Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung. FASEB J. 2006;20:997-9 pubmed..Asbestos-exposed PKCdelta knockout (PKCdelta-/-) mice exhibited decreased expression of lung MMP12 and MMP13 compared with asbestos-exposed wild-type mice...
- Balbin M, Fueyo A, Knauper V, Lopez J, Alvarez J, Sanchez L, et al. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J Biol Chem. 2001;276:10253-62 pubmed..been largely based on the repeatedly unproductive attempts to detect the presence in murine tissues of interstitial collagenase (MMP-1), a major collagenase in many species, including humans...
- López Rivera E, Lizarbe T, Martínez Moreno M, Lopez Novoa J, Rodriguez Barbero A, Rodrigo J, et al. Matrix metalloproteinase 13 mediates nitric oxide activation of endothelial cell migration. Proc Natl Acad Sci U S A. 2005;102:3685-90 pubmed..Stimulation with NO disrupted this complex and significantly increased extracellular MMP-13 abundance, leading to collagen breakdown. Our findings show that MMP-13 is an important effector of NO-activated endothelial migration. ..
- Inada M, Wang Y, Byrne M, Rahman M, Miyaura C, Lopez Otin C, et al. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci U S A. 2004;101:17192-7 pubmedCollagenase-3 (MMP13), a member of the matrix metalloproteinase (MMP) family of neutral endopeptidases, is expressed in the skeleton during embryonic development and is highly overexpressed in human carcinomas and in chondrocytes and ..
- Stickens D, Behonick D, Ortega N, Heyer B, Hartenstein B, Yu Y, et al. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development. 2004;131:5883-95 pubmed..Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal ..
- Gkantidis N, Katsaros C, Chiquet M. Detection of gelatinolytic activity in developing basement membranes of the mouse embryo head by combining sensitive in situ zymography with immunolabeling. Histochem Cell Biol. 2012;138:557-71 pubmed publisher..relationship in situ between gelatinolytic activity and immunostaining for gelatinases MMP-2 and MMP-9, collagenase 3 (MMP-13) and MT1-MMP (MMP-14), a major activator of pro-gelatinases...
- Otero M, Plumb D, Tsuchimochi K, Dragomir C, Hashimoto K, Peng H, et al. E74-like factor 3 (ELF3) impacts on matrix metalloproteinase 13 (MMP13) transcriptional control in articular chondrocytes under proinflammatory stress. J Biol Chem. 2012;287:3559-72 pubmed publisher..The proximal MMP13 promoter contains evolutionarily conserved E26 transformation-specific sequence binding sites that are closely ..
- Chan Y, Roy S, Huang Y, Khanna S, Sen C. The microRNA miR-199a-5p down-regulation switches on wound angiogenesis by derepressing the v-ets erythroblastosis virus E26 oncogene homolog 1-matrix metalloproteinase-1 pathway. J Biol Chem. 2012;287:41032-43 pubmed publisher..Thus, down-regulation of miR-199a-5p is involved in the induction of wound angiogenesis through derepressing of the Ets-1-MMP1 pathway.
- Selvamurugan N, Shimizu E, Lee M, Liu T, Li H, Partridge N. Identification and characterization of Runx2 phosphorylation sites involved in matrix metalloproteinase-13 promoter activation. FEBS Lett. 2009;583:1141-6 pubmed publisher..Thus, we have identified the Runx2 phosphorylation sites necessary for PKA stimulated MMP-13 promoter activation and this event may be critical for bone remodeling. ..
- Hosaka Y, Saito T, Sugita S, Hikata T, Kobayashi H, Fukai A, et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci U S A. 2013;110:1875-80 pubmed publisher..The RBPj?-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA. ..
- Yong V, Krekoski C, Forsyth P, Bell R, Edwards D. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 1998;21:75-80 pubmed..Therefore, both the identity of the MMP and its cellular origin could determine whether disease pathogenesis or regeneration occurs, and thus synthetic MMP inhibitors might be valuable for treating some CNS diseases. ..
- Bedair H, Liu T, Kaar J, Badlani S, Russell A, Li Y, et al. Matrix metalloproteinase-1 therapy improves muscle healing. J Appl Physiol (1985). 2007;102:2338-45 pubmed..01). These results suggest that the direct injection of MMP-1 into the zone of injury during fibrosis can enhance muscle regeneration by increasing the number of myofibers and decreasing the amount of fibrous tissue. ..
- Vandenbroucke R, Dejonckheere E, Van Hauwermeiren F, Lodens S, De Rycke R, Van Wonterghem E, et al. Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF. EMBO Mol Med. 2013;5:1000-16 pubmed publisher..Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases...
- Gkantidis N, Blumer S, Katsaros C, Graf D, Chiquet M. Site-specific expression of gelatinolytic activity during morphogenesis of the secondary palate in the mouse embryo. PLoS ONE. 2012;7:e47762 pubmed publisher..Mmp2 and Mmp14 (MT1-MMP), but not Mmp9 and Mmp13, mRNAs were expressed in the mesenchyme around the epithelial folds of the elevated palatal shelves; this was ..
- Aizawa R, Yamada A, Suzuki D, Iimura T, Kassai H, Harada T, et al. Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development. Mech Dev. 2012;129:38-50 pubmed publisher..In situ hybridization analysis revealed that expressions of Col10 and Mmp13 were reduced in non-resorbed hypertrophic cartilage, indicating that deletion of Cdc42 inhibited their terminal ..
- Holm E, Aubin J, Hunter G, Beier F, Goldberg H. Loss of bone sialoprotein leads to impaired endochondral bone development and mineralization. Bone. 2015;71:145-54 pubmed publisher..These results suggest that BSP is an important and multifaceted protein that regulates both chondrocyte proliferation and apoptosis as well as transition from cartilage to bone during development of endochondral bone. ..
- Zieba J, Forlenza K, Khatra J, Sarukhanov A, Durán I, Rigueur D, et al. TGF? and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions. PLoS Genet. 2016;12:e1005936 pubmed publisher..Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. ..
- Kapila S, Park Y, Ahmad N, Hosomichi J, Hayami T, Tacon C. Mechanisms for relaxin's modulation of MMPs and matrix loss in fibrocartilages. Ital J Anat Embryol. 2013;118:62-5 pubmed
- Deng Y, Wu A, Li P, Li G, Qin L, Song H, et al. Yap1 Regulates Multiple Steps of Chondrocyte Differentiation during Skeletal Development and Bone Repair. Cell Rep. 2016;14:2224-2237 pubmed publisher..Taken together, our work provides insights into the mechanism by which Yap1 regulates endochondral ossification, which may help the development of therapeutic treatment for bone regeneration. ..
- Ionescu A, Kozhemyakina E, Nicolae C, Kaestner K, Olsen B, Lassar A. FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program. Dev Cell. 2012;22:927-39 pubmed publisher..addition, exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates...
- Sounni N, Dehne K, van Kempen L, Egeblad M, Affara N, Cuevas I, et al. Stromal regulation of vessel stability by MMP14 and TGFbeta. Dis Model Mech. 2010;3:317-32 pubmed publisher..Antagonists of this pathway could be therapeutically exploited to improve the delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery. ..
- Takarada T, Yoneda Y. Transactivation by Runt related factor-2 of matrix metalloproteinase-13 in astrocytes. Neurosci Lett. 2009;451:99-104 pubmed publisher..protein core binding factor-beta and their targets such as osteopontin (OPN) and matrix metalloproteinase-13 (MMP13), but not for collagen-I or osteocalcin...
- Kim B, Abdel Rahman M, Wang T, Pouly S, Mahmoud A, Cebulla C. Retinal MMP-12, MMP-13, TIMP-1, and TIMP-2 expression in murine experimental retinal detachment. Invest Ophthalmol Vis Sci. 2014;55:2031-40 pubmed publisher..Immunohistochemistry revealed moderate to strong MMP-13 levels in subretinal space macrophages. Fibrosis can develop in the HA-RD model. There is an upregulation of select MMPs that may modulate the wound healing process following RD. ..
- Koenig G, Rowe R, Day S, Sabeh F, Atkinson J, Cooke K, et al. MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction. Am J Pathol. 2012;180:1863-78 pubmed publisher..This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction. ..
- Sasagawa S, Takemori H, Uebi T, Ikegami D, Hiramatsu K, Ikegawa S, et al. SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice. Development. 2012;139:1153-63 pubmed publisher..These results demonstrate an essential role for SIK3 in facilitating chondrocyte hypertrophy during skeletogenesis and growth plate maintenance. ..
- Randall L, Hall R. Temperospatial expression of matrix metalloproteinases 1, 2, 3, and 9 during early tooth development. Connect Tissue Res. 2002;43:205-11 pubmed..This study reports the temperospatial expression of MMPs 1, 2, 3, and 9 during early tooth development, and points to them having a key role during this important developmental period. ..
- Lane J, Yumoto K, Azhar M, Ninomiya Tsuji J, Inagaki M, Hu Y, et al. Tak1, Smad4 and Trim33 redundantly mediate TGF-Î²3 signaling during palate development. Dev Biol. 2015;398:231-41 pubmed publisher..Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for ..
- Kong W, Longaker M, Lorenz H. Cyclophilin C-associated protein is a mediator for fibronectin fragment-induced matrix metalloproteinase-13 expression. J Biol Chem. 2004;279:55334-40 pubmed..Our data are the first to demonstrate that deletion of CyC-AP can abolish fibronectin fragment-induced MMP-13 expression through an unknown mechanism. CyC-AP is an important factor for the regulation of MMP-13 expression. ..
- Goto H, Ishihara Y, Kikuchi T, Izawa A, Ozeki N, Okabe E, et al. Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression. PLoS ONE. 2015;10:e0140942 pubmed publisher..Polymerase chain reaction array analysis demonstrated a ~5-fold increase in matrix metalloproteinase 13 (MMP-13) mRNA expression of IL-1Ra siRNA-transfected Ca9-22 human oral squamous epithelial carcinoma ..