Ontology type: schema:ScholarlyArticle Open Access: True
2015-12-02
AUTHORSSergio Alonso, Beatriz González, Tatiana Ruiz-Larroya, Mercedes Durán Domínguez, Takaharu Kato, Akihiro Matsunaga, Koichi Suzuki, Alex Y. Strongin, Pepita Gimènez-Bonafé, Manuel Perucho
ABSTRACTBackgroundADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC). We explored the association of methylation with tumor genotype and phenotype.ResultsThe methylation status of the CpG island in the promoter of ADAMTS19 was determined in 252 colorectal, 65 pancreatic, 33 breast and 169 ovarian primary tumors, 70 CRC metastases, and 10 CRC cell lines. Tumor-specific methylation of ADAMTS19 was significantly more frequent in gastrointestinal than in gynecological cancers (odds ratio (OR) = 2.9, confidence interval (CI) = (1.9–4.7), p = 5.2 × 10−7) and was independent of the methylation of adjacent loci in CRC. Hypermethylation associated with CRC with mutated BRAF oncogene (OR = 10.1, CI = (3.1–42.9), p = 6.3 × 10−6) and with the mucinous phenotype in CRC (OR = 2.1, CI = (1.1–4.1), p = 0.023) and ovarian cancer (OR = 60, CI = (16–346), p = 4 × 10−16). Methylation was significantly more frequent in CRC metastases homing to the ovary and omentum than in those homing to the liver and lung (OR = 6.1, CI = (1.8–22.2), p = 0.001). Differentiating local from distant metastatic spread, methylation negatively associated with tumor progression (p = 0.031) but positively with depth of invasion (p = 0.030). Hypermethylation associated with transcriptional repression in CRC cell lines, and treatment with 5′-AZA-2′-deoxycytidine led to reactivation of mRNA expression. shRNA-mediated silencing of ADAMTS19 had no effect on the in vitro proliferation rate of CRC cells but significantly diminished their collective migration speed (56 %, p = 3.3 × 10−4) and potential to migrate in collagen I (64 %, p = 4.3 × 10−10).ConclusionsOur results highlight the frequent involvement of ADAMTS19 epigenetic silencing in CRC and mucinous ovarian cancer. The mechanistic preferences for the target organ of metastatic spread may lead to the development of diagnostic CRC biomarkers. The association with the mucinous phenotype also may have diagnostic applications for ovarian cancer. More... »
PAGES124
http://scigraph.springernature.com/pub.10.1186/s13148-015-0158-1
DOIhttp://dx.doi.org/10.1186/s13148-015-0158-1
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PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/26634009
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25 | ″ | schema:description | BackgroundADAMTS19 encodes a member of the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) protein family with emerging roles in carcinogenesis and metastasis. ADAMTS shares several distinct protein modules including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. In a previous work, we found ADAMTS19 frequently hypermethylated in colorectal cancer (CRC). We explored the association of methylation with tumor genotype and phenotype.ResultsThe methylation status of the CpG island in the promoter of ADAMTS19 was determined in 252 colorectal, 65 pancreatic, 33 breast and 169 ovarian primary tumors, 70 CRC metastases, and 10 CRC cell lines. Tumor-specific methylation of ADAMTS19 was significantly more frequent in gastrointestinal than in gynecological cancers (odds ratio (OR) = 2.9, confidence interval (CI) = (1.9–4.7), p = 5.2 × 10−7) and was independent of the methylation of adjacent loci in CRC. Hypermethylation associated with CRC with mutated BRAF oncogene (OR = 10.1, CI = (3.1–42.9), p = 6.3 × 10−6) and with the mucinous phenotype in CRC (OR = 2.1, CI = (1.1–4.1), p = 0.023) and ovarian cancer (OR = 60, CI = (16–346), p = 4 × 10−16). Methylation was significantly more frequent in CRC metastases homing to the ovary and omentum than in those homing to the liver and lung (OR = 6.1, CI = (1.8–22.2), p = 0.001). Differentiating local from distant metastatic spread, methylation negatively associated with tumor progression (p = 0.031) but positively with depth of invasion (p = 0.030). Hypermethylation associated with transcriptional repression in CRC cell lines, and treatment with 5′-AZA-2′-deoxycytidine led to reactivation of mRNA expression. shRNA-mediated silencing of ADAMTS19 had no effect on the in vitro proliferation rate of CRC cells but significantly diminished their collective migration speed (56 %, p = 3.3 × 10−4) and potential to migrate in collagen I (64 %, p = 4.3 × 10−10).ConclusionsOur results highlight the frequent involvement of ADAMTS19 epigenetic silencing in CRC and mucinous ovarian cancer. The mechanistic preferences for the target organ of metastatic spread may lead to the development of diagnostic CRC biomarkers. The association with the mucinous phenotype also may have diagnostic applications for ovarian cancer. |
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32 | ″ | schema:keywords | ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family |
33 | ″ | ″ | ADAMTS19 |
34 | ″ | ″ | BRAF oncogene |
35 | ″ | ″ | CRC biomarkers |
36 | ″ | ″ | CRC cell lines |
37 | ″ | ″ | CRC cells |
38 | ″ | ″ | CRC metastasis |
39 | ″ | ″ | ConclusionsOur results |
40 | ″ | ″ | CpG islands |
41 | ″ | ″ | adjacent loci |
42 | ″ | ″ | applications |
43 | ″ | ″ | association |
44 | ″ | ″ | association of methylation |
45 | ″ | ″ | biomarkers |
46 | ″ | ″ | breast |
47 | ″ | ″ | cancer |
48 | ″ | ″ | carcinogenesis |
49 | ″ | ″ | cell lines |
50 | ″ | ″ | cells |
51 | ″ | ″ | collagen I |
52 | ″ | ″ | colorectal |
53 | ″ | ″ | colorectal cancer |
54 | ″ | ″ | depth |
55 | ″ | ″ | depth of invasion |
56 | ″ | ″ | development |
57 | ″ | ″ | diagnostic applications |
58 | ″ | ″ | disintegrin-like domain |
59 | ″ | ″ | distant metastatic spread |
60 | ″ | ″ | distinct protein modules |
61 | ″ | ″ | domain |
62 | ″ | ″ | effect |
63 | ″ | ″ | epigenetic inactivation |
64 | ″ | ″ | epigenetic silencing |
65 | ″ | ″ | expression |
66 | ″ | ″ | family |
67 | ″ | ″ | frequent involvement |
68 | ″ | ″ | gastrointestinal |
69 | ″ | ″ | genes |
70 | ″ | ″ | genotypes |
71 | ″ | ″ | gynecological cancer |
72 | ″ | ″ | hypermethylation |
73 | ″ | ″ | inactivation |
74 | ″ | ″ | invasion |
75 | ″ | ″ | involvement |
76 | ″ | ″ | islands |
77 | ″ | ″ | lines |
78 | ″ | ″ | liver |
79 | ″ | ″ | loci |
80 | ″ | ″ | lung |
81 | ″ | ″ | mRNA expression |
82 | ″ | ″ | mechanistic preference |
83 | ″ | ″ | members |
84 | ″ | ″ | metalloproteinase domain |
85 | ″ | ″ | metastasis |
86 | ″ | ″ | metastatic spread |
87 | ″ | ″ | methylation |
88 | ″ | ″ | methylation status |
89 | ″ | ″ | migration speed |
90 | ″ | ″ | module |
91 | ″ | ″ | motif |
92 | ″ | ″ | mucinous ovarian cancer |
93 | ″ | ″ | mucinous phenotype |
94 | ″ | ″ | oncogene |
95 | ″ | ″ | organs |
96 | ″ | ″ | ovarian cancer |
97 | ″ | ″ | ovarian primary tumors |
98 | ″ | ″ | phenotype |
99 | ″ | ″ | potential |
100 | ″ | ″ | preferences |
101 | ″ | ″ | previous work |
102 | ″ | ″ | primary tumor |
103 | ″ | ″ | progression |
104 | ″ | ″ | proliferation rate |
105 | ″ | ″ | promoter |
106 | ″ | ″ | propeptide region |
107 | ″ | ″ | protein family |
108 | ″ | ″ | protein modules |
109 | ″ | ″ | rate |
110 | ″ | ″ | reactivation |
111 | ″ | ″ | region |
112 | ″ | ″ | repression |
113 | ″ | ″ | results |
114 | ″ | ″ | role |
115 | ″ | ″ | share |
116 | ″ | ″ | silencing |
117 | ″ | ″ | speed |
118 | ″ | ″ | spread |
119 | ″ | ″ | status |
120 | ″ | ″ | target organs |
121 | ″ | ″ | thrombospondin type 1 motif |
122 | ″ | ″ | transcriptional repression |
123 | ″ | ″ | treatment |
124 | ″ | ″ | tumor genotype |
125 | ″ | ″ | tumor progression |
126 | ″ | ″ | tumor-specific methylation |
127 | ″ | ″ | tumors |
128 | ″ | ″ | vitro proliferation rate |
129 | ″ | ″ | work |
130 | ″ | schema:name | Epigenetic inactivation of the extracellular matrix metallopeptidase ADAMTS19 gene and the metastatic spread in colorectal cancer |
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313 | ″ | schema:name | Institució Catalana de Recerca i Estudis Avançats (ICREA), Catalan Institution for Research and Advanced Studies. Pg. Lluís Companys 23, 08010, Barcelona, Spain |
314 | ″ | ″ | Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’investigació en ciéncies de la salut Germans Trias I Pujol, (IGTP), Campus Can Ruti, 08916, Badalona, Barcelona, Spain |
315 | ″ | ″ | Sanford Burnham Prebys Medical Dicovery Institute, 10901 N. Torrey Pines Rd. La Jolla, 92037, San Diego, CA, USA |
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318 | ″ | schema:name | Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Institut d’investigació en ciéncies de la salut Germans Trias I Pujol, (IGTP), Campus Can Ruti, 08916, Badalona, Barcelona, Spain |
319 | ″ | ″ | Sanford Burnham Prebys Medical Dicovery Institute, 10901 N. Torrey Pines Rd. La Jolla, 92037, San Diego, CA, USA |
320 | ″ | rdf:type | schema:Organization |
321 | grid-institutes:grid.5239.d | schema:alternateName | Cancer Genetics Laboratory, IBGM-CSIC, University of Valladolid, 47005, Valladolid, Spain |
322 | ″ | schema:name | Cancer Genetics Laboratory, IBGM-CSIC, University of Valladolid, 47005, Valladolid, Spain |
323 | ″ | rdf:type | schema:Organization |