PubMed:20857420 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/20857420","sourcedb":"PubMed","sourceid":"20857420","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/20857420","text":"Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells.\nDeep vein thrombosis associated with advanced cancer is known as Trousseau's syndrome. We hypothesized that thrombin, an activator of protease-activated receptor (PAR)-1 and PAR-4 contributes to tumor metastasis. In this study, we demonstrated that thrombin and the PAR-1 activating peptide (AP) SFLLRN, but not the PAR-4 AP GYPGKF, induced HIF-1α activities, protein expression, and cell motility in colorectal cancer cells, and these actions were significantly inhibited by the PAR-1 antagonist SCH79797. Moreover, thrombin-induced HIF-1α activity and cell motility were blocked by inhibiting important mediators of signaling transduction, including the ERK, PI3K, and mTOR pathways. These results showed that thrombin induced HIF-1α protein expression through PAR-1 and HIF-1α translational de novo protein synthesis. Twist can regulate epithelial-mesenchymal transition (EMT) and increase tumor metastasis. However, we observed that thrombin-induced HIF-1α increased Twist mRNA and its protein level was mediated by the modulation of PAR-1 activation and the HIF-1α translational pathway. In addition, Twist could increase N-cadherin but not E-cadherin to promote tumor metastasis. Overexpression of dominant-negative HIF-1α reversed thrombin-mediated Twist and Twist-induced N-cadherin expression. Moreover, siTwist inhibited Twist-induced N-cadherin and Thrombin-induced cell motility. In conclusion, our study showed that thrombin-induced HIF-1α upregulated Twist at the transcriptional level to enhance cell motility. These findings show that thrombin upregulates Twist via HIF-1α to make tumor cells malignant and also establish a link between the coagulation disorder and cancer metastasis.","tracks":[{"project":"sentences","denotations":[{"id":"TextSentencer_T1","span":{"begin":0,"end":140},"obj":"Sentence"},{"id":"TextSentencer_T2","span":{"begin":141,"end":227},"obj":"Sentence"},{"id":"TextSentencer_T3","span":{"begin":228,"end":353},"obj":"Sentence"},{"id":"TextSentencer_T4","span":{"begin":354,"end":647},"obj":"Sentence"},{"id":"TextSentencer_T5","span":{"begin":648,"end":826},"obj":"Sentence"},{"id":"TextSentencer_T6","span":{"begin":827,"end":961},"obj":"Sentence"},{"id":"TextSentencer_T7","span":{"begin":962,"end":1051},"obj":"Sentence"},{"id":"TextSentencer_T8","span":{"begin":1052,"end":1233},"obj":"Sentence"},{"id":"TextSentencer_T9","span":{"begin":1234,"end":1326},"obj":"Sentence"},{"id":"TextSentencer_T10","span":{"begin":1327,"end":1443},"obj":"Sentence"},{"id":"TextSentencer_T11","span":{"begin":1444,"end":1532},"obj":"Sentence"},{"id":"TextSentencer_T12","span":{"begin":1533,"end":1666},"obj":"Sentence"},{"id":"TextSentencer_T13","span":{"begin":1667,"end":1841},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":140},"obj":"Sentence"},{"id":"T2","span":{"begin":141,"end":227},"obj":"Sentence"},{"id":"T3","span":{"begin":228,"end":353},"obj":"Sentence"},{"id":"T4","span":{"begin":354,"end":647},"obj":"Sentence"},{"id":"T5","span":{"begin":648,"end":826},"obj":"Sentence"},{"id":"T6","span":{"begin":827,"end":961},"obj":"Sentence"},{"id":"T7","span":{"begin":962,"end":1051},"obj":"Sentence"},{"id":"T8","span":{"begin":1052,"end":1233},"obj":"Sentence"},{"id":"T9","span":{"begin":1234,"end":1326},"obj":"Sentence"},{"id":"T10","span":{"begin":1327,"end":1443},"obj":"Sentence"},{"id":"T11","span":{"begin":1444,"end":1532},"obj":"Sentence"},{"id":"T12","span":{"begin":1533,"end":1666},"obj":"Sentence"},{"id":"T13","span":{"begin":1667,"end":1841},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"TextSentencer_T1","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T2","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T3","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T4","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T5","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T6","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T7","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T8","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T9","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T10","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T11","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T12","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T13","pred":"source","obj":"sentences"},{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"},{"subj":"T9","pred":"source","obj":"sentences"},{"subj":"T10","pred":"source","obj":"sentences"},{"subj":"T11","pred":"source","obj":"sentences"},{"subj":"T12","pred":"source","obj":"sentences"},{"subj":"T13","pred":"source","obj":"sentences"}]},{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":1723,"end":1729},"obj":"gene:3091"},{"id":"T1","span":{"begin":1798,"end":1818},"obj":"disease:C0005779"},{"id":"T2","span":{"begin":1723,"end":1729},"obj":"gene:3091"},{"id":"T3","span":{"begin":1823,"end":1829},"obj":"disease:C0006826"},{"id":"T4","span":{"begin":1723,"end":1729},"obj":"gene:3091"},{"id":"T5","span":{"begin":1823,"end":1829},"obj":"disease:C1306459"},{"id":"T6","span":{"begin":1723,"end":1729},"obj":"gene:3091"},{"id":"T7","span":{"begin":1830,"end":1840},"obj":"disease:C0027627"},{"id":"T8","span":{"begin":1723,"end":1729},"obj":"gene:3091"},{"id":"T9","span":{"begin":1830,"end":1840},"obj":"disease:C2939420"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"},{"id":"R3","pred":"associated_with","subj":"T4","obj":"T5"},{"id":"R4","pred":"associated_with","subj":"T6","obj":"T7"},{"id":"R5","pred":"associated_with","subj":"T8","obj":"T9"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"},{"subj":"T4","pred":"source","obj":"DisGeNET"},{"subj":"T5","pred":"source","obj":"DisGeNET"},{"subj":"T6","pred":"source","obj":"DisGeNET"},{"subj":"T7","pred":"source","obj":"DisGeNET"},{"subj":"T8","pred":"source","obj":"DisGeNET"},{"subj":"T9","pred"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