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An inflammation-promoting protein triggers deactivation of atumor-suppressor that usually blocks cancer formation via the NOTCH signaling pathway, a team of researchersled by scientists at The University of Texas MD Anderson CancerCenter reports today in Molecular Cell. Working in liver cancer cell lines, the team discovered a mechanism by which tumornecrosis factor alpha (TNF ) stimulates tumor formation, saidsenior author Mien-Chie Hung, Ph.D., professor and chair of MDAnderson's Department of Molecular and Cellular Oncology. Hung alsois MD Anderson's vice president for basic research. "We've discovered cross-talk between the TNF inflammation andNOTCH signaling pathways, which had been known to separatelypromote cancer development and growth," Hung said. Liver cancer isone of several cancers, including pancreatic and breast, associatedwith inflammation. Their findings have potential implications for a new class ofanti-cancer drugs currently in clinical trials. "Pharmaceuticalcompanies are developing NOTCH inhibitors," Hung said. "TNF nowpresents a potential resistance mechanism that activates NOTCHsignaling in a non-traditional way." Pathways also unite in colon, lung, prostate cancers "In addition, co-activation of these two pathways was also observedin colon, lung and prostate cancers, suggesting that the cross-talkbetween these two pathways may be more generally relevant," Hungsaid. However, TNF also presents an opportunity to personalize therapy,Hung said. The presence of TNF or a separate protein that itactivates called IKK alpha may serve as useful biomarkers to guidetreatment. "If a patient has only NOTCH activated, then the NOTCH inhibitoralone might work. But if TNF or IKK are also activated, thenthe NOTCH inhibitor alone might not work very well and combinationtherapy would be warranted," Hung said. "We'll try this in an animal model and then go to clinical trial ifit holds up," Hung said. A path from inflammation to liver cancer In a series of experiments, Hung and colleagues connected thefollowing molecular cascade: TNF , a proinflammatory cytokine, signals through a cell'smembrane, activating IKK , a protein kinase that regulates otherproteins by attaching phosphate groups (one phosphate atom, fouroxygen atoms) to them. IKK moves into the cell nucleus, where it phosphorylatesFOXA2, atranscription factor that normally fires up the tumor suppressorNUMB. NUMB usually blocks a protein called NICD, the activated portion ofNOTCH1 that slips into the cell nucleus to activate genes thatconvert the normal cell to a malignant one. But when FOXA2 is phosphorylated, it does not activate NUMB. WithNUMB disabled, NOTCH1 is activated. New understanding, new targetsfor cancer therapy In liver cancer (hepatocellular carcinoma) tumors, IKK , thephosphorylated version of FOXA2 and NOTCH1 are expressed moreheavily than in normal liver tissue. Expression of all three iscorrelated in liver cancer tumors, the team found. The authors conclude that identifying the link between TNF andNOTCH1 pathways provides a new starting point for understanding themolecular basis for TNF -related tumor growth and for identifyingnew targets for cancer therapy. Finding ways to inhibit FOXA2 phosphorylation or to activate NUMBwould provide new options for treating and perhaps preventingcancer, Hung said. Co-authors with Hung are first author Mo Liu, Dung-Fang Lee,Chun-Te Chen, Hong-Jen Lee, Chun-Ju Chang, Jung-Mao Hsu, Hsu-PingKuo, Weiya Xia, Yongkun Wei, Chao-Kai Chou, and Yi Du, all of MDAnderson's Department of Molecular and Cellular Oncology; Liu alsois a graduate student in The University of Texas Graduate School ofBiomedical Sciences at Houston, a joint program of MD Anderson andThe University of Texas Health Science Center at Houston; Chia-JuiYen, National Cheng Kung University College of Medicine, Tainan,Taiwan; Long-Yuan Li, Wei-Chao Chang and Pei-Chun Chiu of theGraduate Institute of Cancer Biology, China Medical University,Taichung, Taiwan; Debanjan Dhar and Michael Karin, Laboratory ofGene Regulation and Signal Transduction, University of California,San Diego; and Chung-Hsuan Chen, The Genomics Research Center,Academica Sinica, Taipei, Taiwan. Wei-Chao Chang also is associatedwith Academic Sinica. Funding for this research was provided by the National CancerInstitute, including MD Anderson's Cancer Center Support Grant fromthe NCI, National Science Council of Taiwan, Taiwan Department ofHealth; The MD Anderson-China Medical University and HospitalSister Institution Fund, the Kadoorie Charitable Foundation and aresearch assistant scholarship to Mo Liu by the University of TexasGraduate School of Biomedical Sciences at Houston. Additional References Citations. The e-commerce company in China offers quality products such as Polyester Staple Fiber Manufacturer , Ring Spun Yarn Manufacturer, and more. For more , please visit Hollow Polyester Staple Fiber today!
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