title: Cysteine-rich intestinal protein 2 (CRIP2) acts as a repressor of NF-kappaB-mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis.
abstract: Chromosome 14 was transferred into tumorigenic nasopharyngeal carcinoma and esophageal carcinoma cell lines by a microcell-mediated chromosome transfer approach. Functional complementation of defects present in the cancer cells suppressed tumor formation. A candidate tumor-suppressor gene, cysteine-rich intestinal protein 2 (CRIP2), located in the hot spot for chromosomal loss at 14q32.3, was identified as an important candidate gene capable of functionally suppressing tumor formation. Previous studies have shown that CRIP2 is associated with development. To date, no report has provided functional evidence supporting a role for CRIP2 in tumor development. The present study provides unequivocal evidence that CRIP2 can functionally suppress tumorigenesis. CRIP2 is significantly down-regulated in nasopharyngeal carcinoma cell lines and tumors. CRIP2 reexpression functionally suppresses in vivo tumorigenesis and angiogenesis; these effects are induced by its transcription-repressor capability. It interacts with the NF-κB/p65 to inhibit its DNA-binding ability to the promoter regions of the major proangiogenesis cytokines critical for tumor progression, including IL6, IL8, and VEGF. In conclusion, we provide compelling evidence that CRIP2 acts as a transcription repressor of the NF-κB-mediated proangiogenic cytokine expression and thus functionally inhibits tumor formation and angiogenesis.
authors.affiliation: Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Arthur Kwok Leung
authors.initials: AK
authors.lastname: Cheung
authors.forename: Josephine M Y
authors.initials: JM
authors.lastname: Ko
authors.forename: Hong Lok
authors.initials: HL
authors.lastname: Lung
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Stanbridge
authors.forename: Eugene
authors.initials: E
authors.lastname: Zabarovsky
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Lisa
authors.initials: L
authors.lastname: Kashima
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Dora Lai-Wan
authors.initials: DL
authors.lastname: Kwong
authors.forename: Daniel
authors.initials: D
authors.lastname: Chua
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Maria Li
authors.initials: ML
authors.lastname: Lung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D042501:Angiogenic Proteins / Q000032:analysis; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D006801:Humans; D060588:LIM Domain Proteins; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D042501:Angiogenic Proteins; C486176:CRIP2 protein, human; D016207:Cytokines; D060588:LIM Domain Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins