title: The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice.
abstract: Although it has been suggested that Dll3, one of the Notch ligands, promotes the proliferation and inhibits the apoptosis of cancer cells, the role of Dll3 in cancers remains unclear. In this study, we found that in the murine Lewis lung carcinoma (LLC) cells, the level of Dll3 mRNA changed upon tumor microenvironment (TME) stimulation, namely, decreased under hypoxia or stimulated with tumor necrosis factor (TNF)-α. Dll3 was also expressed at higher level in human lung carcinoma tissues than in the para-carcinoma tissues. Overexpression of Dll3 in LLC cells promoted cell proliferation and reduced apoptosis in vitro, and enhanced tumor growth when inoculated in vivo in mice. The Dll3-mediated proliferation could be due to increased Akt phosphorylation in LLC cells, because an Akt inhibitor counteracted Dll3-induced proliferation. Moreover, Dll3 overexpression promoted PI3K/Akt signaling through inhibiting Notch signaling.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Department of General Thoracic Surgery, Affiliated Hospital of Logistics University of Chinese People's Armed Police Forces, Tianjin 300162, China.
authors.forename: San-Ming
authors.initials: SM
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xian-Chun
authors.initials: XC
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Juan-Li
authors.initials: JL
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zi-Yan
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Tian-Fang
authors.initials: TF
authors.lastname: Chang
authors.affiliation: Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Ruan
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: zhengqj@fmmu.edu.cn.
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; Department of Biochemistry and Molecular Biology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: huahan@fmmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C496666:DLL3 protein, human; C511877:Dll3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: Delta-like 3; Hypoxia; Lung cancer; Notch; TNF-α