title: Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.
abstract: Gastric carcinoma is one of the most common malignancies and a lethal cancer in the world. Notch signaling and transcription factors STAT3 (signal transducer and activator of transcription 3) and Twist regulate tumor development and are critical regulators of gastric cancer progression. Herein, the relationship among Notch, STAT3 and Twist pathways in the control of gastric cancer progression was studied. We found that Twist and phosphorylated STAT3 levels were promoted by the activated Notch1 receptor in human stomach adenocarcinoma SC-M1, embryonic kidney HEK293 and erythroleukemia K562 cells. Notch1 signaling dramatically induced Twist promoter activity through a C promoter binding factor-1-independent manner and STAT3 phosphorylation. Overexpression of Notch1 receptor intracellular domain (N1IC) enhanced the interaction between nuclear STAT3 and Twist promoter in cells. Gastric cancer progression of SC-M1 cells was promoted by N1IC through STAT3 phosphorylation and Twist expression including colony formation, migration and invasion. STAT3 regulated gastric cancer progression of SC-M1 cells via Twist. N1IC also elevated the progression of other gastric cancer cells such as AGS and KATO III cells through STAT3 and Twist. The N1IC-promoted tumor growth and lung metastasis of SC-M1 cells in mice were suppressed by the STAT3 inhibitor JSI-124 and Twist knockdown. Furthermore, Notch1 and Notch ligand Jagged1 expressions were significantly associated with phosphorylated STAT3 and Twist levels in gastric cancer tissues of patients. Taken together, these results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy.
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University Taipei 112, Taiwan.
authors.forename: Kai-Wen
authors.initials: KW
authors.lastname: Hsu
authors.forename: Rong-Hong
authors.initials: RH
authors.lastname: Hsieh
authors.forename: Kuo-Hung
authors.initials: KH
authors.lastname: Huang
authors.forename: Anna
authors.initials: A
authors.lastname: Fen-Yau Li
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.forename: Tzu-Yin
authors.initials: TY
authors.lastname: Wang
authors.forename: Min-Jen
authors.initials: MJ
authors.lastname: Tseng
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
authors.forename: Tien-Shun
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C497761:NOTCH1 protein, human; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1