Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling.

Abstract	Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene that is downregulated in various cancers. In the present study, we analyzed the regulatory function of RUNX3 on Jagged-1 (JAG1) expression and cancer stem cell (CSC) signaling in hepatocellular carcinoma (HCC). Eleven HCC cell lines and 30 human HCC tissues were used. RUNX3 and JAG1 expression levels were analyzed by immunoblotting and immunohistochemistry. Ectopic RUNX3 expression was induced by introducing RUNX3 cDNA into the RUNX3-negative HCC cell line Hep3B and Huh7 cells. Furthermore endogenous RUNX3 expression was knocked down by RUNX3 siRNA in SK-Hep-1 cells. In order to analyze JAG1 transcriptional regulation, we conducted reporter assays, chromatin immunoprecipitation (ChIP) assays and electrophoretic mobility shift assays (EMSAs). Tumorigenicity was analyzed using a SCID mouse liver injection model. An inverse correlation was observed between RUNX3 expression and JAG1 expression in most HCC cell lines and tissues. Restoring RUNX3 expression decreased the expression of JAG1 in Hep3B and Huh7 cells, whereas JAG1 expression was upregulated in RUNX3 siRNA-treated SK-Hep-1 cells. Reporter assays, ChIP assays and EMSAs revealed that RUNX3 directly bound to the transcriptional regulatory region of JAG1 and suppressed JAG1 transcription. Moreover, RUNX3 restoration downregulated CSCs by suppressing JAG1-mediated Notch signaling. The tumorigenic capacity of RUNX3-expressing Hep3B cells was lower compared to that of control Hep3B cells. RUNX3 expression suppressed JAG1 expression and resulted in downregulation of tumorigenesis by suppression of JAG1-mediated CSCs.
Authors	Shin-Ichi Nishina, Hidenori Shiraha, Yutaka Nakanishi, Shigetomi Tanaka, Minoru Matsubara, Nobuyuki Takaoka, Masayuki Uemura, Shigeru Horiguchi, Junro Kataoka, Masaya Iwamuro, Takahito Yagi, Kazuhide Yamamoto
Journal	Oncology reports (Oncol Rep) Vol. 26 Issue 3 Pg. 523-31 (Sep 2011) ISSN: 1791-2431 [Electronic] Greece
PMID	21637926 (Publication Type: Journal Article)
Chemical References	Calcium-Binding Proteins Core Binding Factor Alpha 3 Subunit Intercellular Signaling Peptides and Proteins JAG1 protein, human Jag1 protein, mouse Jagged-1 Protein Membrane Proteins Receptors, Notch Recombinant Proteins Runx3 protein, human Serrate-Jagged Proteins Luciferases, Firefly
Topics	Adolescent Adult Aged Aged, 80 and over Animals Calcium-Binding Proteins (genetics, metabolism) Carcinoma, Hepatocellular (metabolism, pathology) Cell Line, Tumor Core Binding Factor Alpha 3 Subunit (genetics, metabolism) Female Gene Expression Regulation, Neoplastic Genes, Reporter Humans Intercellular Signaling Peptides and Proteins (genetics, metabolism) Jagged-1 Protein Liver Neoplasms (metabolism, pathology) Luciferases, Firefly (biosynthesis, genetics) Male Membrane Proteins (genetics, metabolism) Mice Mice, SCID Middle Aged Neoplasm Transplantation Neoplastic Stem Cells (metabolism) Receptors, Notch (metabolism) Recombinant Proteins (genetics, metabolism) Regulatory Elements, Transcriptional Serrate-Jagged Proteins Signal Transduction Transcription, Genetic Transplantation, Heterologous Tumor Burden Young Adult

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