title: Small interfering RNA-directed targeting of RON alters invasive and             oncogenic phenotypes of human hepatocellular carcinoma cells.
abstract: The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly             expressed in various cancers including human hepatocellular carcinoma (HCC) and             involved in tumor progression. The aims of the current study were to evaluate             whether RON affects tumor cell behavior and oncogenic signaling cascades in HCC             cells. We investigated the biologic role of RON on tumor cell behavior and oncogenic             signaling cascades including Akt, c-Raf and extracellular signal-regulated kinase             (ERK) by using the small interfering RNA (siRNA) in HCC cell lines, chang, HepG2             and Huh7. Knockdown of RON suppressed tumor cell migration and invasion in all             tested HCC cell lines. The proportion of apoptotic cells induced by knockdown             of RON was greater than that induced by transfection of the scramble siRNA in             all tested HCC cell lines. Knockdown of RON resulted in cell cycle arrest in the             G2/M phase of chang and Huh7 cells, and sub G1 phase of HepG2 cells. Knockdown             of RON activated cleaved caspase-3 and PARP, and down-regulated the expression             of Bcl-2, Bcl-xL and survivin, leading to induction of apoptosis in all tested             cell lines. Knockdown of RON negatively regulates the progression of the cell             cycle by decreasing cyclin D1 and D3, and increasing p21 and p27 in all tested             cell lines. The phosphorylation of Akt, c-Raf and ERK1/2 signal proteins was significantly             blocked by knockdown of RON in all tested cell lines. These results suggest that             RON is associated with invasive and oncogenic phenotypes such as tumor cell migration,             invasion, resistance to apoptosis and cell cycle arrest through the modulation             of Akt, c-Raf and ERK signaling cascades in HCC cells.
authors.affiliation: Department of Internal Medicine, Chonnam National University                     Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Sung-Bum
authors.initials: SB
authors.lastname: Cho
authors.forename: Young-Lan
authors.initials: YL
authors.lastname: Park
authors.forename: Young-A
authors.initials: YA
authors.lastname: Song
authors.forename: Kyu-Yeol
authors.initials: KY
authors.lastname: Kim
authors.forename: Gi-Hoon
authors.initials: GH
authors.lastname: Lee
authors.forename: Dae-Ho
authors.initials: DH
authors.lastname: Cho
authors.forename: Dae-Seong
authors.initials: DS
authors.lastname: Myung
authors.forename: Kang-Jin
authors.initials: KJ
authors.lastname: Park
authors.forename: Wan-Sik
authors.initials: WS
authors.lastname: Lee
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.forename: Sung-Kyu
authors.initials: SK
authors.lastname: Choi
authors.forename: Kyung-Keun
authors.initials: KK
authors.lastname: Kim
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Joo
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases