title: Silencing of reversion-inducing cysteine-rich protein with Kazal motifs stimulates hyperplastic phenotypes through activation of epidermal growth factor receptor and hypoxia-inducible factor-2α.
abstract: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a tumor suppressor) is down-regulated by the oncogenic signals and hypoxia, but the biological function of RECK in early tumorigenic hyperplastic phenotypes is largely unknown. Knockdown of RECK by small interfering RNA (siRECK) or hypoxia significantly promoted cell proliferation in various normal epithelial cells. Hypoxia as well as knockdown of RECK by siRNA increased the cell cycle progression, the levels of cyclin D1 and c-Myc, and the phosphorylation of Rb protein (p-pRb), but decreased the expression of p21(cip1), p27(kip1), and p16(ink4A). HIF-2α was upregulated by knockdown of RECK, indicating HIF-2α is a downstream target of RECK. As knockdown of RECK induced the activation of epidermal growth factor receptor (EGFR) and treatment of an EGFR kinase inhibitor, gefitinib, suppressed HIF-2α expression induced by the silencing of RECK, we can suggest that the RECK silenicng-EGFR-HIF-2α axis might be a key molecular mechanism to induce hyperplastic phenotype of epithelial cells. It was also found that shRNA of RECK induced larger and more numerous colonies than control cells in an anchorage-independent colony formation assay. Using a xenograft assay, epithelial cells with stably transfected with shRNA of RECK formed a solid mass earlier and larger than those with control cells in nude mice. In conclusion, the suppression of RECK may promote the development of early tumorigenic hyperplastic characteristics in hypoxic stress.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea ; School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea ; School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Kheun Byeol
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea ; School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Minh Phuong
authors.initials: MP
authors.lastname: Nguyen
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Gyu Hwan
authors.initials: GH
authors.lastname: Park
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kwon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D003114:Colony-Forming Units Assay; D066246:ErbB Receptors / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006965:Hyperplasia / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D011799:Quinazolines; D034741:RNA, Small Interfering / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D058851:GPI-Linked Proteins; D000077156:Gefitinib; D011799:Quinazolines; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C492025:Reck protein, mouse