title: Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome-wide shRNA screen.
abstract: Therapeutic effectiveness against metastatic or even locally advanced pancreatic ductal adenocarcinoma (PDAC) is dismal, with 5-year survival less than 5%. Even in patients who undergo potentially curative resection, most patients' tumors recur in the liver. Improving therapies targeting or preventing liver metastases is crucial for improving prognosis. To identify genes suppressing metastasis, a genome-wide shRNA screen was done using the human non-metastatic PDAC cell line, S2-028. After identification of candidates, functional validation was done using intrasplenic and orthotopic injections in athymic mice. HMP19 strongly inhibited metastasis but also partially attenuated tumor growth in the pancreas. Knockdown of HMP19 increased localization of activated ERK1/2 in the nucleus, corresponding to facilitated cell proliferation, decreased p27(Kip1) and increased cyclin E1. Over-expression of HMP19 exerted the opposite effects. Using a tissue microarray of 84 human PDAC, patients with low expression of HMP19 showed significantly higher incidence of liver metastasis (p = 0.0175) and worse prognosis (p = 0.018) after surgery. HMP19, a new metastasis/tumor suppressor in PDAC, appears to alter signaling that leads to cell proliferation and appears to offer prognostic value in human PDAC.
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.|Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, Kagoshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurahara
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bohl
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, Kagoshima, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, Kagoshima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nishizono
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Sitaram
authors.initials: S
authors.lastname: Harihar
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Rahul
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.|University of Kansas Cancer Center, Kansas City, KS.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS.|University of Kansas Cancer Center, Kansas City, KS.
authors.forename: Danny R
authors.identifier: 0000-0002-1951-4947
authors.initials: DR
authors.lastname: Welch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D034741:RNA, Small Interfering
keywords: ERK; cell cycle; cyclin E; metastasis; metastasis suppressor; p27kip1; pancreatic ductal adenocarcinoma; shRNA