title: Targeting gastrin-releasing peptide suppresses neuroblastoma progression via upregulation of PTEN signaling.
abstract: We have previously demonstrated the role of gastrin-releasing peptide (GRP) as an autocrine growth factor for neuroblastoma. Here, we report that GRP silencing regulates cell signaling involved in the invasion-metastasis cascade. Using a doxycycline inducible system, we demonstrate that GRP silencing decreased anchorage-independent growth, inhibited migration and neuroblastoma cell-mediated angiogenesis in vitro, and suppressed metastasis in vivo. Targeted inhibition of GRP decreased the mRNA levels of oncogenes responsible for neuroblastoma progression. We also identified PTEN/AKT signaling as a key mediator of the tumorigenic properties of GRP in neuroblastoma cells. Interestingly, PTEN overexpression decreased GRP-mediated migration and angiogenesis; a novel role for this, otherwise, understated tumor suppressor in neuroblastoma. Furthermore, activation of AKT (pAKT) positively correlated with neuroblastoma progression in an in vivo tumor-metastasis model. PTEN expression was slightly decreased in metastatic lesions. A similar phenomenon was observed in human neuroblastoma sections, where, early-stage localized tumors had a higher PTEN expression relative to pAKT; however, an inverse expression pattern was observed in liver lesions. Taken together, our results argue for a dual purpose of targeting GRP in neuroblastoma--1) decreasing expression of critical oncogenes involved in tumor progression, and 2) enhancing activation of tumor suppressor genes to treat aggressive, advanced-stage disease.
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Pritha
authors.initials: P
authors.lastname: Paul
authors.forename: Jingbo
authors.initials: J
authors.lastname: Qiao
authors.forename: Kwang Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Carmelle
authors.initials: C
authors.lastname: Romain
authors.forename: Sora
authors.initials: S
authors.lastname: Lee
authors.forename: Natasha
authors.initials: N
authors.lastname: Volny
authors.forename: Bret
authors.initials: B
authors.lastname: Mobley
authors.forename: Hernan
authors.initials: H
authors.lastname: Correa
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D004789:Enzyme Activation; D019886:Gastrin-Releasing Peptide / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D019886:Gastrin-Releasing Peptide; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references.citation: Int J Cell Biol. 2012;2012:306879
references.pmid: 22505926
references.citation: Cancer Res. 1999 Jan 15;59(2):442-9
references.pmid: 9927060
references.citation: Ann Surg. 2002 May;235(5):621-9; discussion 629-30
references.pmid: 11981207
references.citation: Exp Cell Res. 2001 Mar 10;264(1):29-41
references.pmid: 11237521
references.citation: Eur J Cancer. 2000 May;36(7):901-8
references.pmid: 10785596
references.citation: Cancer Lett. 2008 Dec 18;272(2):177-85
references.pmid: 18579285
references.citation: Cancer Lett. 2007 Aug 18;253(2):273-81
references.pmid: 17383815
references.citation: Biochim Biophys Acta. 2007 Jun;1770(6):927-32
references.pmid: 17379415
references.citation: Science. 1998 Jun 5;280(5369):1614-7
references.pmid: 9616126
references.citation: Cancer Res. 1998 Dec 1;58(23):5285-90
references.pmid: 9850049
references.citation: Curr Opin Cell Biol. 1997 Oct;9(5):701-6
references.pmid: 9330874
references.citation: Oncotarget. 2012 Dec;3(12):1576-87
references.pmid: 23211542
references.citation: World J Surg. 2005 Mar;29(3):281-6
references.pmid: 15706438
references.citation: Ann Surg. 2005 May;241(5):684-91; discussion 691-2
references.pmid: 15849504
references.citation: Nat Rev Cancer. 2003 Jun;3(6):453-8
references.pmid: 12778135
references.citation: Oncogene. 2008 Sep 18;27(41):5497-510
references.pmid: 18794884
references.citation: Cancer Res. 2007 Jan 15;67(2):735-45
references.pmid: 17234785
references.citation: Br J Cancer. 2006 Jan 16;94(1):13-7
references.pmid: 16306876
references.citation: N Engl J Med. 1985 Oct 31;313(18):1111-6
references.pmid: 4047115
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12891-6
references.pmid: 18753628
references.citation: Am J Epidemiol. 1987 Dec;126(6):1063-74
references.pmid: 3687918
references.citation: Cancer Genet Cytogenet. 2001 Mar;125(2):151-5
references.pmid: 11369059
references.citation: Int J Cancer. 2011 Feb 15;128(4):743-52
references.pmid: 20949625
references.citation: Cancer Metastasis Rev. 2003 Dec;22(4):359-74
references.pmid: 12884911
references.citation: Cancer Treat Rev. 2010 Jun;36(4):307-17
references.pmid: 20227189
references.citation: Surgery. 2011 Mar;149(3):425-32
references.pmid: 21035156
references.citation: Int J Cancer. 2004 May 1;109(5):673-9
references.pmid: 14999773
references.citation: Cancer Lett. 1998 Nov 13;133(1):27-33
references.pmid: 9929157