title: Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: a possible role of Wnt and Akt signaling.
abstract: Emerging evidence indicates that human mesenchymal stem cells (hMSCs) can be recruited to tumor sites, and affect the growth of human malignancies. However, little is known about the underlying molecular mechanisms. Here, we observed the effects of hMSCs on the human cholangiocarcinoma cell line, HCCC-9810, using an animal transplantation model, and conditioned media from human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). Animal studies showed that hUC-MSCs can inhibit the growth of cholangiocarcinoma xenograft tumors. In cell culture, conditioned media from hUC-MSCs inhibited proliferation and induced apoptosis of tumor cells in a dose- and time-dependent manner. The proliferation inhibition rate increased from 6.21% to 49.86%, whereas the apoptosis rate increased from 9.3% to 48.1% when HCCC-9810 cells were cultured with 50% hUC-MSC conditioned media for 24 h. Immunoblot analysis showed that the expression of phosphor-PDK1 (Ser241), phosphor-Akt (Ser 437 and Thr308), phosphorylated glycogen synthase kinase 3β (phospho-GSK-3β(Ser9)), β-catenin, cyclin-D1, and c-myc were down-regulated. We further demonstrated that CHIR99021, a GSK-3β inhibitor reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells and increased the expression of β-catenin. The GSK-3β activator, sodium nitroprusside dehydrate (SNP), augmented the anti-tumor effects of hUC-MSCs and decreased the expression of β-catenin. IGF-1 acted as an Akt activator, and also reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells. All these results suggest that hUC-MSCs could inhibit the malignant phenotype of HCCC-9810 human cholangiocarcinoma cell line. The cross-talk role of Wnt/β-catenin and PI3K/Akt signaling pathway, with GSK-3β as the key enzyme bridging these pathways, may contribute to the inhibition of cholangiocarcinoma cells by hUC-MSCs.
authors: Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors: Juan
authors: J
authors: Liu
authors: Guoqing
authors: G
authors: Han
authors: Hui
authors: H
authors: Liu
authors: Chengyong
authors: C
authors: Qin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014470:Umbilical Cord / Q000166:cytology; D051153:Wnt Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D051153:Wnt Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
references: Oncogene. 2006 Jan 19;25(3):329-37
references: 16421604
references: J Immunol Methods. 1986 Nov 6;93(2):157-65
references: 3490518
references: Science. 1997 Apr 4;276(5309):71-4
references: 9082988
references: Proc Natl Acad Sci U S A. 1999 May 11;96(10):5522-7
references: 10318916
references: Pathobiology. 2012;79(2):101-6
references: 22286058
references: Mol Carcinog. 2012 Jan;51(1):25-39
references: 22162229
references: Stem Cells. 2007 Feb;25(2):319-31
references: 17053211
references: Science. 1999 Apr 2;284(5411):143-7
references: 10102814
references: Acta Biochim Biophys Sin (Shanghai). 2011 Feb;43(2):143-8
references: 21196449
references: Cancer Res. 2009 Feb 15;69(4):1343-9
references: 19190323
references: World J Gastroenterol. 2007 Dec 28;13(48):6470-7
references: 18161916
references: Panminerva Med. 2004 Mar;46(1):61-74
references: 15238882
references: Cancer Res. 2003 Feb 1;63(3):728-34
references: 12566320
references: Science. 1998 Sep 4;281(5382):1509-12
references: 9727977
references: J Biol Chem. 2007 Apr 13;282(15):11221-9
references: 17287208
references: J Cell Biochem. 2012 Jun;113(6):2027-39
references: 22275115
references: J Exp Med. 2006 May 15;203(5):1235-47
references: 16636132
references: J Clin Invest. 2000 Aug;106(4):533-9
references: 10953028
references: Digestion. 2002;66(3):131-44
references: 12481159
references: J Gastrointest Surg. 2007 Nov;11(11):1488-96; discussion 1496-7
references: 17805937
references: Methods Cell Biol. 2008;86:101-19
references: 18442646
references: Stem Cells. 2011 Jan;29(1):11-9
references: 21280155
references: Science. 2001 Jun 29;292(5526):2439-40
references: 11431552
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11917-23
references: 13679583
references: Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24
references: 12781368
references: J Natl Cancer Inst. 2004 Nov 3;96(21):1593-603
references: 15523088
references: Neoplasia. 2006 Apr;8(4):279-89
references: 16756720
references: BMC Cancer. 2012 Jul 23;12:303
references: 22823957
references: Pediatr Transplant. 2004 Jun;8 Suppl 5:28-32
references: 15125703
references: Nat Rev Cancer. 2003 Nov;3(11):832-44
references: 14668814
references: Cancer Res. 2005 Apr 15;65(8):3307-18
references: 15833864
references: Cancer Lett. 2008 Nov 8;270(2):242-9
references: 18565645
references: Nature. 2007 Oct 4;449(7162):557-63
references: 17914389
references: Cell Res. 2008 Apr;18(4):500-7
references: 18364678
references: Cancer. 2004 Sep 15;101(6):1345-56
references: 15316903
references: PLoS One. 2007 Nov 07;2(11):e1155
references: 17982507
references: Cancer Cell. 2003 Dec;4(6):499-515
references: 14706341
references: Histochem Cell Biol. 2003 Sep;120(3):213-21
references: 12904970
references: Cancer. 2009 Jan 15;115(2):311-23
references: 19109817
references: Cancer Biol Ther. 2008 Feb;7(2):245-51
references: 18059192
references: Biochem Biophys Res Commun. 2011 Feb 18;405(3):333-7
references: 21130731
references: Oncogene. 1999 May 6;18(18):2883-91
references: 10362259
references: Hepatology. 2008 Jul;48(1):308-21
references: 18536057
references: Cancer Sci. 2005 Mar;96(3):149-56
references: 15771617
references: Circ Res. 2004 Jul 9;95(1):9-20
references: 15242981
references: Nature. 1995 Dec 21-28;378(6559):785-9
references: 8524413
references: Cancer Cell. 2002 Mar;1(2):145-55
references: 12086873
references: Cell Cycle. 2004 May;3(5):571-3
references: 15107603