title: Overexpression of CDX2 in gastric cancer cells promotes the development of multidrug resistance.
abstract: Modulator of multidrug resistance (MDR) gene is a direct transcriptional target of CDX2. However, we still speculate whether CDX2 affects MDR through other ways. In this study, a cisplatin-resistant (SGC7901/DDP) and a 5-fluoro-2, 4(1h,3h)pyrimidinedione-resistant (BGC823/5-FU) gastric cancer cell line with stable overexpression of CDX2 were established. The influence of overexpression of CDX2 on MDR was assessed by measuring IC50 of SGC7901/DDP and BGC823/5-FU cells to cisplatin, doxorubicin, and 5-fluorouracil, rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. In addition, we determined the in vivo effects of CDX2-overexpression lentiviral vector (LV-CDX2-GFP) on tumor size, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining. Results showed that LV-CDX2-GFP led to up-regulation of CDX2 mRNA and protein expression. It significantly inhibited the sensitivity of SGC7901/DDP and BGC823/5-FU cells to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after CDX2 up-regulation. This notion was further supported by the observation that up-regulation of CDX2 blocked entry into the M-phase of the cell cycle. Furthermore, up-regulation of CDX2 significantly decreased intracellular accumulation of doxorubicin. In molecular studies, quantitative reverse-transcriptase real-time polymerase chain reaction and western blotting revealed that CDX2 up-regulation could suppress expression of Caspase-3, Caspase-9 and PTEN, and increased the expression of MDR1, MRP, mTOR, HIF-1α.
authors: Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Lin-Hai
authors: LH
authors: Yan
authors: Department of Surgery, The First Affiliated Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Wei-Yuan
authors: WY
authors: Wei
authors: Department of Surgery, The First Affiliated Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Wen-Long
authors: WL
authors: Cao
authors: Department of Surgery, The First Affiliated Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Xiao-Shi
authors: XS
authors: Zhang
authors: Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Yu-Bo
authors: YB
authors: Xie
authors: Department of Surgery, The First Affiliated Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China.
authors: Qiang
authors: Q
authors: Xiao
keywords: Homeobox gene CDX2; drug resistance; gastric cancer; lentiviral vector; murine model
references: Cancer Treat Rev. 2006 Oct;32(6):407-16
references: 16889900
references: Curr Top Med Chem. 2004;4(13):1347-56
references: 15379649
references: Cancer Res. 2010 Nov 15;70(22):9185-96
references: 21045158
references: Cancer Res. 2010 Sep 1;70(17 ):6767-78
references: 20699370
references: Annu Rev Pharmacol Toxicol. 2014;54:95-117
references: 24050699
references: J Biol Chem. 2003 Jun 6;278(23):20582-92
references: 12663670
references: J Exp Clin Cancer Res. 2012 Mar 16;31:23
references: 22424291
references: Cell Oncol. 2007;29(4):335-49
references: 17641417
references: Cancer Res. 2001 Mar 1;61(5):1862-8
references: 11280739
references: Int J Mol Med. 2004 Jun;13(6):865-8
references: 15138626
references: Nat Rev Cancer. 2006 Aug;6(8):583-92
references: 16862189
references: J Biol Chem. 2003 Jun 27;278(26):23432-40
references: 12697749
references: J Biol Chem. 2005 Feb 11;280(6):4321-8
references: 15569687
references: Br J Pharmacol. 2009 Apr;156(7):1054-66
references: 19298255
references: Nat Rev Cancer. 2004 May;4(5):335-48
references: 15122205
references: Int J Prev Med. 2011 Apr;2(2):101-2
references: 21603016
references: Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477-81
references: 7972087
references: Mol Pharmacol. 2004 Jul;66(1):25-32
references: 15213293
references: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8549-56
references: 16361536
references: BMC Pharmacol Toxicol. 2013 Sep 20;14:47
references: 24053678
references: Cancer Sci. 2008 Jul;99(7):1455-60
references: 18422753
references: Carcinogenesis. 1993 Oct;14(10):2177-80
references: 8222071
references: Int J Cancer. 1996 Apr 10;66(2):274-9
references: 8603824
references: Cancer Res. 2004 Nov 1;64(21):7740-7
references: 15520178
references: J Pathol. 2003 Jan;199(1):36-40
references: 12474224
references: Oncogene. 2006 Apr 6;25(15):2264-72
references: 16314840
references: Anticancer Res. 2009 Apr;29(4):1281-6
references: 19414376
references: J Orthop Res. 2012 Feb;30(2):267-73
references: 21809381
references: World J Gastroenterol. 2013 Jul 14;19(26):4155-65
references: 23864778
references: Oncotarget. 2011 Mar;2(3):135-64
references: 21411864
references: Oncogene. 2003 Oct 20;22(47):7265-79
references: 14576837
references: Cell Death Differ. 2009 Nov;16(11):1493-504
references: 19590512
references: Cancer Res. 2002 Jun 15;62(12):3387-94
references: 12067980