Suppression of KLF8 induces cell differentiation and sensitizes colorectal cancer to 5-fluorouracil

Shi,Xinpeng; Luo,Xiaoyong; Yan,Qingqing; Zhang,Wenjing; Wu,Yao; Zhang,Mengnan; Zhao,Jinjun; Peng,Ying; Chen,Ye; Zhang,Yali; Chen,Cunlong; Cheng,Tianming; Chen,Chudi; Liu,Side; Bai,Yang; Wang,Jide

doi:10.3892/or.2015.4094

Suppression of KLF8 induces cell differentiation and sensitizes colorectal cancer to 5-fluorouracil

Authors:
- Xinpeng Shi
- Xiaoyong Luo
- Qingqing Yan
- Wenjing Zhang
- Yao Wu
- Mengnan Zhang
- Jinjun Zhao
- Ying Peng
- Ye Chen
- Yali Zhang
- Cunlong Chen
- Tianming Cheng
- Chudi Chen
- Side Liu
- Yang Bai
- Jide Wang
View Affiliations

Affiliations: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China, Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, Henan, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, P.R. China
Published online on: June 30, 2015 https://doi.org/10.3892/or.2015.4094
Pages: 1221-1230

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

KLF8 is a member of the KLF transcription factor family that plays an important role in oncogenesis. However, the role of KLF8 in colorectal cancer remains unknown. The aims of the present study were to examine KLF8 expression in colorectal cancers, to determine the role of KLF8 in cell differentiation and to investigate the antiproliferative effect of KLF8 silencing. The expression of KLF8 and phospho-ERK proteins was analyzed, and the effects of KLF8 suppression on cell differentiation and growth were evaluated. In addition, the biological impact of KLF8 knockdown on colorectal cancer cells was investigated in vitro and in vivo. The expression of the KLF8 protein was higher in 10/14 (71.43%) fresh cancer tissues compared with adjacent normal tissues, and the blockade of ERK signaling by U0126 decreased the expression of KLF8 in a time- and dose-dependent manner. Furthermore, KLF8-siRNA induced the expression of carcinoembryonic antigen (CEA) and E-cadherin as well as the maturation of F-actin. KLF8 suppression inhibited serum-dependent, anchorage‑dependent and -independent cell growth. Moreover, KLF8 silencing induced apoptosis and sensitized cancer cells to 5-fluorouracil (5-FU). A strong antitumorigenic effect by lenti-KLF8-shRNA, which was enhanced when combined with 5-FU treatment, was exerted in nude mice. Thus, KLF8 suppression induced cell differentiation and inhibited tumorigenesis.

View Figures

View References

1	Brenner H, Kloor M and Pox CP: Colorectal cancer. Lancet. 383:1490–1502. 2014. View Article : Google Scholar
2	Yu LF, Wang J, Zou B, Lin MC, Wu YL, Xia HH, Sun YW, Gu Q, He H, Lam SK, et al: XAF1 mediates apoptosis through an extracellular signal-regulated kinase pathway in colon cancer. Cancer. 109:1996–2003. 2007. View Article : Google Scholar : PubMed/NCBI
3	Kopelovich L: Heritable colorectal cancer and cancer genes: Systemic expressions. Mol Carcinog. 8:3–6. 1993. View Article : Google Scholar : PubMed/NCBI
4	Ponce NA, Tsui J, Knight SJ, Afable-Munsuz A, Ladabaum U, Hiatt RA and Haas JS: Disparities in cancer screening in individuals with a family history of breast or colorectal cancer. Cancer. 118:1656–1663. 2012. View Article : Google Scholar :
5	Doubeni CA, Major JM, Laiyemo AO, Schootman M, Zauber AG, Hollenbeck AR, Sinha R and Allison J: Contribution of behavioral risk factors and obesity to socioeconomic differences in colorectal cancer incidence. J Natl Cancer Inst. 104:1353–1362. 2012. View Article : Google Scholar : PubMed/NCBI
6	Fernandez E, La Vecchia C, Talamini R and Negri E: Joint effects of family history and adult life dietary risk factors on colorectal cancer risk. Epidemiology. 13:360–363. 2002. View Article : Google Scholar : PubMed/NCBI
7	Wang J, Yang Y, Xia HH, Gu Q, Lin MC, Jiang B, Peng Y, Li G, An X, Zhang Y, et al: Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. Gastroenterology. 132:1066–1076. 2007. View Article : Google Scholar : PubMed/NCBI
8	Zhang W, Jiang B, Guo Z, Sardet C, Zou B, Lam CS, Li J, He M, Lan HY, Pang R, et al: Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer. Carcinogenesis. 31:1220–1229. 2010. View Article : Google Scholar : PubMed/NCBI
9	Warren RS, Yuan H, Matli MR, Gillett NA and Ferrara N: Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 95:1789–1797. 1995. View Article : Google Scholar : PubMed/NCBI
10	Furue H, Matsuo K, Kumimoto H, Hiraki A, Suzuki T, Yatabe Y, Komori K, Kanemitsu Y, Hirai T, Kato T, et al: Decreased risk of colorectal cancer with the high natural killer cell activity NKG2D genotype in Japanese. Carcinogenesis. 29:316–320. 2008. View Article : Google Scholar : PubMed/NCBI
11	Guo Z, Zhang W, Xia G, Niu L, Zhang Y, Wang X, Zhang Y, Jiang B and Wang J: Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation. Mol Carcinog. 49:826–836. 2010.PubMed/NCBI
12	Lee PL, Gelbart T, West C, Adams M, Blackstone R and Beutler E: Three genes encoding zinc finger proteins on human chromosome 6p21.3: Members of a new subclass of the Krüppel gene family containing the conserved SCAN box domain. Genomics. 43:191–201. 1997. View Article : Google Scholar : PubMed/NCBI
13	Le Magnen C, Bubendorf L, Ruiz C, Zlobec I, Bachmann A, Heberer M, Spagnoli GC, Wyler S and Mengus C: Klf4 transcription factor is expressed in the cytoplasm of prostate cancer cells. Eur J Cancer. 49:955–963. 2013. View Article : Google Scholar
14	Yang Y, Nakagawa H, Tetreault MP, Billig J, Victor N, Goyal A, Sepulveda AR and Katz JP: Loss of transcription factor KLF5 in the context of p53 ablation drives invasive progression of human squamous cell cancer. Cancer Res. 71:6475–6484. 2011. View Article : Google Scholar : PubMed/NCBI
15	Ellenrieder V, Buck A, Harth A, Jungert K, Buchholz M, Adler G, Urrutia R and Gress TM: KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology. 127:607–620. 2004. View Article : Google Scholar : PubMed/NCBI
16	Wang X, Zheng M, Liu G, Xia W, McKeown-Longo PJ, Hung MC and Zhao J: Krüppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Res. 67:7184–7193. 2007. View Article : Google Scholar : PubMed/NCBI
17	Fu WJ, Li JC, Wu XY, Yang ZB, Mo ZN, Huang JW, Xia GW, Ding Q, Liu KD and Zhu HG: Small interference RNA targeting Krüppel-like factor 8 inhibits the renal carcinoma 786-0 cells growth in vitro and in vivo. J Cancer Res Clin Oncol. 136:1255–1265. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wu Y, Guo Z, Zhang D, Zhang W, Yan Q, Shi X, Zhang M, Zhao Y, Zhang Y, Jiang B, et al: A novel colon cancer gene therapy using rAAV mediated expression of human shRNA-FHL2. Int J Oncol. 43:1618–1626. 2013.PubMed/NCBI
19	Li JC, Yang XR, Sun HX, Xu Y, Zhou J, Qiu SJ, Ke AW, Cui YH, Wang ZJ, Wang WM, et al: Up-regulation of Krüppel-like factor 8 promotes tumor invasion and indicates poor prognosis for hepatocellular carcinoma. Gastroenterology. 139:2146–2157.e12. 2010. View Article : Google Scholar
20	Wang TB, Hu BG, Liu DW, Shi HP and Dong WG: The influence of lentivirus-mediated CXCR4 RNA interference on hepatic metastasis of colorectal cancer. Int J Oncol. 44:1861–1869. 2014.PubMed/NCBI
21	Dent P: Multi-kinase modulation for colon cancer therapy. Cancer Biol Ther. 14:877–878. 2013. View Article : Google Scholar : PubMed/NCBI
22	Orchel A, Dzierzewicz Z, Parfiniewicz B, Weglarz L and Wilczok T: Butyrate-induced differentiation of colon cancer cells is PKC and JNK dependent. Dig Dis Sci. 50:490–498. 2005. View Article : Google Scholar : PubMed/NCBI
23	Bajenova O, Chaika N, Tolkunova E, Davydov-Sinitsyn A, Gapon S, Thomas P and O'Brien S: Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes. Exp Cell Res. 324:115–123. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yan H, Wang X, Niu J, Wang Y, Wang P and Liu Q: Anti-cancer effect and the underlying mechanisms of gypenosides on human colorectal cancer SW-480 cells. PLoS One. 9:e956092014. View Article : Google Scholar : PubMed/NCBI
25	Yu J, Qiao L, Zimmermann L, Ebert MP, Zhang H, Lin W, Röcken C, Malfertheiner P and Farrell GC: Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo. Hepatology. 43:134–143. 2006. View Article : Google Scholar
26	Tu SP, Liston P, Cui JT, Lin MC, Jiang XH, Yang Y, Gu Q, Jiang SH, Lum CT, Kung HF, et al: Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer. Int J Cancer. 125:688–697. 2009. View Article : Google Scholar : PubMed/NCBI
27	Schnell O, Romagna A, Jaehnert I, Albrecht V, Eigenbrod S, Juerchott K, Kretzschmar H, Tonn JC and Schichor C: Krüppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation. PLoS One. 7:e304292012. View Article : Google Scholar
28	Lu H, Wang X, Urvalek AM, Li T, Xie H, Yu L and Zhao J: Transformation of human ovarian surface epithelial cells by Krüppel-like factor 8. Oncogene. 33:10–18. 2014. View Article : Google Scholar :
29	Bromberg KD, Kluger HM, Delaunay A, Abbas S, DiVito KA, Krajewski S and Ronai Z: Increased expression of the E3 ubiquitin ligase RNF5 is associated with decreased survival in breast cancer. Cancer Res. 67:8172–8179. 2007. View Article : Google Scholar : PubMed/NCBI
30	Franovic A, Holterman CE, Payette J and Lee S: Human cancers converge at the HIF-2alpha oncogenic axis. Proc Natl Acad Sci USA. 106:21306–21311. 2009. View Article : Google Scholar : PubMed/NCBI