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Article

Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells

  • Authors:
    • Wen-Rui Wu
    • Rui Zhang
    • Xiang-De Shi
    • Cao Yi
    • Lei-Bo Xu
    • Chao Liu
  • View Affiliations / Copyright

    Affiliations: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Pancreato-Biliary Surgery, SunYat-sen Memorial Hospital, SunYat-sen University, Guangzhou, Guangdong 510120, P.R. China, SunYat-sen Memorial Hospital, SunYat-sen University, Guangzhou, Guangdong 510120, P.R. China, Department of Emergency, SunYat-sen Memorial Hospital, SunYat-sen University, Guangzhou, Guangdong 510120, P.R. China
  • Pages: 181-188
    |
    Published online on: May 23, 2016
       https://doi.org/10.3892/or.2016.4831
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Abstract

The Notch pathway plays an important role in both stem cell biology and cancer. Notch2 was reported to be upregulated in human hepatocellular carcinoma (HCC) tissues. However, the biological function of Notch2 in human HCC cells has not yet been documented. The aim of this study was to investigate its possible function on the progression of human HCC cells. The expression of Notch2 was detected in four human HCC cell lines by western blotting. Next, Notch2 was knocked down by small interference RNA (siRNA) in human HCC cells. The role of Notch2 in human HCC cells was investigated by cell proliferation assay, colony formation assay, chemoresistance and xenograft formation assay. In the present study, western blotting revealed that the expression of Notch2 was upregulated in human HCC cell lines. Genetic depletion of Notch2 in HCC cells not only resulted in significantly inhibited proliferation, cell cycle progression and colony formation ability but also increased its sensitivity to 5-fluorouracil (5-FU) compared with controls. In addition, upregulation of Notch2 was discovered in CD90 positive HCC cells, CD90 is a marker of hepatic stem cells. Most importantly, knockdown of Notch2 in HCC cells impaired the tumor formation in vivo. Taken together, our findings indicate that Notch2 may confer stemness properties in HCC; downregulation of Notch2 inhibited the proliferation and tumor formation of HCC cells and increase their sensitivity to 5-FU, suggesting Notch2 as a potential therapeutic target for HCC.
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1 

Singh S, Singh PP, Roberts LR and Sanchez W: Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 11:45–54. 2014. View Article : Google Scholar

2 

Motola-Kuba D, Zamora-Valdés D, Uribe M and Méndez-Sánchez N: Hepatocellular carcinoma. An overview. Ann Hepatol. 5:16–24. 2006.PubMed/NCBI

3 

Li Y, Tang ZY and Hou JX: Hepatocellular carcinoma: Insight from animal models. Nat Rev Gastroenterol Hepatol. 9:32–43. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Woo HG, Wang XW, Budhu A, Kim YH, Kwon SM, Tang ZY, Sun Z, Harris CC and Thorgeirsson SS: Association of TP53 mutations with stem cell-like gene expression and survival of patients with hepatocellular carcinoma. Gastroenterology. 140:1063–1070. 2011. View Article : Google Scholar :

5 

Oishi N and Wang XW: Novel therapeutic strategies for targeting liver cancer stem cells. Int J Biol Sci. 7:517–535. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF, et al: miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 7:694–707. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Tong CM, Ma S and Guan XY: Biology of hepatic cancer stem cells. J Gastroenterol Hepatol. 26:1229–1237. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Penton AL, Leonard LD and Spinner NB: Notch signaling in human development and disease. Semin Cell Dev Biol. 23:450–457. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D and Artavanis-Tsakonas S: Human ligands of the Notch receptor. Am J Pathol. 154:785–794. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Yoneya T, Tahara T, Nagao K, Yamada Y, Yamamoto T, Osawa M, Miyatani S and Nishikawa M: Molecular cloning of delta-4, a new mouse and human Notch ligand. J Biochem. 129:27–34. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Galic V, Shawber CJ, Reeves C, Shah M, Murtomaki A, Wright J, Herzog T, Tong GX and Kitajewski J: NOTCH2 expression is decreased in epithelial ovarian cancer and is related to the tumor histological subtype. Pathol Discov. 1:42013. View Article : Google Scholar

12 

Sehrawat A, Sakao K and Singh SV: Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells. Breast Cancer Res Treat. 146:543–555. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Mazur PK, Einwächter H, Lee M, Sipos B, Nakhai H, Rad R, Zimber-Strobl U, Strobl LJ, Radtke F, Klöppel G, et al: Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 107:13438–13443. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Wang WJ, Yao Y, Jiang LL, Hu TH, Ma JQ, Ruan ZP, Tian T, Guo H, Wang SH and Nan KJ: Increased LEF1 expression and decreased Notch2 expression are strong predictors of poor outcomes in colorectal cancer patients. Dis Markers. 35:395–405. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Yu S, Zhang R, Liu F, Wang H, Wu J and Wang Y: Notch inhibition suppresses nasopharyngeal carcinoma by depleting cancer stem-like side population cells. Oncol Rep. 28:561–566. 2012.PubMed/NCBI

16 

Sparks EE, Huppert KA, Brown MA, Washington MK and Huppert SS: Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology. 51:1391–1400. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM and Siveke JT: Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 48:607–616. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Gao J, Song Z, Chen Y, Xia L, Wang J, Fan R, Du R, Zhang F, Hong L, Song J, et al: Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis. 40:114–121. 2008. View Article : Google Scholar

19 

Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D, Bettler B, Heim MH and Tchorz JS: Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology. 57:1607–1619. 2013. View Article : Google Scholar

20 

Jeliazkova P, Jörs S, Lee M, Zimber-Strobl U, Ferrer J, Schmid RM, Siveke JT and Geisler F: Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology. 57:2469–2479. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, et al: NOTCH2 mutations in Alagille syndrome. J Med Genet. 49:138–144. 2012. View Article : Google Scholar : PubMed/NCBI

22 

McCright B, Lozier J and Gridley T: A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 129:1075–1082. 2002.PubMed/NCBI

23 

Tchorz JS, Kinter J, Müller M, Tornillo L, Heim MH and Bettler B: Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice. Hepatology. 50:871–879. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B, Henner WR, Meisner R, Sato A, Shah J, et al: Targeting notch signaling with a notch2/notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res. 21:2084–2095. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Giovannini C, Gramantieri L, Chieco P, Minguzzi M, Lago F, Pianetti S, Ramazzotti E, Marcu KB and Bolondi L: Selective ablation of Notch3 in HCC enhances doxorubicin's death promoting effect by a p53 dependent mechanism. J Hepatol. 50:969–979. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Litten JB, Chen TT, Schultz R, Herman K, Comstock J, Schiffman J, Tomlinson GE and Rakheja D: Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical study. Pediatr Dev Pathol. 14:378–383. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 367:645–648. 1994. View Article : Google Scholar : PubMed/NCBI

28 

Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC and Dirks PB: Tumour-initiating cells: Challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 8:806–823. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Sukowati CH, Anfuso B, Torre G, Francalanci P, Crocè LS and Tiribelli C: The expression of CD90/Thy-1 in hepatocellular carcinoma: An in vivo and in vitro study. PLoS One. 8:e768302013. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wu W, Zhang R, Shi X, Yi C, Xu L and Liu C: Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. Oncol Rep 36: 181-188, 2016.
APA
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., & Liu, C. (2016). Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. Oncology Reports, 36, 181-188. https://doi.org/10.3892/or.2016.4831
MLA
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., Liu, C."Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells". Oncology Reports 36.1 (2016): 181-188.
Chicago
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., Liu, C."Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells". Oncology Reports 36, no. 1 (2016): 181-188. https://doi.org/10.3892/or.2016.4831
Copy and paste a formatted citation
x
Spandidos Publications style
Wu W, Zhang R, Shi X, Yi C, Xu L and Liu C: Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. Oncol Rep 36: 181-188, 2016.
APA
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., & Liu, C. (2016). Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells. Oncology Reports, 36, 181-188. https://doi.org/10.3892/or.2016.4831
MLA
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., Liu, C."Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells". Oncology Reports 36.1 (2016): 181-188.
Chicago
Wu, W., Zhang, R., Shi, X., Yi, C., Xu, L., Liu, C."Notch2 is a crucial regulator of self-renewal and tumorigenicity in human hepatocellular carcinoma cells". Oncology Reports 36, no. 1 (2016): 181-188. https://doi.org/10.3892/or.2016.4831
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