DOI QR코드

DOI QR Code

Prognostic Significance of Hes-1, a Downstream Target of Notch Signaling in Hepatocellular Carcinoma

  • Zou, Jing-Huai (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Xue, Tong-Chun (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Sun, Chun (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Li, Yan (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Liu, Bin-Bin (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Sun, Rui-Xia (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Chen, Jie (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Ren, Zheng-Gang (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education) ;
  • Ye, Sheng-Long (Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education)
  • Published : 2015.05.18

Abstract

Background: Hairy and enhancer of split 1 (Hes-1) protein is a downstream target of Notch signaling and is a basic helix-loop-helix transcriptional repressor. However, definitive evidence for a role in hepatocellular carcinoma (HCC) cells has not been reported. Here, Hes-1 was revealed to an important component of the Notch signaling cascade in HCC cell lines possessing different potential for lung metastasis. Materials and Methods: RNAi mediated by plasmid constructs was used to analyze the role of Hes-1 in MHCC-97L HCC cells by assessing proliferation, apoptosis, cell migration and matrigel invasion following transfection. Hes-1 protein expression analysis in HCC tissue was also conducted by immunohistochemistry. Results: Our studies revealed that Hes-1 was decreased in HCC cell lines with higher lung metastasis potential at both the mRNA and protein levels. Down-regulation of the Hes-1 gene in MHCC-97L cells resulted in increased cell proliferation, reduced apoptosis and increased migration and invasion. Conclusions: Hes-1 has potential prognostic value in post-surgical HCC patients and may be an independent prognostic indicator for overall survival and tumor recurrence. These findings have important implications for understanding the mechanisms by which Hes-1 participates in tumor proliferation and invasion.

Keywords

Hepatocellular carcinoma;lung metastasis;notch-1;Hes-1;Shh

References

  1. Beasley RP (1988). Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer, 61, 1942-56. https://doi.org/10.1002/1097-0142(19880515)61:10<1942::AID-CNCR2820611003>3.0.CO;2-J
  2. Cantarini MC, de la Monte SM, Pang M, et al (2006). Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatol, 44, 446-57.
  3. Caporaso N, Romano M, Marmo R, et al (1991). Hepatitis C virus infection is an additive risk factor for development of hepatocellular carcinoma in patients with cirrhosis. J Hepatol, 12, 367-71. https://doi.org/10.1016/0168-8278(91)90841-X
  4. Colombo M (1999). Hepatitis C virus and hepatocellular carcinoma. Semin Liver Dis, 19, 263-9. https://doi.org/10.1055/s-2007-1007116
  5. Croquelois A, Blindenbacher A, Terracciano L, et al (2005). Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice. Hepatol, 41, 487-96. https://doi.org/10.1002/hep.20571
  6. Dailey DD, Anfinsen KP, Pfaff LE, et al (2013). HES1, a target of Notch signaling, is elevated in canine osteosarcoma, but reduced in the most aggressive tumors. BMC Vet Res, 9, 130. https://doi.org/10.1186/1746-6148-9-130
  7. He J, Gu D, Wu X, et al (2005). Major causes of death among men and women in China. N Engl J Med, 353, 1124-34. https://doi.org/10.1056/NEJMsa050467
  8. Jin GZ, Yu WL, Dong H, et al (2013). SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma. J Hepatol, 59, 510-7. https://doi.org/10.1016/j.jhep.2013.04.028
  9. Kannan S, Fang W, Song G, et al (2011). Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression. Blood, 117, 2891-900. https://doi.org/10.1182/blood-2009-12-253419
  10. Kaushik G, Venugopal A, Ramamoorthy P, et al (2014). Honokiol inhibits melanoma stem cells by targeting notch signaling. Mol Carcinog, Dec 9[Epub ahead of print], PMID: 25491779.
  11. Lindsell CE, Shawber CJ, Boulter J, et al (1995). Jagged: a mammalian ligand that activates Notch1. Cell, 80, 909-17. https://doi.org/10.1016/0092-8674(95)90294-5
  12. Liu J, Ye F, Chen H, et al (2007). Expression of differentiation associated protein Hes1 and Hes5 in cervical squamous carcinoma and its precursors. Int J Gynecol Cancer, 17, 1293-9. https://doi.org/10.1111/j.1525-1438.2007.00930.x
  13. Mo QG, Liang AM, Yang NW, et al (2003). [Surgery-predominant comprehensive therapy for 134 patients with small hepatocellular carcinoma]. Ai Zheng, 22, 189-91.
  14. Parkin DM, Bray F, Ferlay J, et al (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108. https://doi.org/10.3322/canjclin.55.2.74
  15. Portolani N, Coniglio A, Ghidoni S, et al (2006). Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg, 243, 229-35. https://doi.org/10.1097/01.sla.0000197706.21803.a1
  16. Qi R, An H, Yu Y, et al (2003). Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res, 63, 8323-9.
  17. Ranganathan P, Weaver KL, Capobianco AJ (2011). Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer, 11, 338-51. https://doi.org/10.1038/nrc3035
  18. Tang Z, Zhou X, Lin Z, et al (1999). Surgical treatment of hepatocellular carcinoma and related basic research with special reference to recurrence and metastasis. Chin Med J (Engl), 112, 887-91.
  19. Tian J, Tang ZY, Ye SL, et al (1999). New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer, 81, 814-21. https://doi.org/10.1038/sj.bjc.6690769
  20. Weng AP, Aster JC (2004). Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev, 14, 48-54. https://doi.org/10.1016/j.gde.2003.11.004
  21. Ye QF, Zhang YC, Peng XQ, et al (2012). siRNA-mediated silencing of Notch-1 enhances docetaxel induced mitotic arrest and apoptosis in prostate cancer cells. Asian Pac J Cancer Prev, 13, 2485-9. https://doi.org/10.7314/APJCP.2012.13.6.2485

Cited by

  1. Expression and influence of Notch signaling in oral squamous cell carcinoma vol.58, pp.2, 2016, https://doi.org/10.2334/josnusd.15-0535
  2. Effects of the Notch1 signaling pathway on human lung cancer A549 cells vol.43, pp.4-5, 2017, https://doi.org/10.1080/01902148.2017.1341008