Loss of function of Notch1 identifies a poor prognosis group of early stage hepatocellular carcinoma following hepatectomy

Liu,Jian; Liu,Jing-Feng; Wang,Kui; Yan,Zhen-Lin; Wan,Xu-Ying; Huang,Ai-Min; Wang,Yi-Zhou; Li,Jun; Xia,Yong; Shi,Le-Hua; Jiao,Bing-Hua; Zhang,Yongjie; Shen,Feng

doi:10.3892/or.2015.4300

Loss of function of Notch1 identifies a poor prognosis group of early stage hepatocellular carcinoma following hepatectomy

Authors:
- Jian Liu
- Jing-Feng Liu
- Kui Wang
- Zhen-Lin Yan
- Xu-Ying Wan
- Ai-Min Huang
- Yi-Zhou Wang
- Jun Li
- Yong Xia
- Le-Hua Shi
- Bing-Hua Jiao
- Yongjie Zhang
- Feng Shen
View Affiliations

Affiliations: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China, Department of Hepatobiliary Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China, Department of Clinical Database, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China, Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, P.R. China
Published online on: September 21, 2015 https://doi.org/10.3892/or.2015.4300
Pages: 3174-3186

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

Notch1 has previously been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). The present study aimed to investigate the prognostic value of Notch1 in early stage HCC patients after hepatectomy. The differential expression of Notch1 in paired tumor and non-tumorous tissue was evaluated by RT-PCR, western blotting and immunohistochemistry. The correlation between Notch1 expression and the surgical outcome of patients at BCLC stage 0/A and its ≤5 cm subgroup was retrospectively investigated in 206 patients from the Eastern Hepatobiliary Surgery Hospital (training cohort), and prospectively validated in 185 patients from the same center and retrospectively verified in 129 patients from the Fujian Medical University (validation cohort 1 and 2, respectively). Compared with paired non-tumorous tissues, loss of Notch1 was observed in tumor tissue. Patients with normal Notch1 had better prognosis than those with loss of Notch1 in the training cohort and ≤5 cm subgroup (time to recurrence: 38.5±6.1 vs. 16.0±3.2 months, P<0.001 and 53.0±6.1 vs. 21.7±3.5 months, P=0.004; 1-, 3-, 5-year survival rates: 91, 64 and 49% vs. 73, 31 and 22%, P<0.001 and 93, 71, 57% vs. 76, 39, 24%, P<0.001). Notch1 expression was an independent factor for recurrence and survival (hazard ratio: 1.901, 2.154; 2.038 and 2.337). Moreover, Notch1 status affected early tumor recurrence, as the 2-year recurrence rate was 61.2 vs. 26.9% (P<0.001) and 51.2 vs. 21.3% (P=0.002) in tumors with reduced or increased Notch1 expression in this cohort and subgroup. These results were fully confirmed by the study in our prospective and retrospective validation cohorts. The status of Notch1 is useful for predicting the prognosis of patients with early stage HCC undergoing hepatectomy.

View Figures

View References

1	Bosch FX, Ribes J, Díaz M and Cléries R: Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 127(Suppl 1): S5–S16. 2004. View Article : Google Scholar : PubMed/NCBI
2	Yang L, Parkin DM, Whelan S, Zhang S, Chen Y, Lu F and Li L: Statistics on cancer in China: Cancer registration in 2002. Eur J Cancer Prev. 14:329–335. 2005. View Article : Google Scholar : PubMed/NCBI
3	Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA and Giulini SM: Early and late recurrence after liver resection for hepatocellular carcinoma: Prognostic and therapeutic implications. Ann Surg. 243:229–235. 2006. View Article : Google Scholar : PubMed/NCBI
4	Bruix J, Boix L, Sala M and Llovet JM: Focus on hepatocellular carcinoma. Cancer Cell. 5:215–219. 2004. View Article : Google Scholar : PubMed/NCBI
5	Poon RT, Fan ST, Lo CM, Liu CL and Wong J: Intrahepatic recurrence after curative resection of hepatocellular carcinoma: Long-term results of treatment and prognostic factors. Ann Surg. 229:216–222. 1999. View Article : Google Scholar : PubMed/NCBI
6	Shimozawa N and Hanazaki K: Longterm prognosis after hepatic resection for small hepatocellular carcinoma. J Am Coll Surg. 198:356–365. 2004. View Article : Google Scholar : PubMed/NCBI
7	Bruix J and Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar : PubMed/NCBI
8	Llovet JM, Brú C and Bruix J: Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis. 19:329–338. 1999. View Article : Google Scholar : PubMed/NCBI
9	Llovet JM and Bruix J: novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 48(Suppl 1): S20–S37. 2008. View Article : Google Scholar : PubMed/NCBI
10	Izumi R, Shimizu K, Ii T, Yagi M, Matsui O, Nonomura A and Miyazaki I: Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology. 106:720–727. 1994.PubMed/NCBI
11	Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, Takao T, Tamesa T, Tangoku A, Tabuchi H, et al: Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 361:923–929. 2003. View Article : Google Scholar : PubMed/NCBI
12	Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, et al: Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 359:1995–2004. 2008. View Article : Google Scholar : PubMed/NCBI
13	Greenwald I: LIN-12/Notch signaling: Lessons from worms and flies. Genes Dev. 12:1751–1762. 1998. View Article : Google Scholar : PubMed/NCBI
14	Sestan N, Artavanis-Tsakonas S and Rakic P: Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling. Science. 286:741–746. 1999. View Article : Google Scholar : PubMed/NCBI
15	Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM and Wicha MS: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6:R605–R615. 2004. View Article : Google Scholar : PubMed/NCBI
16	Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD and Sklar J: TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 66:649–661. 1991. View Article : Google Scholar : PubMed/NCBI
17	Weng AP and Aster JC: Multiple niches for Notch in cancer: Context is everything. Curr Opin Genet Dev. 14:48–54. 2004. View Article : Google Scholar : PubMed/NCBI
18	Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM and Eberhart CG: Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 66:7445–7452. 2006. View Article : Google Scholar : PubMed/NCBI
19	Dufraine J, Funahashi Y and Kitajewski J: Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 27:5132–5137. 2008. View Article : Google Scholar : PubMed/NCBI
20	Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, Guo Z, Cheng T and Cao X: Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res. 63:8323–8329. 2003.PubMed/NCBI
21	Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, Yu Y and Cao X: Notch1 signaling sensitizes TRAIL-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem. 284:16183–16190. 2009. View Article : Google Scholar : PubMed/NCBI
22	Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, Liu Y, Wang W, Wen Y and Gu J: Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma via reducing Notch1 cleavage. Hepatology. 52:142–154. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wang K, Liu J, Yan ZL, Li J, Shi LH, Cong WM, Xia Y, Zou QF, Xi T, Shen F, et al: Overexpression of aspartyl-(asparaginyl)-β-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome. Hepatology. 52:164–173. 2010. View Article : Google Scholar : PubMed/NCBI
24	Sobin Lh and Wittekind C: TNM Classification of Malignant Tumors. 6th edition. Wiley-Liss; New York: pp. 81–83. 2002
25	Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, et al Panel of Experts in HCC-Design Clinical Trials: Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 100:698–711. 2008. View Article : Google Scholar : PubMed/NCBI
26	Talwalkar JA and Gores GJ: Diagnosis and staging of hepatocellular carcinoma. Gastroenterology. 127(Suppl 1): S126–S132. 2004. View Article : Google Scholar : PubMed/NCBI
27	Yamamoto J, Kosuge T, Saiura A, Sakamoto Y, Shimada K, Sano T, Takayama T, Sugawara Y, Yamaguchi T, Kokudo N, et al: Effectiveness of hepatic resection for early-stage hepatocellular carcinoma in cirrhotic patients: Subgroup analysis according to Milan criteria. Jpn J Clin Oncol. 37:287–295. 2007. View Article : Google Scholar : PubMed/NCBI
28	Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A and Gennari L: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 334:693–699. 1996. View Article : Google Scholar : PubMed/NCBI
29	Vauthey JN, Lauwers GY, Esnaola NF, Do KA, Belghiti J, Mirza N, Curley SA, Ellis LM, Regimbeau JM, Rashid A, et al: Simplified staging for hepatocellular carcinoma. J Clin Oncol. 20:1527–1536. 2002. View Article : Google Scholar : PubMed/NCBI
30	Yin L, Velazquez OC and Liu ZJ: Notch signaling: Emerging molecular targets for cancer therapy. Biochem Pharmacol. 80:690–701. 2010. View Article : Google Scholar : PubMed/NCBI
31	Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, et al: c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20:2096–2109. 2006. View Article : Google Scholar : PubMed/NCBI
32	Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, et al: Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20:3427–3436. 2001. View Article : Google Scholar : PubMed/NCBI
33	Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van noort M, Hui CC, Clevers H, Dotto GP and Radtke F: Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 33:416–421. 2003. View Article : Google Scholar : PubMed/NCBI
34	Wang M, Xue L, Cao Q, Lin Y, Ding Y, Yang P and Che L: Expression of Notch1, Jagged1 and β-catenin and their clinicopathological significance in hepatocellular carcinoma. Neoplasma. 56:533–541. 2009. View Article : Google Scholar
35	Bruix J and Llovet JM: Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 35:519–524. 2002. View Article : Google Scholar : PubMed/NCBI
36	Sun HC, Tang ZY, Li XM, Zhou YN, Sun BR and Ma ZC: Microvessel density of hepatocellular carcinoma: Its relationship with prognosis. J Cancer Res Clin Oncol. 125:419–426. 1999. View Article : Google Scholar : PubMed/NCBI
37	Poon RT, Ng IO, Lau C, Yu WC, Yang ZF, Fan ST and Wong J: Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: A prospective study. J Clin Oncol. 20:1775–1785. 2002. View Article : Google Scholar : PubMed/NCBI
38	Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I and Karsan A: Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J exp Med. 204:2935–2948. 2007. View Article : Google Scholar : PubMed/NCBI