Shi J, Yong-yong H, Ju-Xian S, Wei-Xing G, Li N, Xue J, Shu-Qun C

Language: English
References: 20
Page: 198-206
PDF size: 230.27 Kb.

ABSTRACT

Background. Though there is considerable evidence that sphingosine kinase 1(SPHK1) plays a key role in hepatocellular carcinoma(HCC) progression, the prognostic value of SPHK1 expression in HCC with portal vein tumor thrombus (PVTT) remains unclear. Aims. The purpose of this study was to investigate the relationship of SPHK1 expression with PVTT and HCC recurrence after hepatectomy. Methods. After screening of gene expression profiling of tumor cell lines, real-time PCR and immunohistochemistry were used to investigate the SPHK1 expression in PVTT and HCC samples. The clinical data of 199 HCC patients with nonmain PVTT who underwent liver resection with curative intention were studied. Results. We identified SPHK1 as the most over-expressed gene in PVTT via gene expression profiling of one human PVTT cell line (CSQT-2). SPHK1 expression was an independent factor affecting survival (hazard ratio [HR] 1.799, 95% confidence interval [CI] 1.337–2.368, P ‹ 0.001) and tumor recurrence (HR 1.451, 95% CI 1.087-1.935, P = 0.011). Patients with SPHK1 over-expression had a poorer prognosis than those with SPHK1 under-expression (P ‹ 0.001 and P = 0.011 for survival and tumor recurrence). Conclusions. SPHK1 might represent a novel and useful prognostic marker of HCC progression in patients with PVTT.

REFERENCES

1. Esnaola NF, Mirza N, LauwersGY, Ikai I, Regimbeau JM, Belghiti J, Yamaoka Y, et al. Comparison of clinicopathologic characteristics and outcomes after resection in patients with hepatocellular carcinoma treated in the United States, France, and Japan. Ann Surg 2003; 238: 711-9.

2. Roayaie S, Frischer JS, Emre SH, Fishbein TM, Sheiner PA, Sung M, Miller CM, et al. Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg 2002; 235: 533-9.

3. Poon RT, Fan ST, Ng IO, Wong J. Prognosis after hepatic resection for stage IVA hepatocellular carcinoma: a need for reclassification. Ann Surg 2003; 237: 376-83.

4. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso M del C, Sala M, Brú C, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999; 29: 62-7.

5. Takabe K, Paugh SW, Milstien S, Spiegel S. Inside-out signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 2008; 60: 181-95.

6. Pyne NJ, Pyne S. Sphingosine 1-phosphate and cancer. Nat Rev Cancer 2010;10: 489-503.

7. Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, Zhao R, et al. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res 2012; 72: 726-35.

8. Xia P, Gamble JR, Wang L, Pitson SM, Moretti PA, Wattenberg BW, D’Andrea RJ, et al. An oncogenic role of sphingosine kinase. Curr Biol 2000; 10: 1527-30.

9. Milstien S, Spiegel S. Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. Cancer Cell 2006; 9: 148-50.

10. Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, Grösch S, et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 2008; 112: 41-52.

11. Li W, Yu CP, Xia JT, Zhang L, Weng GX, Zheng HQ, Zheng HQ, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res 2009; 15: 1393-9.

12. Van Brocklyn JR, Jackson CA, Pearl DK, Kotur MS, Snyder PJ, Prior TW. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 2005; 64: 695-705.

13. Shi J, Lai EC, Li N, GuoWX, Xue J, Lau WY, Wu MC, et al. A new classification for hepatocellular carcinoma with portal vein tumor thrombus. J Hepatobiliary Pancreat Sci 2011; 18: 74-80.

14. Shi J, Lai EC, Li N, Guo WX, Xue J, Lau WY, Wu MC, et al. Surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus. Ann Surg Oncol 2010; 17: 2073-80.

15. Lim KC, Chow PK, Allen JC, Chia GS, Lim M, Cheow PC, Chung AY, et al. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann Surg 2011; 254: 108-13.

16. Wang T, Hu HS, FengYX, Shi J, Li N, GuoWX, Xue J, et al. Characterisation of a novel cell line (CSQT-2) with high metastatic activity derived from portal vein tumour thrombus of hepatocellular carcinoma. Br J Cancer 2010; 102: 1618-26.

17. Hu L, Lau SH, Tzang CH, Wen JM, Wang W, Xie D, Huang M, et al. Association of Vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene 2004; 23: 298- 302.

18. Bao M, Chen Z, Xu Y, Zhao Y, Zha R, Huang S, Liu L, et al. Sphingosine kinase 1 promotes tumour cell migration and invasion via the S1P/EDG1 axis in hepatocellular carcinoma. Liver Int 2012; 32: 331-8.

19. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-90.

20. Wang JH, Kuo YH, Wang CC, Chen CL, Cheng YF, Hsu HC, Lu SN. Surgical resection improves the survival of selected hepatocellular carcinoma patients in Barcelona clinic liver cancer stage C. Dig Liver Dis 2013; 45: 510-5.