Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B‑related hepatocellular carcinoma following octreotide long‑acting release treatment

Liu,Yao; Jiang,Li; Mu,Yi

doi:10.3892/ol.2013.1435

Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B‑related hepatocellular carcinoma following octreotide long‑acting release treatment

Authors:
- Yao Liu
- Li Jiang
- Yi Mu
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Affiliations: Department of Pediatric Surgery, National Center for Cardiovascular Disease and Fuwei Hospital, Chinese Acadamy of Medical Sciences, Peking Union Medical College, Beijing 100037, P.R. China, Department of Hepatobiliary Surgery, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, P.R. China
Published online on: July 1, 2013 https://doi.org/10.3892/ol.2013.1435
Pages: 821-828

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Abstract

Liver resections for hepatocellular carcinoma (HCC) in cirrhotic livers are associated with early recurrence and poor survival. Somatostatin analogues (SSAs) have been reported to inhibit cell proliferation by interacting with specific somatostatin receptors (SSTRs) 2 and 5. The present study investigated whether SSTR expression in HCC was associated with the clinical outcome following octreotide long‑acting release (LAR) treatment. Paired tumor and cirrhotic liver samples were obtained following a liver resection from 99 patients with stage I‑II HCC and HBV‑related cirrhosis. The expression of SSTR2 and 5 was assessed using quantitative (q)PCR and immunohistochemistry. The patients were classified into two groups, the high expression (n=47) and low expression (n=52) groups, based on the gene expression levels. The clinicopathological data and survival results of the two groups were compared. When compared with the surrounding cirrhotic tissue, the SSTR2 and 5 mRNA levels were significantly decreased in the HCC tissue. There were no significant differences between the groups with respect to the baseline characteristics. The tumor recurrence rate was significantly lower in the high expression group compared with that of the low expression group (63.83% vs. 82.69%; P=0.033). The 1‑, 3‑ and 5‑year disease‑free and overall survival rates of the high expression group were 97, 89 and 71% and 98, 89 and 74%, respectively. The survival time of the members of the high expression group was longer compared with that of the low expression group. The multivariate analysis revealed that the TNM‑7 stage and SSTR2 expression were independent prognostic factors for survival. In conclusion, SSTR mRNA expression correlated with survival in patients with early‑stage hepatitis B virus (HBV)‑related HCC who were treated with octreotide LAR following surgery. The inhibitory effects of SSAs on tumor growth may be mediated by SSTR expression.

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1	Bosch FX, Ribes J, Cléries R and Díaz M: Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 9:191–211. 2005. View Article : Google Scholar : PubMed/NCBI
2	Yuen MF, Hou JL and Chutaputti A; Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol. 24:346–353. 2009. View Article : Google Scholar : PubMed/NCBI
3	El-Serag HB, Siegel AB, Davila JA, et al: Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the United States: a population-based study. J Hepatol. 44:158–166. 2006. View Article : Google Scholar : PubMed/NCBI
4	Yeh CN, Chen MF, Lee WC and Jeng LB: Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis. J Surg Oncol. 81:195–202. 2002. View Article : Google Scholar : PubMed/NCBI
5	Nagasue N, Ono T, Yamanoi A, et al: Prognostic factors and survival after hepatic resection for hepatocellular carcinoma without cirrhosis. Br J Surg. 88:515–522. 2001. View Article : Google Scholar : PubMed/NCBI
6	Izumi N: Prediction and prevention of intrahepatic recurrence of hepatocellular carcinoma. Hepatol Res. 42:226–232. 2012. View Article : Google Scholar : PubMed/NCBI
7	Susini C and Buscail L: Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol. 17:1733–1742. 2006. View Article : Google Scholar : PubMed/NCBI
8	Reynaert H, Rombouts K, Vandermonde A, et al: Expression of somatostatin receptors in normal and cirrhotic human liver and in hepatocellular carcinoma. Gut. 53:1180–1189. 2004. View Article : Google Scholar : PubMed/NCBI
9	Bläker M, Schmitz M, Gocht A, et al: Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas. J Hepatol. 41:112–118. 2004.PubMed/NCBI
10	Reubi JC, Zimmermann A, Jonas S, et al: Regulatory peptide receptors in human hepatocellular carcinomas. Gut. 45:766–774. 1999. View Article : Google Scholar : PubMed/NCBI
11	Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, et al: Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol. 13:3164–3170. 2007.
12	Cebon J, Findlay M, Hargreaves C, et al; Australasian Gastro-Intestinal Trials Group (AGITG) Ag0001H Investigators. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer. 95:853–861. 2006. View Article : Google Scholar
13	Borbath I and Horsmans Y: The results of a randomized study on the use of long-acting octreotide in hepatocellular carcinoma. Hepatology. 37:477–478. 2003.PubMed/NCBI
14	Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J and Manousos ON: Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut. 42:442–447. 1998. View Article : Google Scholar : PubMed/NCBI
15	Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, et al: The role of sandostatin LAR in treating patients with advanced hepatocellular cancer. Hepatogastroenterology. 49:1245–1250. 2002.PubMed/NCBI
16	Samonakis DN, Moschandreas J, Arnaoutis T, et al: Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep. 9:903–907. 2002.PubMed/NCBI
17	Yuen MF, Poon RT, Lai CL, et al: A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology. 36:687–691. 2002. View Article : Google Scholar : PubMed/NCBI
18	Becker G, Allgaier HP, Olschewski M, et al; HECTOR Study Group. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology. 45:9–15. 2007. View Article : Google Scholar : PubMed/NCBI
19	Barbare JC, Bouché O, Bonnetain F, et al: Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer. 45:1788–1797. 2009. View Article : Google Scholar
20	Edmondson HA and Steiner PE: Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 7:462–503. 1954. View Article : Google Scholar : PubMed/NCBI
21	Sobin LH and Compton CC: TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 116:5336–5339. 2010.
22	Fasciani A, Quilici P, Biscaldi E, et al: Overexpression and functional relevance of somatostatin receptor-1, -2, and -5 in endometrium and endometriotic lesions. J Clin Endocrinol Metab. 95:5315–5319. 2010. View Article : Google Scholar : PubMed/NCBI
23	Raulf F, Pérez J, Hoyer D and Bruns C: Differential expression of five somatostatin receptor subtypes, SSTR1–5, in the CNS and peripheral tissue. Digestion. 55(Suppl 3): 46–53. 1994.
24	Pawlikowski M and Melen-Mucha G: Perspectives of new potential therapeutic applications of somatostatin analogs. Neuro Endocrinol Lett. 24:21–27. 2003.PubMed/NCBI
25	Xie YM, Yan LN, Wei B, Guo MM and Tang CW: Correlation of somatostatin receptor expression in human hepatocellular carcinoma tissue to serum alpha-fetoprotein concentration. Ai Zheng. 26:688–692. 2007.(In Chinese).
26	Li M, Li W, Kim HJ, Yao Q, Chen C and Fisher WE: Characterization of somatostatin receptor expression in human pancreatic cancer using real-time RT-PCR. J Surg Res. 119:130–137. 2004. View Article : Google Scholar : PubMed/NCBI
27	Jia WD, Xu GL, Wang W, et al: A somatostatin analogue, octreotide, inhibits the occurrence of second primary tumors and lung metastasis after resection of hepatocellular carcinoma in mice. Tohoku J Exp Med. 218:155–160. 2009. View Article : Google Scholar
28	Papotti M, Bongiovanni M, Volante M, et al: Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 440:461–475. 2002.
29	Sestini R, Orlando C, Peri A, et al: Quantitation of somatostatin receptor type 2 gene expression in neuroblastoma cell lines and primary tumors using competitive reverse transcription-polymerase chain reaction. Clin Cancer Res. 2:1757–1765. 1996.
30	Orlando C, Raggi CC, Bianchi S, et al: Measurement of somatostatin receptor subtype 2 mRNA in breast cancer and corresponding normal tissue. Endocr Relat Cancer. 11:323–332. 2004. View Article : Google Scholar : PubMed/NCBI
31	Buscail L, Saint-Laurent N, Chastre E, et al: Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer. Cancer Research. 56:1823–1827. 1996.PubMed/NCBI
32	Casini Raggi C, Calabrò A, Renzi D, et al: Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa. Clin Cancer Res. 8:419–427. 2002.PubMed/NCBI
33	Kumar M, Liu ZR, Thapa L and Qin RY: Anti-angiogenic effects of somatostatin receptor subtype2 on human pancreatic cancer xenografts. Carcinogenesis. 25:2075–2081. 2004. View Article : Google Scholar : PubMed/NCBI
34	Zhou T, Xiao X, Xu B, Li H and Zou Y: Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways. Acta Oncol. 48:401–410. 2009. View Article : Google Scholar : PubMed/NCBI
35	Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A and Vigneri R: The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 114:23–37. 2008. View Article : Google Scholar : PubMed/NCBI
36	Guillermet J, Saint-Laurent N, Rochaix P, et al: Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc Natl Acad Sci USA. 100:155–160. 2003. View Article : Google Scholar