High expression of Janus kinase 2 in background normal liver tissue of resected hepatocellular carcinoma is associated with worse prognosis

Sonohara,Fuminori; Nomoto,Shuji; Inokawa,Yoshikuni; Hishida,Mitsuhiro; Takano,Nao; Kanda,Mitsuro; Nishikawa,Yoko; Fujii,Tsutomu; Koike,Masahiko; Sugimoto,Hiroyuki; Kodera,Yasuhiro

doi:10.3892/or.2014.3621

High expression of Janus kinase 2 in background normal liver tissue of resected hepatocellular carcinoma is associated with worse prognosis

Authors:
- Fuminori Sonohara
- Shuji Nomoto
- Yoshikuni Inokawa
- Mitsuhiro Hishida
- Nao Takano
- Mitsuro Kanda
- Yoko Nishikawa
- Tsutomu Fujii
- Masahiko Koike
- Hiroyuki Sugimoto
- Yasuhiro Kodera
View Affiliations

Affiliations: Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Published online on: November 25, 2014 https://doi.org/10.3892/or.2014.3621
Pages: 767-773

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

When assessing hepatocellular carcinoma (HCC), it is important to examine prognostic factors in the background normal liver tissue and consider malignant aspects of the primary lesion. Candidate genes were extracted from the background normal liver samples via multiarray analysis. Control samples, termed supernormal (SN) liver, were obtained from 11 cases of metastatic liver cancer. Corresponding normal (CN) liver tissue was surgically obtained from a typical HCC patient with chronic hepatitis C background for comparison. Expression profile and methylation array demonstrated that Janus kinase 2 (JAK2) gene expression was increased by 2.378‑fold in the CN tissue. Methylation array reported a lower value for CN (0.125) than SN tissues (0.748). We then investigated JAK2 expression by real-time quantitative reverse transcription-polymerase chain reaction in 100 consecutive resected HCC cases. The average expression level of JAK2 (normalized to GAPDH) was significantly lower in CN (9.24±6.43, n=100) than in SN (35.21±21.38, n=11) tissues (P<0.001). As such a result was contrary to our expectation, the case used for array analysis seemed to be a rare incidence. One hundred HCC cases were subsequently divided into two groups based on JAK2 expression in the adjacent normal tissue: one consisting of the upper 70% of cases (n=70) and the other of the remaining 30% (n=30). Higher JAK2 expression in the adjacent tissue demonstrated significant correlation with worse survival (P=0.022). Furthermore, multivariate analysis identified higher JAK2 expression in the background normal liver tissue of HCC as an independent prognostic factor (P=0.032). Our findings suggest that higher JAK2 expression in the background normal liver tissue of HCC may be a good prognostic biomarker for resected HCC.

View Figures

View References

1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
2	Rahbari NN, Mehrabi A, Mollberg NM, et al: Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 253:453–469. 2011. View Article : Google Scholar : PubMed/NCBI
3	Kobayashi A, Kawasaki S, Miyagawa S, et al: Results of 404 hepatic resections including 80 repeat hepatectomies for hepatocellular carcinoma. Hepatogastroenterology. 53:736–741. 2006.PubMed/NCBI
4	Chen MS, Li JQ, Zheng Y, et al: A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 243:321–328. 2006. View Article : Google Scholar : PubMed/NCBI
5	Taura K, Ikai I, Hatano E, Fujii H, Uyama N and Shimahara Y: Implication of frequent local ablation therapy for intrahepatic recurrence in prolonged survival of patients with hepatocellular carcinoma undergoing hepatic resection: an analysis of 610 patients over 16 years old. Ann Surg. 244:265–273. 2006. View Article : Google Scholar : PubMed/NCBI
6	Chen PJ, Chen DS, Lai MY, et al: Clonal origin of recurrent hepatocellular carcinomas. Gastroenterology. 96:527–529. 1989.PubMed/NCBI
7	Imamura H, Matsuyama Y, Tanaka E, et al: Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 38:200–207. 2003. View Article : Google Scholar : PubMed/NCBI
8	Portolani N, Coniglio A, Ghidoni S, et al: 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
9	Cucchetti A, Piscaglia F, Caturelli E, et al: Comparison of recurrence of hepatocellular carcinoma after resection in patients with cirrhosis to its occurrence in a surveilled cirrhotic population. Ann Surg Oncol. 16:413–422. 2009. View Article : Google Scholar
10	Matsuda M, Fujii H, Kono H and Matsumoto Y: Surgical treatment of recurrent hepatocellular carcinoma based on the mode of recurrence: repeat hepatic resection or ablation are good choices for patients with recurrent multicentric cancer. J Hepatobiliary Pancreat Surg. 8:353–359. 2001. View Article : Google Scholar : PubMed/NCBI
11	Morimoto O, Nagano H, Sakon M, et al: Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas. J Hepatol. 39:215–221. 2003. View Article : Google Scholar : PubMed/NCBI
12	Nakata T, Seki N, Miwa S, et al: Identification of genes associated with multiple nodules in hepatocellular carcinoma using cDNA microarray: multicentric occurrence or intrahepatic metastasis? Hepatogastroenterology. 55:865–872. 2008.PubMed/NCBI
13	Nomoto S, Yamashita K, Koshikawa K, Nakao A and Sidransky D: Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma. Clin Cancer Res. 8:481–487. 2002.PubMed/NCBI
14	Nomoto S, Kinoshita T, Kato K, et al: Hypermethylation of multiple genes as clonal markers in multicentric hepatocellular carcinoma. Br J Cancer. 97:1260–1265. 2007. View Article : Google Scholar : PubMed/NCBI
15	Stangegaard M: Gene expression analysis using agilent DNA microarrays. Methods Mol Biol. 529:133–145. 2009. View Article : Google Scholar : PubMed/NCBI
16	Bibikova M and Fan JB: GoldenGate assay for DNA methylation profiling. Methods Mol Biol. 507:149–163. 2009. View Article : Google Scholar
17	Okamura Y, Nomoto S, Hayashi M, et al: Identification of the bleomycin hydrolase gene as a methylated tumor suppressor gene in hepatocellular carcinoma using a novel triple-combination array method. Cancer Lett. 312:150–157. 2011. View Article : Google Scholar : PubMed/NCBI
18	Takai D and Jones PA: The CpG island searcher: a new WWW resource. In Silico Biol. 3:235–240. 2003.PubMed/NCBI
19	Wang Z, Zhang G, Wu J and Jia M: Adjuvant therapy for hepatocellular carcinoma: current situation and prospect. Drug Discov Ther. 7:137–143. 2013.PubMed/NCBI
20	Takenaka K, Adachi E, Nishizaki T, et al: Possible multicentric occurrence of hepatocellular carcinoma: a clinicopathological study. Hepatology. 19:889–894. 1994. View Article : Google Scholar : PubMed/NCBI
21	Kumada T, Nakano S, Takeda I, et al: Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 25:87–92. 1997. View Article : Google Scholar : PubMed/NCBI
22	Amato D and Wang C: Resolution of thrombocytopenia with JAK2 mutation in a patient with Gaucher disease. Blood. 122:4287–4288. 2013. View Article : Google Scholar : PubMed/NCBI
23	Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 352:1779–1790. 2005. View Article : Google Scholar : PubMed/NCBI
24	Hellgren G, Jansson JO, Carlsson LM and Carlsson B: The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver. Growth Horm IGF Res. 9:212–218. 1999. View Article : Google Scholar : PubMed/NCBI
25	GeneCards. Weizmann Institute of Science. 2014, Available from http://www.genecards.org.
26	Calvisi DF, Ladu S, Gorden A, et al: Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 130:1117–1128. 2006. View Article : Google Scholar : PubMed/NCBI
27	Cressman DE, Diamond RH and Taub R: Rapid activation of the Stat3 transcription complex in liver regeneration. Hepatology. 21:1443–1449. 1995. View Article : Google Scholar : PubMed/NCBI
28	Trautwein C, Rakemann T, Niehof M, Rose-John S and Manns MP: Acute-phase response factor, increased binding, and target gene transcription during liver regeneration. Gastroenterology. 110:1854–1862. 1996. View Article : Google Scholar : PubMed/NCBI
29	Ono M, Chia DJ, Merino-Martinez R, Flores-Morales A, Unterman TG and Rotwein P: Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone. Mol Endocrinol. 21:1443–1457. 2007. View Article : Google Scholar : PubMed/NCBI
30	Yeh YT, Lee KT, Tsai CJ, Chen YJ and Wang SN: Prolactin promotes hepatocellular carcinoma through Janus kinase 2. World J Surg. 36:1128–1135. 2012. View Article : Google Scholar : PubMed/NCBI
31	Yoshikawa H, Matsubara K, Qian GS, et al: SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 28:29–35. 2001. View Article : Google Scholar : PubMed/NCBI