High tricellulin expression is associated with better survival in human hepatoblastoma
Krisztina Schlachter
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorMónika Gyugos
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorJudit Halász
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorGábor Lendvai
MTA-SE Tumor Progression Research Group, Semmelweis University, Budapest, Hungary
Search for more papers by this authorKornélia Baghy
First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Search for more papers by this authorMiklós Garami
Second Department of Paediatrics, Semmelweis University, Budapest, Hungary
Search for more papers by this authorBenedek Gyöngyösi
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorZsuzsa Schaff
Second Department of Pathology, Semmelweis University, Budapest, Hungary
MTA-SE Tumor Progression Research Group, Semmelweis University, Budapest, Hungary
Search for more papers by this authorCorresponding Author
András Kiss
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Address for correspondence: A Kiss, MD, PhD, 2nd Department of Pathology, Semmelweis University, H-1091 Budapest, Üllőiút 93, Hungary. e-mail: [email protected]Search for more papers by this authorKrisztina Schlachter
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorMónika Gyugos
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorJudit Halász
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorGábor Lendvai
MTA-SE Tumor Progression Research Group, Semmelweis University, Budapest, Hungary
Search for more papers by this authorKornélia Baghy
First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Search for more papers by this authorMiklós Garami
Second Department of Paediatrics, Semmelweis University, Budapest, Hungary
Search for more papers by this authorBenedek Gyöngyösi
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Search for more papers by this authorZsuzsa Schaff
Second Department of Pathology, Semmelweis University, Budapest, Hungary
MTA-SE Tumor Progression Research Group, Semmelweis University, Budapest, Hungary
Search for more papers by this authorCorresponding Author
András Kiss
Second Department of Pathology, Semmelweis University, Budapest, Hungary
Address for correspondence: A Kiss, MD, PhD, 2nd Department of Pathology, Semmelweis University, H-1091 Budapest, Üllőiút 93, Hungary. e-mail: [email protected]Search for more papers by this authorAbstract
Aims
The more differentiated fetal component of hepatoblastoma (HB) is characterized by increased expression of tight junction (TJ) proteins claudin-1 and -2 when compared with embryonal component. Expression patterns of the recently identified TJ protein tricellulin and the epigenetic regulator enzyme EZH2 were investigated in epithelial subtypes of HB and related to survival.
Methods and results
Twenty-one cases of epithelial HBs subtyped as pure fetal (n = 12) and embryonal/fetal (n = 9), along with 16 non-tumorous samples from surrounding liver, were analysed by immunohistochemistry for tricellulin, β-catenin and EZH2 expression. No significant differences were revealed in overall survival between fetal and embryonal/fetal types of HBs. The fetal component, however, showed considerably increased tricellulin expression while the embryonal component displayed significantly increased nuclear EZH2 positivity, in comparison to other epithelial subtypes and non-tumorous surrounding hepatocytes. Strong nuclear β-catenin staining was notably more frequent in embryonal than in fetal types. High tricellulin expression was associated with significantly increased overall survival (P = 0.03), while elevated EZH2 expression was linked to the presence of distant metastases (P = 0.013).
Conclusions
Our data indicate that patients with treated HBs showing high expression of tricellulin have significantly better overall survival, independent of histological subtype. Increased nuclear expression of EZH2 was associated with the presence of distant metastases.
Supporting Information
| Filename | Description |
|---|---|
| his12436-sup-0001-FigS1.jpgimage/jpg, 667 KB | Figure S1. Moderate tricelulin staining in liver tissue surrounding tumour. |
| his12436-sup-0002-FigS2.jpgimage/jpg, 614.8 KB | Figure S2. Tricellulin staining can be seen along the trabeculae formed by hepatocytes in normal fetal liver obtained from a 14 week spontaneously miscarried fetus. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Agarwala S. Primary malignant liver tumors in children. Indian J. Pediatr. 2012; 79; 793–800.
- 2von Schweinitz D. Hepatoblastoma: recent developments in research and treatment. Semin. Pediatr. Surg. 2012; 21; 21–30.
- 3Zimmermann A. The emerging family of hepatoblastoma tumours: from ontogenesis to oncogenesis. Eur. J. Cancer 2005; 41; 1503–1514.
- 4Meyers RL, Rowland JR, Krailo M et al. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr. Blood Cancer 2009; 53; 1016–1022.
- 5Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res. 2005; 65; 9603–9606.
- 6Halasz J, Holczbauer A, Paska C et al. Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma. Hum. Pathol. 2006; 37; 555–561.
- 7Furuse M. Molecular basis of the core structure of tight junctions. Cold Spring Harb. Perspect. Biol. 2010; 2; a002907.
- 8Korompay A, Borka K, Lotz G et al. Tricellulin expression in normal and neoplastic human pancreas. Histopathology 2012; 60; E76–E86.
- 9Purcell R, Childs M, Maibach R et al. HGF/c-Met related activation of beta-catenin in hepatoblastoma. J. Exp. Clin. Cancer Res. 2011; 30; 96.
- 10Taniguchi K, Roberts LR, Aderca IN et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002; 21; 4863–4871.
- 11Cheng AS, Lau SS, Chen Y et al. EZH2-mediated concordant repression of Wnt antagonists promotes beta-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011; 71; 4028–4039.
- 12Hajosi-Kalcakosz S, Dezso K, Bugyik E et al. Enhancer of zeste homologue 2 (EZH2) is a reliable immunohistochemical marker to differentiate malignant and benign hepatic tumors. Diagn. Pathol. 2012; 7; 86.
- 13Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin. Cancer Res. 2011; 17; 2613–2618.
- 14Sudo T, Utsunomiya T, Mimori K et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br. J. Cancer 2005; 92; 1754–1758.
- 15Perilongo G, Malogolowkin M, Feusner J. Hepatoblastoma clinical research: Lessons learned and future challenges. Pediatr. Blood Cancer 2012; 59; 818–821.
- 16Spector LG, Birch J. The epidemiology of hepatoblastoma. Pediatr. Blood Cancer 2012; 59; 776–779.
- 17Tomlinson GE, Kappler R. Genetics and epigenetics of hepatoblastoma. Pediatr. Blood Cancer 2012; 59; 785–792.
- 18Falix FA, Aronson DC, Lamers WH, Hiralall JK, Seppen J. DLK1, a serum marker for hepatoblastoma in young infants. Pediatr. Blood Cancer 2012; 59; 743–745.
- 19Sakamoto LH, De Camargo B, Cajaiba M, Soares FA, Vettore AL. MT1G hypermethylation: A potential prognostic marker for hepatoblastoma. Pediatr. Res. 2010; 67; 387–393.
- 20Purcell R, Childs M, Maibach R et al. Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study. Eur. J. Cancer 2012; 48; 1853–1859.
- 21Hiyama E, Yamaoka H, Matsunaga T et al. High expression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma. Br. J. Cancer 2004; 91; 972–979.
- 22Kiss A, Szepesi A, Lotz G, Nagy P, Schaff Z. Expression of transforming growth factor-alpha in hepatoblastoma. Cancer 1998; 83; 690–697.
10.1002/(SICI)1097-0142(19980815)83:4<690::AID-CNCR9>3.0.CO;2-O CAS PubMed Web of Science® Google Scholar
- 23Chopra A, Iyer VK, Agarwala S et al. Apoptotic protein expression, glycogen content, DNA ploidy and cell proliferation in hepatoblastoma subtyping and their role in prognostication. Pediatr. Surg. Int. 2010; 26; 1173–1178.
- 24Lee CT, Zhang L, Mounajjed T, Wu TT. High mobility group AT-hook 2 is overexpressed in hepatoblastoma. Hum. Pathol. 2013; 44; 802–810.
- 25Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J. Cell Biol. 2005; 171; 939–945.
- 26Kondoh A, Takano K, Kojima T et al. Altered expression of claudin-1, claudin-7, and tricellulin regardless of human papilloma virus infection in human tonsillar squamous cell carcinoma. Acta Otolaryngol. 2011; 131; 861–868.
- 27Patonai A, Erdelyi-Belle B, Korompay A et al. Claudins and tricellulin in fibrolamellar hepatocellular carcinoma. Virchows Arch. 2011; 458; 679–688.
- 28Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium–mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J. Cell Sci. 2003; 116; 1959–1967.
- 29Masuda R, Semba S, Mizuuchi E, Yanagihara K, Yokozaki H. Negative regulation of the tight junction protein tricellulin by Snail-induced epithelial–mesenchymal transition in gastric carcinoma cells. Pathobiology 2010; 77; 106–113.
- 30Mariano C, Palmela I, Pereira P et al. Tricellulin expression in brain endothelial and neural cells. Cell Tissue Res. 2013; 351; 397–407.
- 31Leotlela PD, Wade MS, Duray PH et al. Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility. Oncogene 2007; 26; 3846–3856.
- 32French AD, Fiori JL, Camilli TC et al. PKC and PKA phosphorylation affect the subcellular localization of claudin-1 in melanoma cells. Int. J. Med. Sci. 2009; 6; 93–101.
- 33Dhawan P, Singh AB, Deane NG et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J. Clin. Invest. 2005; 115; 1765–1776.
- 34Islas S, Vega J, Ponce L, Gonzalez-Mariscal L. Nuclear localization of the tight junction protein ZO-2 in epithelial cells. Exp. Cell Res. 2002; 274; 138–148.
- 35Gottardi CJ, Arpin M, Fanning AS, Louvard D. The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell–cell contacts. Proc. Natl Acad. Sci. USA 1996; 93; 10779–10784.
- 36Yamaoka H, Ohtsu K, Sueda T, Yokoyama T, Hiyama E. Diagnostic and prognostic impact of beta-catenin alterations in pediatric liver tumors. Oncol. Rep. 2006; 15; 551–556.
- 37Hinz S, Kempkensteffen C, Christoph F et al. Expression of the polycomb group protein EZH2 and its relation to outcome in patients with urothelial carcinoma of the bladder. J. Cancer Res. Clin. Oncol. 2008; 134; 331–336.
- 38Sasaki M, Ikeda H, Itatsu K et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab. Invest. 2008; 88; 873–882.
- 39Au SL, Wong CC, Lee JM et al. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 2012; 56; 622–631.
- 40Perilongo G, Shafford E, Maibach R et al. Risk-adapted treatment for childhood hepatoblastoma. Final report of the second study of the International Society of Paediatric Oncology–SIOPEL 2. Eur. J. Cancer 2004; 40; 411–421.
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