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Erschienen in: Medical Oncology 4/2012

01.12.2012 | Original Paper

Coexpression of Bcl-2 with epithelial–mesenchymal transition regulators is a prognostic indicator in hepatocellular carcinoma

verfasst von: Nan Zhao, Bao-cun Sun, Xiu-lan Zhao, Zhi-yong Liu, Tao Sun, Zhi-qiang Qiu, Qiang Gu, Na Che, Xue-yi Dong

Erschienen in: Medical Oncology | Ausgabe 4/2012

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Abstract

The anti-apoptosis factor Bcl-2 is known to contribute to tumorigenesis and metastasis. Epithelial–mesenchymal transition (EMT) may also participate in tumor invasion and metastasis. This study investigated the relationship between coexpression profiles of Bcl-2 and EMT regulators in hepatocellular carcinoma (HCC) tumor samples and clinical outcome. The nuclear (Nu) and cytoplasmic (Cyt) expression of Bcl-2 and the EMT regulators Twist-1, Twist-2, and Snail were determined by immunohistochemical staining in tumor tissue isolated from 97 HCC patients. The clinical prognostic values of both individual protein expression and various expression combinations were investigated using univariate and multivariate survival analysis. Results showed that patients with nuclear expression of Bcl-2 had worse clinical outcomes than patients exhibiting cytoplasmic expression. Overall survival was significantly shorter in HCC patients individually expressing Bcl-2-Nu, Twist-1-Nu, Twist-1-Cyt, and Snail (all P < 0.05). Patients coexpressing Bcl-2-Nu with Twist-1-Nu, Twist-1-Cyt, Twist-2, or Snail had even worse prognoses than those expressing no biomarker or any one biomarker alone (all P < 0.05). Multivariate analysis showed that HCC patients coexpressing Bcl-2-Nu with Twist-1-Cyt had the worst prognosis. This study provides clinical evidence that nuclear expression of Bcl-2 combined with cytoplasmic expression of Twist-1 is a predictor of very poor prognosis in HCC. Coexpression profiles of Bcl-2 and EMT regulators might aid in the selection of the most efficacious therapy for patients with HCC.
Literatur
1.
Zurück zum Zitat Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111:3322–30.PubMedCrossRef Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood. 2008;111:3322–30.PubMedCrossRef
2.
Zurück zum Zitat Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO, Kramer RH. Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res. 2010;8:170–82.PubMedCrossRef Zuo J, Ishikawa T, Boutros S, Xiao Z, Humtsoe JO, Kramer RH. Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis. Mol Cancer Res. 2010;8:170–82.PubMedCrossRef
3.
Zurück zum Zitat Rieger L, Weller M, Bornemann A, Schabet M, Dichgans J, Meyermann R. BCL-2 family protein expression in human malignant glioma: a clinical–pathological correlative study. J Neurol Sci. 1998;155:68–75.PubMedCrossRef Rieger L, Weller M, Bornemann A, Schabet M, Dichgans J, Meyermann R. BCL-2 family protein expression in human malignant glioma: a clinical–pathological correlative study. J Neurol Sci. 1998;155:68–75.PubMedCrossRef
5.
Zurück zum Zitat Del Bufalo D, Biroccio A, Leonetti C, Zupi G. Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. FASEB J. 1997;11:947–53.PubMed Del Bufalo D, Biroccio A, Leonetti C, Zupi G. Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. FASEB J. 1997;11:947–53.PubMed
6.
Zurück zum Zitat Trisciuoglio D, Desideri M, Ciuffreda L, et al. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J Cell Physiol. 2005;205:414–21.PubMedCrossRef Trisciuoglio D, Desideri M, Ciuffreda L, et al. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J Cell Physiol. 2005;205:414–21.PubMedCrossRef
7.
Zurück zum Zitat Biroccio A, Candiloro A, Mottolese M, et al. Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB J. 2000;14:652–60.PubMed Biroccio A, Candiloro A, Mottolese M, et al. Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB J. 2000;14:652–60.PubMed
8.
Zurück zum Zitat Ma C, Zhang J, Durrin LK, et al. The BCL2 major breakpoint region (mbr) regulates gene expression. Oncogene. 2007;26:2649–57.PubMedCrossRef Ma C, Zhang J, Durrin LK, et al. The BCL2 major breakpoint region (mbr) regulates gene expression. Oncogene. 2007;26:2649–57.PubMedCrossRef
9.
Zurück zum Zitat Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59.PubMedCrossRef Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59.PubMedCrossRef
11.
Zurück zum Zitat Heath-Engel HM, Shore GC. Regulated targeting of Bax and Bak to intracellular membranes during apoptosis. Cell Death Differ. 2006;13:1277–80.PubMedCrossRef Heath-Engel HM, Shore GC. Regulated targeting of Bax and Bak to intracellular membranes during apoptosis. Cell Death Differ. 2006;13:1277–80.PubMedCrossRef
12.
Zurück zum Zitat Pinton P, Rizzuto R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 2006;13:1409–18.PubMedCrossRef Pinton P, Rizzuto R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 2006;13:1409–18.PubMedCrossRef
13.
Zurück zum Zitat Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef
14.
Zurück zum Zitat Mani SA, Guo W, Liao MJ, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedCrossRef Mani SA, Guo W, Liao MJ, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedCrossRef
15.
Zurück zum Zitat Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744–9.PubMedCrossRef Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744–9.PubMedCrossRef
16.
Zurück zum Zitat Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66:8319–26.PubMedCrossRef Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66:8319–26.PubMedCrossRef
17.
Zurück zum Zitat Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.PubMedCrossRef Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.PubMedCrossRef
18.
Zurück zum Zitat Sun T, Zhao N, Zhao XL, et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2010;51:545–56.PubMedCrossRef Sun T, Zhao N, Zhao XL, et al. Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology. 2010;51:545–56.PubMedCrossRef
19.
Zurück zum Zitat Rahman MA, Dhar DK, Yamaguchi E, et al. Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res. 2001;7:1325–32.PubMed Rahman MA, Dhar DK, Yamaguchi E, et al. Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res. 2001;7:1325–32.PubMed
20.
Zurück zum Zitat Cheng AL, Huang WG, Chen ZC, et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res. 2008;14:435–45.PubMedCrossRef Cheng AL, Huang WG, Chen ZC, et al. Identification of novel nasopharyngeal carcinoma biomarkers by laser capture microdissection and proteomic analysis. Clin Cancer Res. 2008;14:435–45.PubMedCrossRef
21.
Zurück zum Zitat Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med. 2009;23:469–75.PubMed Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med. 2009;23:469–75.PubMed
22.
Zurück zum Zitat Zhou FF, Yan M, Guo GF, et al. Knockdown of eIF4E suppresses cell growth and migration, enhances chemosensitivity and correlates with increase in Bax/Bcl-2 ratio in triple-negative breast cancer cells. Med Oncol. 2011;28(4):1302-7. Zhou FF, Yan M, Guo GF, et al. Knockdown of eIF4E suppresses cell growth and migration, enhances chemosensitivity and correlates with increase in Bax/Bcl-2 ratio in triple-negative breast cancer cells. Med Oncol. 2011;28(4):1302-7.
23.
Zurück zum Zitat Yook JI, Li XY, Ota I, et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398–406.PubMedCrossRef Yook JI, Li XY, Ota I, et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8:1398–406.PubMedCrossRef
24.
Zurück zum Zitat Yang J, Weinberg RA. Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.PubMedCrossRef Yang J, Weinberg RA. Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.PubMedCrossRef
25.
Zurück zum Zitat Zhao XL, Sun T, Che N, et al. Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial–mesenchymal transition regulator Twist1. J Cell Mol Med. 2011;15:691–700.PubMedCrossRef Zhao XL, Sun T, Che N, et al. Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial–mesenchymal transition regulator Twist1. J Cell Mol Med. 2011;15:691–700.PubMedCrossRef
26.
Zurück zum Zitat Trisciuoglio D, Gabellini C, Desideri M, Ziparo E, Zupi G, Del Bufalo D. Bcl-2 Regulates HIF-1 alpha protein stabilization in hypoxic melanoma cells via the molecular chaperone HSP90. PLoS One. 2010;5(7):e11772. Trisciuoglio D, Gabellini C, Desideri M, Ziparo E, Zupi G, Del Bufalo D. Bcl-2 Regulates HIF-1 alpha protein stabilization in hypoxic melanoma cells via the molecular chaperone HSP90. PLoS One. 2010;5(7):e11772.
27.
Zurück zum Zitat Sun T, Sun BC, Zhao XL, et al. Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma. Hepatology. 2011;54(5):1690-706. doi: 10.1002/hep.24543. Sun T, Sun BC, Zhao XL, et al. Promotion of tumor cell metastasis and vasculogenic mimicry by way of transcription coactivation by Bcl-2 and Twist1: a study of hepatocellular carcinoma. Hepatology. 2011;54(5):1690-706. doi: 10.​1002/​hep.​24543.
28.
Zurück zum Zitat Lee SS, Cho KJ, Hong SI, Myoung NK, Jang JJ. Nuclear overexpression of bcl-2 oncoprotein during the progression of human stomach cancer. J Korean Med Sci. 1998;13:153–8.PubMed Lee SS, Cho KJ, Hong SI, Myoung NK, Jang JJ. Nuclear overexpression of bcl-2 oncoprotein during the progression of human stomach cancer. J Korean Med Sci. 1998;13:153–8.PubMed
29.
Zurück zum Zitat Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81.PubMedCrossRef Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81.PubMedCrossRef
30.
Zurück zum Zitat Zhang X, Wang Q, Ling M-T, Wong YC, Leung SCL, Wang X. Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells. Int J Cancer. 2007;120:1891–8.PubMedCrossRef Zhang X, Wang Q, Ling M-T, Wong YC, Leung SCL, Wang X. Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells. Int J Cancer. 2007;120:1891–8.PubMedCrossRef
31.
Zurück zum Zitat Maestro R, Dei Tos AP, Hamamori Y, et al. twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13:2207–17.PubMedCrossRef Maestro R, Dei Tos AP, Hamamori Y, et al. twist is a potential oncogene that inhibits apoptosis. Genes Dev. 1999;13:2207–17.PubMedCrossRef
32.
Zurück zum Zitat Valsesia-Wittmann S, Magdeleine M, Dupasquier S, et al. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell. 2004;6:625–30.PubMedCrossRef Valsesia-Wittmann S, Magdeleine M, Dupasquier S, et al. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell. 2004;6:625–30.PubMedCrossRef
33.
Zurück zum Zitat Rong Y, Distelhorst CW. Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol. 2008;70:73–91.PubMedCrossRef Rong Y, Distelhorst CW. Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol. 2008;70:73–91.PubMedCrossRef
Metadaten
Titel
Coexpression of Bcl-2 with epithelial–mesenchymal transition regulators is a prognostic indicator in hepatocellular carcinoma
verfasst von
Nan Zhao
Bao-cun Sun
Xiu-lan Zhao
Zhi-yong Liu
Tao Sun
Zhi-qiang Qiu
Qiang Gu
Na Che
Xue-yi Dong
Publikationsdatum
01.12.2012
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 4/2012
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-012-0207-y

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