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Published in: Pathology & Oncology Research 3/2012

01-07-2012 | Research

Upregulation of Bone Morphogenetic Protein 4 is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma

Authors: Xiaodong Guo, Lu Xiong, Lin Zou, Jingmin Zhao

Published in: Pathology & Oncology Research | Issue 3/2012

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Abstract

Bone morphogenetic protein (BMP) 4 plays a crucial role in tumor invasion and metastasis of various human cancers. However, little is known about the correlation of BMP4 expression with clinical aggressiveness and prognosis in hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression of BMP4 in HCC and determine its correlation with tumor progression and prognosis. Immunohistochemistry assay was used to determine the expression of BMP4 in HCC and corresponding paracarcinomatous tissues from 156 patients. The potential prognostic value of BMP4 was investigated by comparing the survival rates between the BMP4-positive and BMP4-negative HCC patients. Immunohistochemically, BMP4 protein expression in the HCC tissues (120/156, 76.9%) was significantly higher than that in the paracarcinomatous tissues (19/156, 12.2%, P < 0.01). The expression of BMP4 in HCC was associated with number of tumor nodules (P = 0.02), Edmondson grade (P = 0.03), TNM stage (P = 0.009), and vascular invasion (P = 0.006). In univariate survival analysis, the significant associations of the BMP4 protein overexpression with shortened patients’ overall and disease-free survival were found (P = 0.001 and 0.006, respectively). Furthermore, its expression was found to be an independent factor for predicting both overall (P = 0.009) and disease-free survival (P = 0.022) of HCC in multivariate analysis. Our data suggest for the first time that BMP4 is overexpressed in HCC tissues and may also act as a novel marker for predicting the recurrence and prognosis of HCC patients after surgery.
Literature
1.
go back to reference Yang H, Lin M, Xiong F, Yang Y, Nie X, McNutt MA, Zhou R (2011) Combined lysosomal protein transmembrane 4 beta-35 and argininosuccinate synthetase expression predicts clinical outcome in hepatocellular carcinoma patients. Surg Today 41:810–817PubMedCrossRef Yang H, Lin M, Xiong F, Yang Y, Nie X, McNutt MA, Zhou R (2011) Combined lysosomal protein transmembrane 4 beta-35 and argininosuccinate synthetase expression predicts clinical outcome in hepatocellular carcinoma patients. Surg Today 41:810–817PubMedCrossRef
2.
go back to reference Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687PubMedCrossRef Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687PubMedCrossRef
3.
go back to reference Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339–346PubMedCrossRef Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339–346PubMedCrossRef
5.
go back to reference Simic P, Vukicevic S (2005) Bone morphogenetic proteins in development and homeostasis of kidney. Cytokine Growth Factor Rev 16:299–308PubMedCrossRef Simic P, Vukicevic S (2005) Bone morphogenetic proteins in development and homeostasis of kidney. Cytokine Growth Factor Rev 16:299–308PubMedCrossRef
6.
go back to reference Marki D, Celi T, Grkovi A, Spanjol J, Fukar Z, Grahovac B, Ethorevi G, Bobinac D (2011) mRNA expression of bone morphogenetic proteins and their receptors in human renal cell carcinoma. Urol Int In press Marki D, Celi T, Grkovi A, Spanjol J, Fukar Z, Grahovac B, Ethorevi G, Bobinac D (2011) mRNA expression of bone morphogenetic proteins and their receptors in human renal cell carcinoma. Urol Int In press
7.
go back to reference Yuen HF, Chan YP, Cheung WL, Wong YC, Wang X, Chan KW (2008) The prognostic significance of BMP-6 signaling in prostate cancer. Mod Pathol 21:1436–1443PubMedCrossRef Yuen HF, Chan YP, Cheung WL, Wong YC, Wang X, Chan KW (2008) The prognostic significance of BMP-6 signaling in prostate cancer. Mod Pathol 21:1436–1443PubMedCrossRef
8.
go back to reference Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K, Mori M (2008) Clinical significance of BMP7 in human colorectal cancer. Ann Surg Oncol 15:1530–1537PubMedCrossRef Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K, Mori M (2008) Clinical significance of BMP7 in human colorectal cancer. Ann Surg Oncol 15:1530–1537PubMedCrossRef
9.
10.
go back to reference Virtanen S, Alarmo EL, Sandström S, Ampuja M, Kallioniemi A (2011) Bone morphogenetic protein −4 and −5 in pancreatic cancer–novel bidirectional players. Exp Cell Res 317:2136–2146PubMedCrossRef Virtanen S, Alarmo EL, Sandström S, Ampuja M, Kallioniemi A (2011) Bone morphogenetic protein −4 and −5 in pancreatic cancer–novel bidirectional players. Exp Cell Res 317:2136–2146PubMedCrossRef
11.
go back to reference McLean K, Gong Y, Choi Y, Deng N, Yang K, Bai S, Cabrera L, Keller E, McCauley L, Cho KR, Buckanovich RJ (2011) Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J Clin Invest 121:3206–3219PubMedCrossRef McLean K, Gong Y, Choi Y, Deng N, Yang K, Bai S, Cabrera L, Keller E, McCauley L, Cho KR, Buckanovich RJ (2011) Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J Clin Invest 121:3206–3219PubMedCrossRef
12.
go back to reference Slattery ML, Lundgreen A, Herrick JS, Kadlubar S, Caan BJ, Potter JD, Wolff RK (2011) Genetic variation in bone morphogenetic protein and colon and rectal cancer. Int J Cancer In press Slattery ML, Lundgreen A, Herrick JS, Kadlubar S, Caan BJ, Potter JD, Wolff RK (2011) Genetic variation in bone morphogenetic protein and colon and rectal cancer. Int J Cancer In press
13.
go back to reference Qiao B, Johnson NW, Chen X, Li R, Tao Q, Gao J (2011) Disclosure of a stem cell phenotype in an oral squamous cell carcinoma cell line induced by BMP-4 via an epithelial-mesenchymal transition. Oncol Rep 26:455–461PubMed Qiao B, Johnson NW, Chen X, Li R, Tao Q, Gao J (2011) Disclosure of a stem cell phenotype in an oral squamous cell carcinoma cell line induced by BMP-4 via an epithelial-mesenchymal transition. Oncol Rep 26:455–461PubMed
14.
go back to reference Ketolainen JM, Alarmo EL, Tuominen VJ, Kallioniemi A (2010) Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4. Breast Cancer Res Treat 124:377–386PubMedCrossRef Ketolainen JM, Alarmo EL, Tuominen VJ, Kallioniemi A (2010) Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4. Breast Cancer Res Treat 124:377–386PubMedCrossRef
15.
go back to reference Shon SK, Kim A, Kim JY, Kim KI, Yang Y, Lim JS (2009) Bone morphogenetic protein-4 induced by NDRG2 expression inhibits MMP-9 activity in breast cancer cells. Biochem Biophys Res Commun 385:198–203PubMedCrossRef Shon SK, Kim A, Kim JY, Kim KI, Yang Y, Lim JS (2009) Bone morphogenetic protein-4 induced by NDRG2 expression inhibits MMP-9 activity in breast cancer cells. Biochem Biophys Res Commun 385:198–203PubMedCrossRef
16.
go back to reference Hjertner O, Hjorth-Hansen H, Borset M, Seidel C, Waage A, Sundan A (2001) Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood 97:516–522PubMedCrossRef Hjertner O, Hjorth-Hansen H, Borset M, Seidel C, Waage A, Sundan A (2001) Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood 97:516–522PubMedCrossRef
17.
go back to reference Maegdefrau U, Arndt S, Kivorski G, Hellerbrand C, Bosserhoff AK (2011) Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. Lab Invest In press Maegdefrau U, Arndt S, Kivorski G, Hellerbrand C, Bosserhoff AK (2011) Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. Lab Invest In press
18.
go back to reference Ishak KG, Anthony PP, Sobin LH (1994) Nonepithelial tumors. In: Ishak KG (ed) Histological typing of tumors of the liver. World Health Organization International Classification of Tumors. Springer, Berlin, pp 22–27 Ishak KG, Anthony PP, Sobin LH (1994) Nonepithelial tumors. In: Ishak KG (ed) Histological typing of tumors of the liver. World Health Organization International Classification of Tumors. Springer, Berlin, pp 22–27
19.
20.
go back to reference Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRef Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRef
21.
go back to reference Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26:2707–2716PubMedCrossRef Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26:2707–2716PubMedCrossRef
22.
go back to reference Shen H, Huang GJ, Gong YW (2003) Effect of transforming growth factor beta and bone morphogenetic proteins on rat hepatic stellate cell proliferation and trans-differentiation. World J Gastroenterol 9:784–787PubMed Shen H, Huang GJ, Gong YW (2003) Effect of transforming growth factor beta and bone morphogenetic proteins on rat hepatic stellate cell proliferation and trans-differentiation. World J Gastroenterol 9:784–787PubMed
23.
go back to reference Slattery ML, Lundgreen A, Herrick JS, Wolff RK, Caan BJ (2011) Genetic variation in the transforming growth factor-β signaling pathway and survival after diagnosis with colon and rectal cancer. Cancer 117:4175–4183PubMedCrossRef Slattery ML, Lundgreen A, Herrick JS, Wolff RK, Caan BJ (2011) Genetic variation in the transforming growth factor-β signaling pathway and survival after diagnosis with colon and rectal cancer. Cancer 117:4175–4183PubMedCrossRef
24.
go back to reference Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L, Gulotta G, Dieli F, de Maria R, Stassi G (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140:297–309PubMedCrossRef Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L, Gulotta G, Dieli F, de Maria R, Stassi G (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140:297–309PubMedCrossRef
25.
go back to reference Lee YC, Cheng CJ, Bilen MA, Lu JF, Satcher RL, Yu-Lee LY, Gallick GE, Maity SN, Lin SH (2011) BMP4 promotes prostate tumor growth in bone through osteogenesis. Cancer Res 71:5194–5203PubMedCrossRef Lee YC, Cheng CJ, Bilen MA, Lu JF, Satcher RL, Yu-Lee LY, Gallick GE, Maity SN, Lin SH (2011) BMP4 promotes prostate tumor growth in bone through osteogenesis. Cancer Res 71:5194–5203PubMedCrossRef
26.
go back to reference Capasso M, Ayala F, Russo R, Avvisati RA, Asci R, Iolascon A (2009) A predicted functional single-nucleotide polymorphism of bone morphogenetic protein-4 gene affects mRNA expression and shows a significant association with cutaneous melanoma in Southern Italian population. J Cancer Res Clin Oncol 135:1799–1807PubMedCrossRef Capasso M, Ayala F, Russo R, Avvisati RA, Asci R, Iolascon A (2009) A predicted functional single-nucleotide polymorphism of bone morphogenetic protein-4 gene affects mRNA expression and shows a significant association with cutaneous melanoma in Southern Italian population. J Cancer Res Clin Oncol 135:1799–1807PubMedCrossRef
27.
go back to reference Deng H, Ravikumar TS, Yang WL (2007) Bone morphogenetic protein-4 inhibits heat-induced apoptosis by modulating MAPK pathways in human colon cancer HCT116 cells. Cancer Lett 256:207–217PubMedCrossRef Deng H, Ravikumar TS, Yang WL (2007) Bone morphogenetic protein-4 inhibits heat-induced apoptosis by modulating MAPK pathways in human colon cancer HCT116 cells. Cancer Lett 256:207–217PubMedCrossRef
28.
go back to reference Hamada S, Satoh K, Hirota M, Fujibuchi W, Kanno A, Umino J, Ito H, Satoh A, Kikuta K, Kume K, Masamune A, Shimosegawa T (2009) Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines. Cancer Sci 100:103–110PubMedCrossRef Hamada S, Satoh K, Hirota M, Fujibuchi W, Kanno A, Umino J, Ito H, Satoh A, Kikuta K, Kume K, Masamune A, Shimosegawa T (2009) Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines. Cancer Sci 100:103–110PubMedCrossRef
29.
go back to reference Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765PubMedCrossRef Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761–765PubMedCrossRef
Metadata
Title
Upregulation of Bone Morphogenetic Protein 4 is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Authors
Xiaodong Guo
Lu Xiong
Lin Zou
Jingmin Zhao
Publication date
01-07-2012
Publisher
Springer Netherlands
Published in
Pathology & Oncology Research / Issue 3/2012
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-011-9488-2

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