Decreased BMP‑7 and p‑Smad1/5/8 expression, and increased levels of gremlin in hepatocellular carcinoma

Wang,Lina; Ding,Qin; Zhao,Li; Pan,Yu; Song,Zhengxia; Qin,Yanan; Yan,Xuebing

doi:10.3892/ol.2018.8918

Decreased BMP‑7 and p‑Smad1/5/8 expression, and increased levels of gremlin in hepatocellular carcinoma

Authors:
- Lina Wang
- Qin Ding
- Li Zhao
- Yu Pan
- Zhengxia Song
- Yanan Qin
- Xuebing Yan
View Affiliations

Affiliations: Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China, Department of Respiratory, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
Published online on: June 6, 2018 https://doi.org/10.3892/ol.2018.8918
Pages: 2113-2118
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

The aim of the present study was to investigate the expression of bone morphogenetic protein‑7 (BMP‑7), gremlin, and p‑Smad/1/5/8 in carcinomatous and para‑carcinoma tissue specimens from patients with hepatocellular carcinoma (HCC). The association of serum BMP‑7 levels with clinicopathological parameters was examined to assess its relevance as a clinical biomarker for HCC. A total of 27 patients with HCC and 7 healthy subjects were included. Gene expression levels of BMP‑7 and p‑Smad1/5/8 were examined by reverse transcription‑quantitative polymerase chain reaction. Immunohistochemical and western blot analysis were performed to determine the protein expression of target genes. The serum levels of BMP‑7 were assessed by enzyme linked immunosorbent assay. The mRNA and protein expression of BMP‑7 and gremlin were significantly down‑ and upregulated in HCC tumor tissues, respectively, compared with para‑carcinoma tissues (P<0.05). The association of BMP‑7 and gremlin expression with the differentiation status of HCC was also analyzed. There was a relatively higher level of BMP‑7 and a lower level of gremlin expression in tumor tissues from patients with highly differentiated HCC when compared with poorly or moderately differentiated HCC (BMP‑7, F=42.29, P<0.01; gremlin, F=37.93, P<0.01). Furthermore, the level of BMP‑7 and p‑Smad1/5/8 was decreased in patients with advanced stages of HCC, when compared with stage I HCC. The findings from the present study suggest that the BMP‑7/p‑Smad signaling pathway may be involved in the pathogenesis of HCC. The serum levels of BMP‑7 may serve as a potential biomarker for HCC.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	London WT and McGlynn KA: Liver cancer. Cancer Epidemiology and Prevention. Schottenfeld D and Fraumeni J Jr: 3rd ed. Oxford University Press; New York, NY; pp. 763–786. 2006, View Article : Google Scholar
3	Wang X, Zhang A and Sun H: Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatology. 57:2072–2077. 2013. View Article : Google Scholar : PubMed/NCBI
4	Ye L and Jiang WG: Bone morphogenetic proteins in tumour associated angiogenesis and implication in cancer therapies. Cancer Lett. 380:586–597. 2015. View Article : Google Scholar : PubMed/NCBI
5	Naber HP, Wiercinska E, Pardali E, van Laar T, Nirmala E, Sundqvist A, van Dam H, van der Horst G, van der Pluijm G, Heckmann B, et al: BMP-7 inhibits TGF-beta-induced invasion of breast cancer cells through inhibition of integrin beta(3) expression. Cell Oncol (Dordr). 35:19–28. 2012. View Article : Google Scholar : PubMed/NCBI
6	Buijs JT, van der Horst G, van den Hoogen C, Cheung H, de Rooij B, Kroon J, Petersen M, van Overveld PG, Pelger RC and van der Pluijm G: The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation. Oncogene. 31:2164–2174. 2012. View Article : Google Scholar : PubMed/NCBI
7	Tate CM, Pallini R, Ricci-Vitiani L, Dowless M, Shiyanova T, D'Alessandris GQ, Morgante L, Giannetti S, Larocca LM, di Martino S, et al: A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. Cell Death Differ. 19:1644–1654. 2012. View Article : Google Scholar : PubMed/NCBI
8	Hou F, Liu R, Liu X, Cui L, Wen Y, Yan S and Yin C: Attenuation of liver fibrosis by herbal compound 861 via upregulation of BMP-7/Smad signaling in the bile duct ligation model rat. Mol Med Rep. 13:4335–4342. 2016. View Article : Google Scholar : PubMed/NCBI
9	Ji X, Jin S, Qu X, Li K, Wang H, He H, He H, Guo F and Dong L: Lysine-specific demethylase 5C promotes hepatocellular carcinoma cell invasion through inhibition BMP7 expression. BMC Cancer. 15:8012015. View Article : Google Scholar : PubMed/NCBI
10	Liu J, Saito K, Maruya Y, Nakamura T, Yamada A, Fukumoto E, Ishikawa M, Iwamoto T, Miyazaki K, Yoshizaki K, et al: Mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-induced Smad1/5/8 phosphorylation. Sci Rep. 6:236702016. View Article : Google Scholar : PubMed/NCBI
11	Lopez-Coviella I, Mellott TM, Kovacheva VP, Berse B, Slack BE, Zemelko V, Schnitzler A and Blusztajn JK: Developmental pattern of expression of BMP receptors and Smads and activation of Smad1 and Smad5 by BMP9 in mouse basal forebrain. Brain Res. 1088:49–56. 2006. View Article : Google Scholar : PubMed/NCBI
12	Brazil DP, Church RH, Surae S, Godson C and Martin F: BMP signalling: Agony and antagony in the family. Trends Cell Biol. 25:249–264. 2015. View Article : Google Scholar : PubMed/NCBI
13	Boers W, Aarrass S, Linthorst C, Pinzani M, Elferink RO and Bosma P: Transcriptional profiling reveals novel markers of liver fibrogenesis: Gremlin and insulin-like growth factor-binding proteins. J Biol Chem. 281:16289–16295. 2006. View Article : Google Scholar : PubMed/NCBI
14	Guimei M, Baddour N, Elkaffash D, Abdou L and Taher Y: Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: An immunohistochemical and PCR study of human liver biopsies. BMC Res Notes. 5:3902012. View Article : Google Scholar : PubMed/NCBI
15	Professional Committee of Chinese Anti-Cancer Association of liver cancer: Primary liver cancer diagnosis and staging criteria. Zhonghua Hepatology. 9:3242001.
16	Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Miao Y, Zong M, Jiang T, Yuan X, Guan S, Wang Y and Zhou D: A comparative analysis of ESM-1 and vascular endothelial cell marker (CD34/CD105) expression on pituitary adenoma invasion. Pituitary. 19:194–201. 2016. View Article : Google Scholar : PubMed/NCBI
19	Tejeda-Maldonado J, Garcia-Juarez I, Aguirre-Valadez J, Gonzalez-Aguirre A, Vilatoba-Chapa M, Armengol-Alonso A, Escobar-Penagos F, Torre A, Sánchez-Ávila JF and Carrillo-Pérez DL: Diagnosis and treatment of hepatocellular carcinoma: An update. World J Hepatol. 7:362–376. 2015. View Article : Google Scholar : PubMed/NCBI
20	Yang T, Chen SL, Lu XJ, Shen CY, Liu Y and Chen YP: Bone morphogenetic protein 7 suppresses the progression of hepatic fibrosis and regulates the expression of gremlin and transforming growth factor beta1. Mol Med Rep. 6:246–252. 2012.PubMed/NCBI
21	Wang LP, Dong JZ, Xiong LJ, Shi KQ, Zou ZL, Zhang SN, Cao ST, Lin Z and Chen YP: BMP-7 attenuates liver fibrosis via regulation of epidermal growth factor receptor. Int J Clin Exp Pathol. 7:3537–3547. 2014.PubMed/NCBI
22	Chen BL, Peng J, Li QF, Yang M, Wang Y and Chen W: Exogenous bone morphogenetic protein-7 reduces hepatic fibrosis in Schistosoma japonicum-infected mice via transforming growth factor-beta/Smad signaling. World J Gastroenterol. 19:1405–1415. 2013. View Article : Google Scholar : PubMed/NCBI
23	Jones CN, Tuleuova N, Lee JY, Ramanculov E, Reddi AH, Zern MA and Revzin A: Cultivating hepatocytes on printed arrays of HGF and BMP7 to characterize protective effects of these growth factors during in vitro alcohol injury. Biomaterials. 31:5936–5944. 2010. View Article : Google Scholar : PubMed/NCBI
24	Li W, Cai HX, Ge XM, Li K, Xu WD and Shi WH: Prognostic significance of BMP7 as an oncogene in hepatocellular carcinoma. Tumour Biol. 34:669–674. 2013. View Article : Google Scholar : PubMed/NCBI
25	Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H and Kalluri R: Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 282:23337–23347. 2007. View Article : Google Scholar : PubMed/NCBI
26	Aktug Demir N, Kolgelier S, Inkaya AC, Sumer S, Demir LS, Pehlivan FS, Arslan M and Arpaci A: Are bone morphogenetic protein-7 (BMP-7) serum levels correlated with development of hepatic fibrosis? J Infect Dev Ctries. 8:605–610. 2014. View Article : Google Scholar : PubMed/NCBI
27	Tacke F, Gabele E, Bataille F, Schwabe RF, Hellerbrand C, Klebl F, Straub RH, Luedde T, Manns MP, Trautwein C, et al: Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. Dig Dis Sci. 52:3404–3415. 2007. View Article : Google Scholar : PubMed/NCBI
28	Daniele B, Bencivenga A, Megna AS and Tinessa V: Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology. 127(Suppl 1): S108–S112. 2004. View Article : Google Scholar : PubMed/NCBI