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Transducin (Beta)-Like 1 X-Linked Receptor 1 Correlates with Clinical Prognosis and Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma

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Abstract

Background

Recent studies have demonstrated that transducin (beta)-like 1 X-linked receptor 1 (TBLR1) is involved in tumor progression. However, the exact role and clinical significance of TBLR1 in hepatocellular carcinoma (HCC) are poorly understood.

Aim

In this study, we aimed to investigate the expression and clinical significance of TBLR1 in HCC.

Methods

Quantitative polymerase chain reaction and immunohistochemical staining were performed to detect the expression levels of TBLR1 in HCC tissue and adjacent noncancerous tissue (ANT). The relationships between TBLR1 expression and clinicopathological factors were examined in this study. The effects of TBLR1 on epithelial–mesenchymal transition (EMT) of HCC cells were investigated in vitro.

Results

The expression levels of TBLR1 were elevated in HCC cell lines. TBLR1 mRNA in HCC tissue was markedly higher (P < 0.001) than that in ANT. High expression of TBLR1 is closely related to serum alpha fetoprotein (P = 0.047), BCLC stage (P < 0.001), maximum size of tumors (P < 0.001), tumor embolus (P < 0.001), and histological grade (P < 0.001). The disease-free survival and overall survival of HCC patients with high expression of TBLR1 were significantly shorter. Furthermore, we found that EMT of HCC cells could be induced by up-regulating TBLR1 and be inhibited by down-regulating TBLR1. ICG-001, the inhibitor of Wnt/β-catenin signaling, could suppress induction of EMT mediated by TBLR1.

Conclusions

Our finding suggested that TBLR1 is likely to be a potential prognostic indicator and therapeutic target for HCC and that TBLR1 may be implicated in EMT of HCC cells.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol. 2014;35:9–20.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lee TK, Poon RT, Yuen AP, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial–mesenchymal transition. Clin Cancer Res. 2006;12:5369–5376.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang C, Guo F, Xu G, Ma J, Shao F. STAT3 cooperates with Twist to mediate epithelial–mesenchymal transition in human hepatocellular carcinoma cells. Oncol Rep. 2015;33:1872–1882.

    PubMed  Google Scholar 

  5. Zhai B, Yan HX, Liu SQ, Chen L, Wu MC, Wang HY. Reduced expression of E-cadherin/catenin complex in hepatocellular carcinomas. World J Gastroenterol. 2008;14:5665–5673.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Zhai X, Zhu H, Wang W, Zhang S, Zhang Y, Mao G. Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. Med Oncol. 2014;31:970.

    Article  PubMed  Google Scholar 

  7. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–196.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology. 2005;129:1375–1383.

    Article  CAS  PubMed  Google Scholar 

  9. Wang J, Ou J, Guo Y, et al. TBLR1 is a novel prognostic marker and promotes epithelial–mesenchymal transition in cervical cancer. Br J Cancer. 2014;111:112–124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Giannelli G, Villa E, Lahn M. Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014;74:1890–1894.

    Article  CAS  PubMed  Google Scholar 

  11. Yoon HG, Chan DW, Huang ZQ, et al. Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J. 2003;22:1336–1346.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell. 2004;116:511–526.

    Article  CAS  PubMed  Google Scholar 

  13. Perissi V, Scafoglio C, Zhang J, et al. TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints. Mol Cell. 2008;29:755–766.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Choi HK, Choi KC, Yoo JY, et al. Reversible SUMOylation of TBL1-TBLR1 regulates beta-catenin-mediated Wnt signaling. Mol Cell. 2011;43:203–216.

    Article  CAS  PubMed  Google Scholar 

  15. Li J, Wang CY. TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol. 2008;10:160–169.

    Article  CAS  PubMed  Google Scholar 

  16. Li X, Liang W, Liu J, et al. Transducin (beta)-like 1 X-linked receptor 1 promotes proliferation and tumorigenicity in human breast cancer via activation of beta-catenin signaling. Breast Cancer Res. 2014;16:465.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Liu Y, Sun W, Zhang K, et al. Identification of genes differentially expressed in human primary lung squamous cell carcinoma. Lung Cancer. 2007;56:307–317.

    Article  PubMed  Google Scholar 

  18. Bruix J, Sherman M, American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.

    Article  CAS  PubMed  Google Scholar 

  20. Arensman MD, Telesca D, Lay AR, et al. The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth. Mol Cancer Ther. 2014;13:2303–2314.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Wang CJ, Zhou ZG, Holmqvist A, et al. Survivin expression quantified by Image Pro-Plus compared with visual assessment. Appl Immunohistochem Mol Morphol. 2009;17:530–535.

    Article  CAS  PubMed  Google Scholar 

  22. Daniels G, Li Y, Gellert LL, et al. TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth. Endocr Relat Cancer. 2014;21:127–142.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Daniels G, Jha R, Shen Y, Logan SK, Lee P. Androgen receptor coactivators that inhibit prostate cancer growth. Am J Clin Exp Urol. 2014;2:62–70.

    PubMed Central  PubMed  Google Scholar 

  24. Mima K, Hayashi H, Kuroki H, et al. Epithelial–mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: clinical significance of transforming growth factor-beta signaling. Oncol Lett. 2013;5:149–154.

    PubMed Central  PubMed  Google Scholar 

  25. Gotzmann J, Huber H, Thallinger C, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J Cell Sci. 2002;115:1189–1202.

    CAS  PubMed  Google Scholar 

  26. Li L, Li W. Epithelial–mesenchymal transition in human cancer: comprehensive reprogramming of metabolism, epigenetics, and differentiation. Pharmacol Ther. 2015;150:33–46.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Q, Bai X, Chen W, et al. Wnt/beta-catenin signaling enhances hypoxia-induced epithelial–mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. Carcinogenesis. 2013;34:962–973.

    Article  PubMed  Google Scholar 

  28. Yang M, Li SN, Anjum KM, et al. A double-negative feedback loop between Wnt-beta-catenin signaling and HNF4alpha regulates epithelial–mesenchymal transition in hepatocellular carcinoma. J Cell Sci. 2013;126:5692–5703.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was under the support of Natural Science Project of Hunan Province (No. B2014-071).

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Correspondence to Jiye Zhu.

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The authors confirm that there are no conflicts of interest.

Additional information

Xuejun Kuang and Jiye Zhu have contributed equally to this work.

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Kuang, X., Zhu, J., Peng, Z. et al. Transducin (Beta)-Like 1 X-Linked Receptor 1 Correlates with Clinical Prognosis and Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma. Dig Dis Sci 61, 489–500 (2016). https://doi.org/10.1007/s10620-015-3879-2

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