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BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma

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Abstract

Background

Our previous study found that B cell translocation gene 2 (BTG2) was hyper-methylated and down-regulated in side population (SP) cells of hepatocellular carcinoma (HCC) cell line. However, its clinical significances and biological impacts on HCC SP cells remained unclear.

Aims

To investigate the prognostic value of BTG2 gene in HCC and its influences on cancer stem cells (CSCs)-like traits of HCC cell line SP cells.

Methods

BTG2 expression in human HCC and adjacent non-cancerous tissues was detected by immunohistochemical staining and quantitative real-time PCR, and also obtained from GEO and TCGA data. Its prognostic values were assessed. Its biological influences on HCC cell line SP cells were evaluated using cell viability, cell cycle, plate clone-forming assay, and chemoresistance in vitro and tumorigenicity in vivo.

Results

BTG2 expression was significantly suppressed in human HCC compared to adjacent non-cancerous tissues. BTG2 expression was correlated with TNM stage, tumor size and vascular invasion. Lower expression of BTG2 was associated with poorer overall survival and disease-free survival. In vitro, overexpression of BTG2 substantially suppressed cell proliferation and accumulation of HCC cell line SP cells in G0/G1 phase. Colony formation ability was markedly suppressed by BTG2 overexpression. Moreover, sensitivity of HCC cell line SP cells to 5-fluorouracil was substantially increased by overexpression of BTG2. Furthermore, tumorigenicity of HCC cell line SP cells transfected with BTG2 plasmids was significantly reduced in vivo.

Conclusions

BTG2 gene could regulate the CSC-like traits of HCC cell line SP cells, and it represented as a molecular prognostic marker for HCC.

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References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111.

    Article  CAS  PubMed  Google Scholar 

  2. Ma S, Chan KW, Hu L, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132:2542–2556.

    Article  CAS  PubMed  Google Scholar 

  3. Yamashita T, Ji J, Budhu A, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–1024.

    Article  CAS  PubMed  Google Scholar 

  4. Yang ZF, Ho DW, Ng MN, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13:153–166.

    Article  CAS  PubMed  Google Scholar 

  5. Zhai JM, Yin XY, Hou X, et al. Analysis of the genome-wide DNA methylation profile of side population cells in hepatocellular carcinoma. Dig Dis Sci. 2013;58:1934–1947.

    Article  CAS  PubMed  Google Scholar 

  6. Boiko AD, Porteous S, Razorenova OV, Krivokrysenko VI, Williams BR, Gudkov AV. A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev. 2006;20:236–252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mah WC, Thurnherr T, Chow PK, et al. Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. PLoS One. 2014;9:e104158.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sung WK, Zheng H, Li S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genetics. 2012;44:765–769.

    Article  CAS  PubMed  Google Scholar 

  9. Burchard J, Zhang C, Liu AM, et al. microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma. Mol Syst Biol. 2010;6:402.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chang B, Li S, He Q, et al. Deregulation of Bmi-1 is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma. Biochim Biophys Acta. 2014;1840:3285–3291.

    Article  CAS  PubMed  Google Scholar 

  11. Duriez C, Falette N, Audoynaud C, et al. The human BTG2/TIS21/PC3 gene: genomic structure, transcriptional regulation and evaluation as a candidate tumor suppressor gene. Gene. 2002;282:207–214.

    Article  CAS  PubMed  Google Scholar 

  12. Ficazzola MA, Fraiman M, Gitlin J, et al. Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis. Carcinogenesis. 2001;22:1271–1279.

    Article  CAS  PubMed  Google Scholar 

  13. Struckmann K, Schraml P, Simon R, et al. Impaired expression of the cell cycle regulator BTG2 is common in clear cell renal cell carcinoma. Cancer Res. 2004;64:1632–1638.

    Article  CAS  PubMed  Google Scholar 

  14. Kawakubo H, Brachtel E, Hayashida T, et al. Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein. Cancer Res. 2006;66:7075–7082.

    Article  CAS  PubMed  Google Scholar 

  15. Wei S, Hao C, Li X, Zhao H, Chen J, Zhou Q. Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells. Tumour Biol. 2012;33:1223–1230.

    Article  CAS  PubMed  Google Scholar 

  16. Hu X, Xing L, Jiao Y, et al. BTG2 overexpression increases the radiosensitivity of breast cancer cells in vitro and in vivo. Oncol Res. 2013;20:457–465.

    Article  CAS  PubMed  Google Scholar 

  17. Coppola V, Musumeci M, Patrizii M, et al. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition. Oncogene. 2013;32:1843–1853.

    Article  CAS  PubMed  Google Scholar 

  18. Park TJ, Kim JY, Oh SP, et al. TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop. Hepatology. 2008;47:1533–1543.

    Article  CAS  PubMed  Google Scholar 

  19. Chen Y, Chen C, Zhang Z, et al. Expression of B-cell translocation gene 2 is associated with favorable prognosis in hepatocellular carcinoma patients and sensitizes irradiation-induced hepatocellular carcinoma cell apoptosis in vitro and in nude mice. Oncol Lett. 2017;13:2366–2372.

    PubMed  PubMed Central  Google Scholar 

  20. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–319.

    Article  CAS  PubMed  Google Scholar 

  21. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–284.

    Article  CAS  PubMed  Google Scholar 

  22. Sachlos E, Risueno RM, Laronde S, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012;149:1284–1297.

    Article  CAS  PubMed  Google Scholar 

  23. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–1174.

    Article  PubMed  Google Scholar 

  24. Oshimori N, Oristian D, Fuchs E. TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015;160:963–976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Van Amerongen R, Bowman AN, Nusse R. Developmental stage and time dictate the fate of Wnt/beta-catenin-responsive stem cells in the mammary gland. Cell Stem Cell. 2012;11:387–400.

    Article  PubMed  Google Scholar 

  26. Vermeulen L, De Sousa EMF, van der Heijden M, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–476.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81472261), the Natural Science Foundation of Guangdong Province (No. 2015A030313032), the Science and Technology Development Projects of Guangdong Province, China (No. 2013B021800122), the Science and Technology Development Projects of Guangzhou, Guangdong, China (No. 201604020044).

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Author notes

  1. Chen-Song Huang and Jing-Ming Zhai have contributed equally to this work.

Authors and Affiliations

  1. Department of Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Chen-Song Huang, Xiao-Xu Zhu, Jian-Peng Cai, Wei Chen, Jian-Hui Li & Xiao-Yu Yin

  2. Department of General Surgery, The First Affiliated Hospital, Henan Science and Technology University, Luoyang, 471000, China

    Jing-Ming Zhai

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  1. Chen-Song Huang
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  2. Jing-Ming Zhai
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  4. Jian-Peng Cai
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  5. Wei Chen
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Correspondence to Xiao-Yu Yin.

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Huang, CS., Zhai, JM., Zhu, XX. et al. BTG2 Is Down-Regulated and Inhibits Cancer Stem Cell-Like Features of Side Population Cells in Hepatocellular Carcinoma. Dig Dis Sci 62, 3501–3510 (2017). https://doi.org/10.1007/s10620-017-4829-y

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  • DOI: https://doi.org/10.1007/s10620-017-4829-y

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