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Upregulation of HOXB7 promotes the tumorigenesis and progression of gastric cancer and correlates with clinical characteristics

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Tumor Biology

Abstract

Several examples of aberrant homeobox gene expression have been found across a range of cancers, and it is also confirmed that homeobox genes play a critical roles in tumorigenesis and progression. Notwithstanding homeobox B7 (HOXB7) has been documented that its deregulation promotes carcinogenesis and development in gastrointestinal tract, its function in gastric cancer has not been investigated. In this study, HOXB7 expression was examined to be distinctly upregulated in gastric carcinoma GC cell lines and in the tumor relative to normal gastric tissue. High HOXB7 expression was correlated with tumor differentiation (P = 0.025) and TNM stage (P = 0.008). HOXB7 knockdown in BGC-823 and SGC-7901 resulted in decreased migration and invasion with alteration of epithelial-mesenchymal transition (EMT) proteins and influenced proliferation, apoptosis, and cell cycle. Furthermore, complementary DNA (cDNA) microarray, qPCR, and Western blotting were performed to explore potential downstream target genes of HOXB7. HOXB7 is generally overexpressed in GC, associated with patient clinical characteristics, and specifically promotes GC cell malignant biological properties through PIK3R3/AKT signaling pathways, indicating HOXB7 as a causal factor in promoting tumor progression.

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References

  1. Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Cancer Netw. 2010;8:437–47.

    CAS  Google Scholar 

  2. Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R. Guidelines for the management of oesophageal and gastric cancer. Gut. 2011;60:1449–72.

    Article  CAS  PubMed  Google Scholar 

  3. Saka M, Morita S, Fukagawa T, Katai H. Present and future status of gastric cancer surgery. J Pn J Clin Oncol. 2011;41:307–13.

    Article  Google Scholar 

  4. Villanueva MT. Combination therapy: update on gastric cancer in East Asia. Nat Rev Clin Oncol. 2011;8:690.

    Article  PubMed  Google Scholar 

  5. Wu WK, Lee CW, Cho CH, Fan D, Wu K, Yu J, et al. MicroRNA dysregulation in gastric cancer: a new player enters the game. Oncogene. 2010;29:5761–71.

    Article  CAS  PubMed  Google Scholar 

  6. Thiel A, Ristimaki A. Gastric cancer: basic aspects. Helicobacter. 2012;17 Suppl 1:26–9.

    Article  CAS  PubMed  Google Scholar 

  7. Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893–904.

    Article  CAS  PubMed  Google Scholar 

  8. Samuel S, Naora H. Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer. 2005;41:2428–37.

    Article  CAS  PubMed  Google Scholar 

  9. Krumlauf R. Hox genes in vertebrate development. Cell. 1994;78:191–201.

    Article  CAS  PubMed  Google Scholar 

  10. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361–71.

    Article  CAS  PubMed  Google Scholar 

  11. Gu ZD, Chen XM, Zhang W, Gu J. Chen KN: [Expression of 39 HOX genes in esophageal cancer cell lines]. Zhonghua Wei Chang Wai Ke Za Zhi. 2007;10:365–7.

    PubMed  Google Scholar 

  12. Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2002;2:777–85.

    Article  CAS  PubMed  Google Scholar 

  13. Foronda D, de Navas LF, Garaulet DL, Sanchez-Herrero E. Function and specificity of Hox genes. Int J Dev Biol. 2009;53:1404–19.

    Article  PubMed  Google Scholar 

  14. Hombria JC, Lovegrove B. Beyond homeosis—HOX function in morphogenesis and organogenesis. Differentiation. 2003;71:461–76.

    Article  PubMed  Google Scholar 

  15. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361–71.

    Article  CAS  PubMed  Google Scholar 

  16. Beck F. Homeobox genes in gut development. Gut. 2002;51:450–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu YY, Pan YS, Zhu ZG. Homeobox genes and their functions on development and neoplasm in gastrointestinal tract. Eur J Surg Oncol. 2007;33:129–32.

    Article  CAS  PubMed  Google Scholar 

  18. Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, et al. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 2011;17:3569–78.

    Article  CAS  PubMed  Google Scholar 

  19. Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, et al. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 2006;66:9527–34.

    Article  CAS  PubMed  Google Scholar 

  20. Storti P, Donofrio G, Colla S, Airoldi I, Bolzoni M, Agnelli L, et al. HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients. Leukemia. 2011;25:527–37.

    Article  CAS  PubMed  Google Scholar 

  21. Bondos SE, Tan XX, Matthews KS. Physical and genetic interactions link hox function with diverse transcription factors and cell signaling proteins. Mol Cell Proteomics. 2006;5:824–34.

    Article  CAS  PubMed  Google Scholar 

  22. Taghon T, Thys K, De Smedt M, Weerkamp F, Staal FJ, Plum J, et al. Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: Implications for human T-cell development. Leukemia. 2003;17:1157–63.

    Article  CAS  PubMed  Google Scholar 

  23. Lu Z, Hardt J, Kim JJ. Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol Hum Reprod. 2008;14:357–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Garin E, Lemieux M, Coulombe Y, Robinson GW, Jeannotte L. Stromal Hoxa5 function controls the growth and differentiation of mammary alveolar epithelium. Dev Dyn. 2006;235:1858–71.

    Article  CAS  PubMed  Google Scholar 

  25. Kongsuwan K, Webb E, Housiaux P, Adams JM. Expression of multiple homeobox genes within diverse mammalian haemopoietic lineages. EMBO J. 1988;7:2131–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Cantile M, Franco R, Schiavo G, Procino A, Cindolo L, Botti G, et al. The HOX genes network in uro-genital cancers: mechanisms and potential therapeutic implications. Curr Med Chem. 2011;18:4872–84.

    Article  CAS  PubMed  Google Scholar 

  27. Cillo C, Schiavo G, Cantile M, Bihl MP, Sorrentino P, Carafa V, et al. The HOX gene network in hepatocellular carcinoma. Int J Cancer. 2011;129:2577–87.

    Article  CAS  PubMed  Google Scholar 

  28. Kanai M, Hamada J, Takada M, Asano T, Murakawa K, Takahashi Y, et al. Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep. 2010;23:843–51.

    CAS  PubMed  Google Scholar 

  29. De Souza SDM, Bitu CC, Zecchin KG, Graner E, Lopes MA, Kowalski LP, et al. Overexpression of HOXB7 homeobox gene in oral cancer induces cellular proliferation and is associated with poor prognosis. Int J Oncol. 2010;36:141–9.

    Google Scholar 

  30. Chen H, Lee JS, Liang X, Zhang H, Zhu T, Zhang Z, et al. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 2008;68:3637–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Svingen T, Tonissen KF. Altered HOX gene expression in human skin and breast cancer cells. Cancer Biol Ther. 2003;2:518–23.

    Article  CAS  PubMed  Google Scholar 

  32. Makiyama K, Hamada J, Takada M, Murakawa K, Takahashi Y, Tada M, et al. Aberrant expression of HOX genes in human invasive breast carcinoma. Oncol Rep. 2005;13:673–9.

    CAS  PubMed  Google Scholar 

  33. Bitu CC, Carrera M, Lopes MA, Kowalski LP, Soares FA, Coletta RD. HOXB7 expression is a prognostic factor for oral squamous cell carcinoma. Histopathology. 2012;60:662–5.

    Article  PubMed  Google Scholar 

  34. Yuan W, Zhang X, Xu Y, Li S, Hu Y, Wu S. Role of HOXB7 in regulation of progression and metastasis of human lung adenocarcinoma. Mol Carcinog. 2014;53:49–57.

    Article  CAS  PubMed  Google Scholar 

  35. Nguyen KA, Arensman M, Lay AR, Rao NP, Donahue T, Li X, et al. HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma. Cancer-Am Cancer Soc. 2013;119:529–39.

    Google Scholar 

  36. Care A, Felicetti F, Meccia E, Bottero L, Parenza M, Stoppacciaro A, et al. HOXB7: a key factor for tumor-associated angiogenic switch. Cancer Res. 2001;61:6532–9.

    CAS  PubMed  Google Scholar 

  37. Care A, Silvani A, Meccia E, Mattia G, Stoppacciaro A, Parmiani G, et al. HOXB7 constitutively activates basic fibroblast growth factor in melanomas. Mol Cell Biol. 1996;16:4842–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bhatlekar S, Fields JZ, Boman BM. HOX genes and their role in the development of human cancers. J Mol Med (Berl). 2014;92:811–23.

    Article  CAS  Google Scholar 

  39. Massague J. G1 cell-cycle control and cancer. Nature. 2004;432:298–306.

    Article  CAS  PubMed  Google Scholar 

  40. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.

    Article  CAS  PubMed  Google Scholar 

  41. Wu DM, Zhang P, Liu RY, Sang YX, Zhou C, Xu GC, et al. Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K/Akt pathway in colorectal carcinoma. Febs Lett. 2014;588:1921–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants by Natural Science Foundation of Zhejiang Province (CN) [Grant No. LY15H160027].

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Authors and Affiliations

  1. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China

    Jia-qin Cai, **ao-wu Xu, Yi-** Mou, Ke Chen, Yu Pan & Di Wu

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  1. Jia-qin Cai
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  2. **ao-wu Xu
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  3. Yi-** Mou
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  4. Ke Chen
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Correspondence to Yi-** Mou.

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Cai, Jq., Xu, Xw., Mou, YP. et al. Upregulation of HOXB7 promotes the tumorigenesis and progression of gastric cancer and correlates with clinical characteristics. Tumor Biol. 37, 1641–1650 (2016). https://doi.org/10.1007/s13277-015-3948-3

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  • DOI: https://doi.org/10.1007/s13277-015-3948-3

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