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Tumor Biology

, Volume 37, Issue 5, pp 5751–5760 | Cite as

Tumor suppressor NGX6 inhibits the growth and metastasis of multiple cancers

  • Shiwei He
  • Yancheng Zhong
  • Cijun Shuai
  • Dan Gao
  • Pingpin Wei
  • Guiyuan Li
  • Shuping Peng
Review
  • 265 Downloads

Abstract

Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a membrane protein primarily located in the nuclear membrane and cell membrane. Several groups reported that NGX6 gene was down-regulated in nasopharyngeal carcinoma (NPC), gastric cancer, lung cancer, liver cancer, and colorectal cancer and even less in the carcinomas with metastasis. Current studies have demonstrated that NGX6 possesses various biological functions, such as regulating protein expression of related genes, involving cell signal transduction pathways, negatively controlling cell cycle progression, inhibiting angiogenesis, and increasing the sensitivity of patients to anti-cancer drugs. Some factors regulating the expression level of NGX6 gene also have been studied. The methylation of promoter of NGX6 and histone H3K9 negatively regulates its expression, similar to the function of transcription factor special protein-1 (Sp1). However, the regulatory factor early growth response gene 1 (Egr-1) is provided with positive regulation function. This review will summarize the progress of those studies on NGX6 and elucidate the potential application of NGX6 for some malignant diseases.

Keywords

Tumor suppressor NGX6 Growth Metastasis 

Notes

Acknowledgments

This work was supported by the Natural Science Foundation of China (81572577), Program for New Century Excellent Talents in University (NCET-12-0544), Overseas, Hong Kong & Macao Scholars Collaborated Researching Fund of National Natural Science Foundation of China (81428018), 111 Project (111-2-12), National 863 Plan (2012AA02A206), Fundamental Research Funds for the Central Universities (2013JSJJ046), Hunan Province Natural Science Foundation of China (10JJ7003), and Open-End Fund for the Valuable and Precision Instruments of Central South University.

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Cao Y, DePinho RA, Ernst M, Vousden K. Cancer research: past, present and future. Nat Rev Cancer. 2011;11(10):749–54.CrossRefPubMedGoogle Scholar
  2. 2.
    McNeish IA, Bell SJ, Lemoine NR. Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Ther. 2004;11(6):497–503.CrossRefPubMedGoogle Scholar
  3. 3.
    Salazar-Montes AM, Hernandez-Ortega LD, Lucano-Landeros MS, Armendariz-Borunda J. New gene therapy strategies for hepatic fibrosis. World J Gastroenterol. 2015;21(13):3813–25.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yang J, Bin L, Li Z, Zhang X, Qian J, Zhang B, et al. Refined localization and cloning of a novel putative tumor suppressor gene associated with nasopharyngeal carcinoma on chromosome 9p21-22. Chin J Cancer. 2000;19(1):6–9.Google Scholar
  5. 5.
    Ma J, Zhou J, Fan S, Wang L, Li X, Yan Q, et al. Role of a novel EGF-like domain-containing gene NGX6 in cell adhesion modulation in nasopharyngeal carcinoma cells. Carcinogenesis. 2005;26(2):281–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Lin ZF, Shen XY, Lu FZ, Ruan Z, Huang HL, Zhen J. Reveals new lung adenocarcinoma cancer genes based on gene expression. Eur Rev Med Pharmacol. 2012;16(9):1249–56.Google Scholar
  7. 7.
    Su Z, Wang X, Shen S, Wang L, Li Y, Li N, et al. Expression of 2 transcripts of NGX6 gene in colorectal cancer and the correlation with carcinoembryonic antigen. J Cent South Univ (Med Sci). 2010;35(5):401–08.Google Scholar
  8. 8.
    Li X, Li J, Huang Y, Dong L, Zhang Q, Tan C, et al. Expression and purification of NGX6 in Escherichia coli. Life Sci Res. 2003;7(2):151–55.Google Scholar
  9. 9.
    Tang X, Long C, Liu F, Lv H, Hu J, Shen S. Expression of BRD7 and NGX6 gene in acute leukemia. Cancer Res Prev Treat. 2008;35(9):635–38.Google Scholar
  10. 10.
    Peng SP, Li XL, Wang L, Ou-Yang J, Ma J, Wang LL, et al. The role of NGX6 and its deletion mutants in the proliferation, adhesion and migration of nasopharyngeal carcinoma 5-8F cells. Oncology. 2006;71(3–4):273–81.PubMedGoogle Scholar
  11. 11.
    Wang L, Xiang B, Yi M, Zhang WL, Yang JB, Peng SP, et al. Identification of a new seven-span transmembrane protein: NGX6a is downregulated in nasopharyngeal carcinoma and is associated with tumor metastasis. J Histochem Cytochem. 2010;58(1):41–51.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu MJ, Wang XY, Shen SR, Li N, Zhang DC, Peng Y, et al. Cloning and identification of promoter of suppressed-tumor gene NGX6. Prog Biochem Biophys. 2010;37(10):1082–9.CrossRefGoogle Scholar
  13. 13.
    Ma J, Zhou J, Li X, Gong J, He X, Tang K, et al. Changes of expression profile induced by NGX6 transfection in nasopharyngeal carcinoma cells. Chin J Biochem Mol Biol. 2002;18(4):416–22.Google Scholar
  14. 14.
    Wang L, Zhang Q, Ma J, Peng C, Cao L, Tang K, et al. Role of NGX6 in nasopharyngeal carcinoma with high ability of metastasis cell line 5-8F. Prog Biochem Biophys. 2005;32(7):618–24.Google Scholar
  15. 15.
    Wang XY, Wu MH, Liu F, Li Y, Li N, Li GY, et al. Differential miRNA expression and their target genes between NGX6-positive and negative colon cancer cells. Mol Cell Biochem. 2010;345(1–2):283–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Peng S, Fan S, Li X, Wang L, Liu H, Zhou M, et al. The expression of ezrin in NPC and its interaction with NGX6, a novel candidate suppressor. Cancer Sci. 2007;98(3):341–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Li X, Wu M, Li G. Functional genomics of nasopharyngeal carcinoma a susceptibility/suppressor gene. J Cent South Univ (Med Sci). 2007;33(7):553–58.Google Scholar
  18. 18.
    Wang L, Li XL, Xiang B, Zhou M, Li XY, Xiong W, et al. NGX6a is degraded through a proteasome-dependent pathway without ubiquitination mediated by Ezrin, a cytoskeleton-membrane linker. J Biol Chem. 2014;289(52):35731–42.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Guo Q, Shen S, Liao M, Lian P, Wang X. NGX6 inhibits cell invasion and adhesion through suppression of Wnt/beta-catenin signal pathway in colon cancer. Acta Biochim Biophys Sin (Shanghai). 2010;42(7):450–56.CrossRefGoogle Scholar
  20. 20.
    Li Y, Luo Y, Wang X, Shen S, Yu H, Yang J, et al. Tumor suppressor gene NGX6 induces changes in protein expression profiles in colon cancer HT-29 cells. Acta Biochim Biophys Sin (Shanghai). 2012;44(7):584–90.CrossRefGoogle Scholar
  21. 21.
    Lian P, Guo Q, Peng Y, Xiao Z, Liu F, Wang X, et al. Effect of NGX6 gene with 5-FU on the apoptosis of colon cancer cells. Chin J Clin Oncol. 2009;36(21):1239–42,47.Google Scholar
  22. 22.
    Peng S, Li X, Li H, Wang L, Zhou M, Zhou H, et al. Inhibitory effect of NGX6 gene on migration and mobility of nasopharyngeal carcinoma cells. Chin J Biochem Mol Biol. 2007;23(4):309–15.Google Scholar
  23. 23.
    Liu F, Wang XY, Lian P, Xiao ZM, Shen SR, Ma J, et al. Effect of NGX6 on gene expression profile of colon carcinoma cell line HT-29. Chin J Cancer. 2005;24(9):1064–70.Google Scholar
  24. 24.
    Liu F, Shen S, Li H, Wang X, Peng Y, Liao M, et al. Effects of NGX6 on the transcriptional activation of β-catenin signal pathway. J Cent South Univ (Med Sci). 2007;32(6):985–91.Google Scholar
  25. 25.
    Guo Q, Wu M, Lian P, Liao M, Xiao Z, Wang X, et al. Synergistic effect of indomethacin and NGX6 on proliferation and invasion by human colorectal cancer cells through modulation of the Wnt/beta-catenin signaling pathway. Mol Cell Biochem. 2009;330(1–2):71–81.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu MH, Li XY, Li XL, Li GY. Signaling transduction network mediated by tumor suppressor/susceptibility genes in NPC. Curr Genom. 2009;10(4):216–22.CrossRefGoogle Scholar
  27. 27.
    Wang L, Ma J, Li J, Li X, Zhang Q, Peng S, et al. NGX6 gene inhibits cell proliferation and plays a negative role in EGFR pathway in nasopharyngeal carcinoma cells. J Cell Biochem. 2005;95(1):64–73.CrossRefPubMedGoogle Scholar
  28. 28.
    Wang L. Molecular mechanism of Ezrin facilitating degradation of NGX6a protein promoting invasion and metastasis in nasopharyngeal carcinoma cells [Doctoral thesis]. Hunan: Central South University; 2009.Google Scholar
  29. 29.
    Peng Y, Li H, Wu M, Wang X, Fan S, Liu F, et al. NGX6 inhibits AP-1 and Ets-1 expression and down-regulates cyclin D1 in human colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 2009;41(6):504–14.CrossRefGoogle Scholar
  30. 30.
    Wang XY, Shen SR, Liu F, Peng Y, Li GY, Fan SQ. Inhibitory effects of NGX6 gene on EGFR/K-ras/JNK/c-Jun/cyclin D1 signal pathway in the colon cancer. Prog Biochem Biophys. 2008;35(5):570–6.Google Scholar
  31. 31.
    Zhao WJ, Wang K. NGX6 expression improves the sensitivity of tamoxifen-resistant MCF-7 cells through modulation of the Smad signaling pathway. Int J Oncol. 2013;42(6):2060–68.PubMedGoogle Scholar
  32. 32.
    Wang G, Jiang Q, Zhang R, Shen S, Li Y. Expression of NGX6, CyclinD1 protein in esophageal squamous cell carcinoma tissue and their significance. China Oncol. 2010;20(12):887–91.Google Scholar
  33. 33.
    Wang XY, Shen SR, Liu F, Li XL, Fan SQ. Effects of NGX6 gene on cell cycle in colon cancer cell line HT-29. Prog Biochem Biophys. 2006;33(1):45–50.Google Scholar
  34. 34.
    Ma J, Li J, Zhou J, Li XL, Tang K, Zhou M, et al. Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array. J Cancer Res Clin Oncol. 2002;128(12):683–90.CrossRefPubMedGoogle Scholar
  35. 35.
    Li J, Huang Y, Zhang Q, Tan C, Li X, Li G. NGX6 effect on the cell cycle of NPC cell line HNE1 cells. Life Sci Res. 2002;6(4):300–04.Google Scholar
  36. 36.
    Zhang H, Tao F, Cao X, Yang Z. Expressions of NGX6 and p21 WAF1 in colorectal carcinoma and their clinical significance. Mod Pract Med. 2012;14(7):733–34,810.Google Scholar
  37. 37.
    Lian P, Guo Q, Peng Y, Xiao Z, Liu F, Wang X, et al. Nasopharyngeal carcinoma-associated gene 6 inhibits tumor angiogenesis in colon cancer. World Chin J Digestol. 2009;17(25):2577–84.CrossRefGoogle Scholar
  38. 38.
    Zhang J, Wang Z, Shi X, Meng W, Ma F, Wang J, et al. NGX6 gene combined with cisplatin in treatment of lung cancer in vitro and in vivo. Chin J Biochem Pharm. 2015;35(5):33–6.Google Scholar
  39. 39.
    Fan S, Zhang W, Zhou M, Peng S, Li G. Study of in situ expression of NGX6 in the several common types of cancer and its clinical significance. Prog Biochem Biophys. 2008;35(9):1014–20.Google Scholar
  40. 40.
    Wang X, Shen S, Liu H, Zhang X, Peng C, Huang H, et al. Effects of tumor suppressor gene NGX6 on growth of human colon cancer cell line HT-29. World Chin J Digestol. 2004;12(3):574–79.Google Scholar
  41. 41.
    Zhang XM, Wang XY, Sheng SR, Wang JR, Li J. Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer. World J Gastroenterol. 2003;9(8):1729–33.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Xiao Z, Shen S, Lian P, Wang X, Liu F. Intraspleenic tumor model of nude mice in the anti-metastasis roles of a NGX6 gene against colon cancer. J Cent South Univ (Med Sci). 2007;32(5):753–57.Google Scholar
  43. 43.
    Lian P, Guo Q, Peng Y, Xiao ZM, Liu F, Wang XY, et al. The role of NGX6 gene on apoptosis of human colon cancer. Prog Biochem Biophys. 2008;35(10):1154–60.Google Scholar
  44. 44.
    Zhang X, Sheng S, Wang X, Wang J, Li J. Expression of tumor related gene NGX6 in gastric cancer and colorectal cancer. World Chin J Digestol. 2001;10(8):873–76.Google Scholar
  45. 45.
    Xiao J, Zhou Y, Liu B. Correlation of NGX6 expression with clinicopathologic features and prognosis in colon cancer. Int J Clin Exp Med. 2015;8(8):13644–48.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Liu J, Zhu X, Xu X, Dai D. DNA promoter and histone H3 methylation downregulate NGX6 in gastric cancer cells. Med Oncol. 2014;31(1):817.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhang H, Cao X, Fan G, Sun G, Yang Z, Gu H, et al. Expression of NGX6 and cyclin D1 in gastric carcinoma and its clinical significance. Chin J Cancer Prev Treat. 2012;19(18):612–14.Google Scholar
  48. 48.
    Xiao J, Shen S. Expression and significance of NGX6 gene in human hepatocellular carcinoma. J Cent South Univ (Med Sci). 2008;33(10):937–41.Google Scholar
  49. 49.
    Eskandari-Nasab E, Hashemi M, Rezaei H, Fazaeli A, Mashhadi MA, Moghaddam SS, et al. Evaluation of UDP-glucuronosyltransferase 2B17 (UGT2B17) and dihydrofolate reductase (DHFR) genes deletion and the expression level of NGX6 mRNA in breast cancer. Mol Biol Rep. 2012;39(12):10531–39.CrossRefPubMedGoogle Scholar
  50. 50.
    Xiao J, Zhou Y, Zhu W. Association of ultrasonographic features with NGX6 expression and prognosis in invasive ductal breast carcinoma. Int J Clin Exp Pathol. 2015;8(6):6458–65.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Xiong W, Zeng ZY, Li XL, Li WF, Li J, He L, et al. Single-nucleotide polymorphisms in NGX6 gene and their correlation with nasopharyngeal carcinoma. Acta Bioch Bioph Sin (Shanghai). 2002;34(4):512–15.Google Scholar
  52. 52.
    Liu M, Peng Y, Wang X, Guo Q, Shen S, Li G. NGX6 gene mediated by promoter methylation as a potential molecular marker in colorectal cancer. BMC Cancer. 2010;10:160.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Liu M, Wang X, Peng Y, Shen S, Li G. Egr-1 regulates the transcription of NGX6 gene through a Sp1/Egr-1 overlapping site in the promoter. BMC Mol Biol. 2014;15:14.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chew MMS, Gan SY, Khoo ASB, Tan EL. Interleukins, laminin and Epstein-Barr virus latent membrane protein 1 (EBV LMP1) Promote metastatic phenotype in nasopharyngeal carcinoma. BMC Cancer. 2010;10:574.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cross D, Burmester JK. Gene therapy for cancer treatment: past, present and future. Clin Med Res. 2006;4(3):218–27.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Li J, Huang Y, Li W, Tan C, Zhang Q, Peng C, et al. The effects of NGX6 on cells from human nasopharyngeal carcinoma cell line HNE1. Chin J Biochem Mol Biol. 2002;18(4):398–03.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Shiwei He
    • 1
    • 2
  • Yancheng Zhong
    • 1
    • 2
  • Cijun Shuai
    • 3
  • Dan Gao
    • 1
    • 2
  • Pingpin Wei
    • 1
    • 2
  • Guiyuan Li
    • 1
    • 2
  • Shuping Peng
    • 1
    • 2
  1. 1.Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
  2. 2.Cancer Research Institute, School of Basic Medical ScienceCentral South UniversityChangshaChina
  3. 3.Orthopedic Biomedical Materials InstituteCentral South UniversityChangshaChina

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