- Volume 44 Issue 9
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Possible role of Pax-6 in promoting breast cancer cell proliferation and tumorigenesis
- Zong, Xiangyun ;
- Yang, Hongjian ;
- Yu, Yang ;
- Zou, Dehong ;
- Ling, Zhiqiang ;
- He, Xiangming ;
- Meng, Xuli
- Received : 2011.01.28
- Accepted : 2011.07.15
- Published : 2011.09.30
Pax 6, a member of the paired box (Pax) family, has been implicated in oncogenesis. However, its therapeutic potential has been never examined in breast cancer. To explore the role of Pax6 in breast cancer development, a lentivirus based short hairpin RNA (shRNA) delivery system was used to knockdown Pax6 expression in estrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cells. Effect of Pax6 silencing on breast cancer cell proliferation and tumorigenesis was analyzed. Pax6-RNAi-lentivirus infection remarkably downregulated the expression levels of Pax6 mRNA and protein in MCF-7 and MDA-MB-231 cells. Accordingly, the cell viability, DNA synthesis, and colony formation were strongly suppressed, and the tumorigenesis in xenograft nude mice was significantly inhibited. Moreover, tumor cells were arrested at G0/G1 phase after Pax6 was knocked down. Pax6 facilitates important regulatory roles in breast cancer cell proliferation and tumor progression, and could serve as a diagnostic marker for clinical investigation.
Breast cancer;Lentivirus;Pax6 shRNA
- Walther, C., Guenet, J. L., Simon, D., Deutsch, U., Jostes, B., Goulding, M. D., Plachov, D., Balling, R. and Gruss, P. (1991) Pax: a murine multigene family of paired box-containing genes. Genomics 11, 424-434. https://doi.org/10.1016/0888-7543(91)90151-4
- Walther, C. and Gruss, P. (1991) Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113, 1435-1449.
- Hill, R. E., Favor, J., Hogan, B. L., Ton, C. C., Saunders, G. F., Hanson, I. M., Prosser, J., Jordan, T., Hastie, N. D. and van Heyningen, V. (1992) Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature 355, 750. https://doi.org/10.1038/355750a0
- Kioussi, C., O'Connell, S., St-Onge, L., Treier, M., Gleiberman, A. S., Gruss, P. and Rosenfeld, M. G. (1999) Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc. Natl. Acad. Sci. U.S.A. 96, 14378-14382. https://doi.org/10.1073/pnas.96.25.14378
- Dohrmann, C., Gruss, P. and Lemaire, L. (2000) Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas. Mech. Dev. 92, 47-54. https://doi.org/10.1016/S0925-4773(99)00324-X
- Maekawa, M., Takashima, N., Arai, Y., Nomura, T., Inokuchi, K., Yuasa, S. and Osumi, N. (2005) Pax6 is required for production and maintenance of progenitor cells in postnatal hippocampal neurogenesis. Genes Cells 10, 1001-1014. https://doi.org/10.1111/j.1365-2443.2005.00893.x
- Osumi, N., Shinohara, H., Numayama-Tsuruta, K. and Maekawa, M. (2008) Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem. Cells 26, 1663-1672. https://doi.org/10.1634/stemcells.2007-0884
- Sakurai, K. and Osumi, N. (2008) The neurogenesis- controlling factor, Pax6, inhibits proliferation and promotes maturation in murine astrocytes. J. Neurosci. 28, 4604-4612. https://doi.org/10.1523/JNEUROSCI.5074-07.2008
- Warren, N., Caric, D., Pratt, T., Clausen, J. A., Asavaritikrai, P., Mason, J. O., Hill, R. E. and Price, D. J. (1999) The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex. Cereb. Cortex 9, 627-635. https://doi.org/10.1093/cercor/9.6.627
- Simpson, T. I. and Price, D. J. (2002) Pax6; a pleiotropic player in development. Bioessays 24, 1041-1051. https://doi.org/10.1002/bies.10174
- Zhang, J., Lu, J. P., Suter, D. M., Krause, K. H., Fini, M. E., Chen, B. and Lu, Q. (2010) Isoform- and dose-sensitive feedback interactions between paired box 6 gene and delta- catenin in cell differentiation and death. Exp. Cell. Res. 316, 1070-1081. https://doi.org/10.1016/j.yexcr.2010.01.006
- Shimizu, N., Watanabe, H., Kubota, J., Wu, J., Saito, R., Yokoi, T., Era, T., Iwatsubo, T., Watanabe, T., Nishina, S., Azuma, N., Katada, T. and Nishina, H. (2009) Pax6-5a promotes neuronal differentiation of murine embryonic stem cells. Biol. Pharm. Bull. 32, 999-1003. https://doi.org/10.1248/bpb.32.999
- Mascarenhas, J. B., Young, K. P., Littlejohn, E. L., Yoo, B. K., Salgia, R. and Lang, D. (2009) PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene. J. Biol. Chem. 284, 27524-27532. https://doi.org/10.1074/jbc.M109.047209
- Hellwinkel, O. J., Kedia, M., Isbarn, H., Budaus, L. and Friedrich, M. G. (2008) Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours. BJU Int. 101, 753-757. https://doi.org/10.1111/j.1464-410X.2007.07322.x
- Shyr, C. R., Tsai, M. Y., Yeh, S., Kang, H. Y., Chang, Y. C., Wong, P. L., Huang, C. C., Huang, K. E. and Chang, C. (2010) Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth. Prostate 70, 190-199.
- Vouyovitch, C. M., Vidal, L., Borges, S., Raccurt, M., Arnould, C., Chiesa, J., Lobie, P. E., Lachuer, J. and Mertani, H. C. (2008) Proteomic analysis of autocrine/paracrine effects of human growth hormone in human mammary carcinoma cells. Adv. Exp. Med. Biol. 617, 493-500. https://doi.org/10.1007/978-0-387-69080-3_49
- Muratovska, A., Zhou, C., He, S., Goodyer, P. and Eccles, M. R. (2003) Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22, 7989-7997. https://doi.org/10.1038/sj.onc.1206766
- Nizamutdinova, I. T., Lee, G. W., Son, K. H., Jeon, S. J., Kang, S. S., Kim, Y. S., Lee, J. H., Seo, H. G., Chang, K. C. and Kim, H. J. (2008) Tanshinone I effectively induces apoptosis in estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cells. Int. J. Oncol. 33, 485-491.
- Anandappa, S. Y., Sibson, R., Platt-Higgins, A., Winstanley, J. H., Rudland, P. S. and Barraclough, R. (2000) Variant estrogen receptor alpha mRNAs in human breast cancer specimens. Int. J. Cancer 88, 209-216. https://doi.org/10.1002/1097-0215(20001015)88:2<209::AID-IJC10>3.0.CO;2-M
- Kashiwagi, Y., Kato, N., Sassa, T., Nishitsuka, K., Yamamoto, T., Takamura, H. and Yamashita, H. (2010) Cotylenin A inhibits cell proliferation and induces apoptosis and PAX6 mRNA transcripts in retinoblastoma cell lines. Mol. Vis. 16, 970-982.
- Niemeier, L. A., Dabbs, D. J., Beriwal. S., Striebel, J. M. and Bhargava, R. (2010) Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod. Pathol. 23, 205-212. https://doi.org/10.1038/modpathol.2009.159
- Phipps, S. M., Love, W. K., White, T., Andrews, L. G. and Tollefsbol, T. O. (2009) Retinoid-induced histone deacetylation inhibits telomerase activity in estrogen receptornegative breast cancer cells. Anticancer Res. 29, 4959-4964.
- Zhang, D., LaFortune, T. A., Krishnamurthy, S., Esteva, F. J., Cristofanilli, M., Liu, P., Lucci, A., Singh, B., Hung, M. C., Hortobagyi, G. N. and Ueno, N. T (2009). Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Clin Cancer Res.15, 6639-6648. https://doi.org/10.1158/1078-0432.CCR-09-0951
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