Functional Analysis of HOXD9 in Human Gliomas and Glioma Cancer Stem Cells

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2011 May 24

PMID 21600039

Citations 50

Authors

Masanao Tabuse

Shigeki Ohta

Yohei Ohashi

Raita Fukaya

Aya Misawa

Kazunari Yoshida

Takeshi Kawase

Hideyuki Saya

Cecile Thirant

Herve Chneiweiss

Yumi Matsuzaki

Hideyuki Okano

Yutaka Kawakami

Masahiro Toda

Affiliations

Soon will be listed here.

Abstract

Background: HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.

Results: In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).

Conclusions: Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target.

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References

Mohankumar K, Perry J, Kannan N, Kohno K, Gluckman P, Emerald B . Transcriptional activation of signal transducer and activator of transcription (STAT) 3 and STAT5B partially mediate homeobox A1-stimulated oncogenic transformation of the immortalized human mammary epithelial cell. Endocrinology. 2008; 149(5):2219-29. DOI: 10.1210/en.2007-1320. View

Patru C, Romao L, Varlet P, Coulombel L, Raponi E, Cadusseau J . CD133, CD15/SSEA-1, CD34 or side populations do not resume tumor-initiating properties of long-term cultured cancer stem cells from human malignant glio-neuronal tumors. BMC Cancer. 2010; 10:66. PMC: 2841664. DOI: 10.1186/1471-2407-10-66. View

Shah N, Sukumar S . The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010; 10(5):361-71. DOI: 10.1038/nrc2826. View

Vescovi A, Galli R, Reynolds B . Brain tumour stem cells. Nat Rev Cancer. 2006; 6(6):425-36. DOI: 10.1038/nrc1889. View

Abdel-Fattah R, Xiao A, Bomgardner D, Pease C, Lopes M, Hussaini I . Differential expression of HOX genes in neoplastic and non-neoplastic human astrocytes. J Pathol. 2006; 209(1):15-24. DOI: 10.1002/path.1939. View

Williams N, Gaynor R, Scoggin S, Verma U, Gokaslan T, Simmang C . Identification and validation of genes involved in the pathogenesis of colorectal cancer using cDNA microarrays and RNA interference. Clin Cancer Res. 2003; 9(3):931-46. View

Gao N, White P, Kaestner K . Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell. 2009; 16(4):588-99. PMC: 2673200. DOI: 10.1016/j.devcel.2009.02.010. View

Liu D, Gu Z, Cao X, Liu H, Li J . Immunocytochemical detection of HoxD9 and Pbx1 homeodomain protein expression in Chinese esophageal squamous cell carcinomas. World J Gastroenterol. 2005; 11(10):1562-6. PMC: 4305705. DOI: 10.3748/wjg.v11.i10.1562. View

Kanemura Y, Mori H, Kobayashi S, Islam O, Kodama E, Yamamoto A . Evaluation of in vitro proliferative activity of human fetal neural stem/progenitor cells using indirect measurements of viable cells based on cellular metabolic activity. J Neurosci Res. 2002; 69(6):869-79. DOI: 10.1002/jnr.10377. View

10.

Hetschko H, Voss V, Horn S, Seifert V, Prehn J, Kogel D . Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma. J Neurooncol. 2007; 86(3):265-72. DOI: 10.1007/s11060-007-9472-6. View

11.

Benjamin R, Capparella J, Brown A . Classification of glioblastoma multiforme in adults by molecular genetics. Cancer J. 2003; 9(2):82-90. DOI: 10.1097/00130404-200303000-00003. View

12.

Ohashi Y, Ueda M, Kawase T, Kawakami Y, Toda M . Identification of an epigenetically silenced gene, RFX1, in human glioma cells using restriction landmark genomic scanning. Oncogene. 2004; 23(47):7772-9. DOI: 10.1038/sj.onc.1208058. View

13.

Singh S, Clarke I, Terasaki M, Bonn V, Hawkins C, Squire J . Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003; 63(18):5821-8. View

14.

Willert K, Brown J, Danenberg E, Duncan A, Weissman I, Reya T . Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003; 423(6938):448-52. DOI: 10.1038/nature01611. View

15.

Barber B, Rastegar M . Epigenetic control of Hox genes during neurogenesis, development, and disease. Ann Anat. 2010; 192(5):261-74. DOI: 10.1016/j.aanat.2010.07.009. View

16.

Son M, Woolard K, Nam D, Lee J, Fine H . SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell. 2009; 4(5):440-52. PMC: 7227614. DOI: 10.1016/j.stem.2009.03.003. View

17.

Murat A, Migliavacca E, Gorlia T, Lambiv W, Shay T, Hamou M . Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol. 2008; 26(18):3015-24. DOI: 10.1200/JCO.2007.15.7164. View

18.

Flagiello D, Poupon M, Cillo C, Dutrillaux B, Malfoy B . Relationship between DNA methylation and gene expression of the HOXB gene cluster in small cell lung cancers. FEBS Lett. 1996; 380(1-2):103-7. DOI: 10.1016/0014-5793(96)00017-8. View

19.

Gangemi R, Griffero F, Marubbi D, Perera M, Capra M, Malatesta P . SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 2008; 27(1):40-8. DOI: 10.1634/stemcells.2008-0493. View

20.

Warot X, Lakkaraju S, Favier B, Haack H, Birling C, Dierich A . Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Development. 1996; 122(2):461-72. DOI: 10.1242/dev.122.2.461. View