Skip to main content

Advertisement

SpringerLink
Log in

Homeobox B8 Targets Sterile Alpha Motif Domain-Containing Protein 9 and Drives Glioma Progression

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Gliomas are the most commonly occurring tumors of the central nervous system. Glioblastoma multiforme (GBM) is the most malignant and aggressive brain cancer in adults. Further understanding of the mechanisms underlying the aggressive nature of GBM is urgently needed. Here we identified homeobox B8 (HOXB8), a member of the homeobox family, as a crucial contributor to the aggressiveness of GBM. Data mining of publicly accessible RNA sequence datasets and our patient cohorts confirmed a higher expression of HOXB8 in the tumor tissue of GBM patients, and a strong positive correlation between the expression level and pathological grading of tumors and a negative correlation between the expression level and the overall survival rate. We next showed that HOXB8 promotes the proliferation and migration of glioblastoma cells and is crucial for the activation of the PI3K/AKT pathway and expression of epithelial–mesenchymal transition-related genes, possibly through direct binding to the promoter of SAMD9 (Sterile Alpha Motif Domain-Containing Protein 9) and activating its transcription. Collectively, we identified HOXB8 as a critical contributor to the aggressiveness of GBM, which provides insights into a potential therapeutic target for GBM and opens new avenues for improving its treatment outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Ostrom QT, Gittleman H, Stetson L, Virk SM, Barnholtz-Sloan JS. Epidemiology of gliomas. Cancer Treat Res 2015, 163: 1–14.

    Article  Google Scholar 

  2. Schwab DE, Lepski G, Borchers C, Trautmann K, Paulsen F, Schittenhelm J. Immunohistochemical comparative analysis of MAP-2, NOGO-A, OLIG-2 and WT-1 expression in WHO 2016 classified neuroepithelial tumours and their prognostic value. Pathol Res Pract 2018, 214: 15–24.

    Article  CAS  Google Scholar 

  3. DeWeerdt S. The genomics of brain cancer. Nature 2018, 561: S54–S55.

    Article  CAS  Google Scholar 

  4. Xie H, Wang M, Bonaldo Mde F, Rajaram V, Stellpflug W, Smith C, et al. Epigenomic analysis of Alu repeats in human ependymomas. Proc Natl Acad Sci U S A 2010, 107: 6952–6957.

    Article  CAS  Google Scholar 

  5. Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017, 355.

  6. Perry A, Wesseling P. Histologic classification of gliomas. Handb Clin Neurol 2016, 134: 71–95.

    Article  Google Scholar 

  7. Birk HS, Han SJ, Butowski NA. Treatment options for recurrent high-grade gliomas. CNS Oncol 2017, 6: 61–70.

    Article  CAS  Google Scholar 

  8. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016, 164: 550–563.

    Article  CAS  Google Scholar 

  9. Sehmer EA, Hall GJ, Greenberg DC, O’Hara C, Wallingford SC, Wright KA, et al. Incidence of glioma in a northwestern region of England, 2006-2010. Neuro Oncol 2014, 16: 971–974.

    Article  Google Scholar 

  10. Lu VM, Welby JP, Mahajan A, Laack NN, Daniels DJ. Reirradiation for diffuse intrinsic pontine glioma: a systematic review and meta-analysis. Childs Nerv Syst 2019, 35: 739–746.

    Article  Google Scholar 

  11. Kieran MW, Goumnerova L, Manley P, Chi SN, Marcus KJ, Manzanera AG, et al. Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. Neuro Oncol 2019, 21: 537–546.

    Article  CAS  Google Scholar 

  12. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 2010, 10: 361–371.

    Article  CAS  Google Scholar 

  13. Quinonez SC, Innis JW. Human HOX gene disorders. Mol Genet Metab 2014, 111: 4–15.

    Article  CAS  Google Scholar 

  14. Kutejova E, Engist B, Self M, Oliver G, Kirilenko P, Bobola N. Six2 functions redundantly immediately downstream of Hoxa2. Development 2008, 135: 1463–1470.

    Article  CAS  Google Scholar 

  15. Domsch K, Papagiannouli F, Lohmann I. The HOX-apoptosis regulatory interplay in development and disease. Curr Top Dev Biol 2015, 114: 121–158.

    Article  CAS  Google Scholar 

  16. Bakalenko NI, Novikova EL, Nesterenko AY, Kulakova MA. Hox gene expression during postlarval development of the polychaete Alitta virens. Evodevo 2013, 4: 13.

    Article  CAS  Google Scholar 

  17. Pastori C, Kapranov P, Penas C, Peschansky V, Volmar CH, Sarkaria JN, et al. The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc Natl Acad Sci U S A 2015, 112: 8326–8331.

    Article  CAS  Google Scholar 

  18. Hutlet B, Theys N, Coste C, Ahn MT, Doshishti-Agolli K, Lizen B, et al. Systematic expression analysis of Hox genes at adulthood reveals novel patterns in the central nervous system. Brain Struct Funct 2016, 221: 1223–1243.

    Article  CAS  Google Scholar 

  19. Vider BZ, Zimber A, Hirsch D, Estlein D, Chastre E, Prevot S, et al. Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun 1997, 232: 742–748.

    Article  CAS  Google Scholar 

  20. Sugimachi K, Matsumura T, Hirata H, Uchi R, Ueda M, Ueo H, et al. Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br J Cancer 2015, 112: 532–538.

    Article  CAS  Google Scholar 

  21. Ding WJ, Zhou M, Chen MM, Qu CY. HOXB8 promotes tumor metastasis and the epithelial-mesenchymal transition via ZEB2 targets in gastric cancer. J Cancer Res Clin Oncol 2017, 143: 385–397.

    Article  CAS  Google Scholar 

  22. Stavnes HT, Holth A, Don T, Kaern J, Vaksman O, Reich R, et al. HOXB8 expression in ovarian serous carcinoma effusions is associated with shorter survival. Gynecol Oncol 2013, 129: 358–363.

    Article  CAS  Google Scholar 

  23. Kelppe J, Thoren H, Ristimaki A, Haglund C, Sorsa T, Hagstrom J. BRAF V600E expression in ameloblastomas-A 36-patient cohort from Helsinki University Hospital. Oral Dis 2019, 25: 1169–1174.

    Article  Google Scholar 

  24. Nishida H, Kashima K, Yano S, Daa T, Arakane M, Oyama Y, et al. A biotin tagging immunoelectron microscopy for paraffin-embedded sections. Appl Immunohistochem Mol Morphol 2019. https://doi.org/10.1097/pai.0000000000000735.

    Article  PubMed  Google Scholar 

  25. Sousa DA, Silva K, Cascon CM, Silva FBF, Mello MFV, Leite JDS, et al. Epidermal growth factor receptor 2 immunoexpression in gastric cells of domestic cats with H. heilmannii infection. Acta Histochem 2019, 121: 413–418.

    Article  Google Scholar 

  26. Schimanski CC, Frerichs K, Rahman F, Berger M, Lang H, Galle PR, et al. High miR-196a levels promote the oncogenic phenotype of colorectal cancer cells. World J Gastroenterol 2009, 15: 2089–2096.

    Article  CAS  Google Scholar 

  27. Hershkovitz D, Gross Y, Nahum S, Yehezkel S, Sarig O, Uitto J, et al. Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis. J Invest Dermatol 2011, 131: 662–669.

    Article  CAS  Google Scholar 

  28. Tanaka M, Shimbo T, Kikuchi Y, Matsuda M, Kaneda Y. Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ-E) or type I interferon. Int J Cancer 2010, 126: 1982–1991.

    Article  CAS  Google Scholar 

  29. Li CF, MacDonald JR, Wei RY, Ray J, Lau K, Kandel C, et al. Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics 2007, 8: 92.

    Article  Google Scholar 

  30. Ma Q, Yu T, Ren YY, Gong T, Zhong DS. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer. Biochem Biophys Res Commun 2014, 454: 157–161.

    Article  CAS  Google Scholar 

  31. Tang S, Zheng X, He L, Qiao L, Jing D, Ni Z, et al. Significance of SAMD9 expression in esophageal squamous cell carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2014, 30: 411–413.

    CAS  PubMed  Google Scholar 

  32. Yan X, Mai L, Lin C, He W, Yin G, Yu J, et al. CSF-based analysis for identification of potential serum biomarkers of neural tube defects. Neurosci Bull 2017, 33: 436–444.

    Article  CAS  Google Scholar 

  33. Paech D, Dreher C, Regnery S, Meissner JE, Goerke S, Windschuh J, et al. Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients. Eur Radiol 2019, 29: 4957–4967.

    Article  Google Scholar 

  34. Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011, 146: 209–221.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to give special thanks to Dr. Wangshu Xu for her helpful editing improvements and Dr. Hongqiang Du for his contributions to trial management. This work was supported by the National Natural Science Foundation of China (31571298).

Author information

Authors and Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Wenping Ma, Qi Cui, Junjie Luo, Yueying Jiao & Hongshan Zhao

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China

    Wenping Ma & Runfa Tian

  3. Beijing Neurosurgical Institute, Beijing, 100050, China

    Wenping Ma

  4. The Second Affiliated Hospital of Zhejiang University School of Medicine, Changxing Campus, Changxing, 313100, China

    Hongze Jin

  5. Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Wenjie Liu

  6. Department of Radiology, The First Hospital of Harbin Medical University, Harbin, 150001, China

    Xiaojuan Li

  7. Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Xingang Zhou

  8. Sansure Biotech Inc., Changsha, 410205, China

    Xinwu Guo

  9. Department of Intervention Therapy, The Fourth Medical Center of PLA General Hospital, Beijing, 100037, China

    Youtao Yu

  10. Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China

    Haifeng Yang

Authors
  1. Wenping Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongze Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenjie Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaojuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xingang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinwu Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Runfa Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qi Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Junjie Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yueying Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Youtao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Haifeng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hongshan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Youtao Yu, Haifeng Yang or Hongshan Zhao.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1980 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, W., Jin, H., Liu, W. et al. Homeobox B8 Targets Sterile Alpha Motif Domain-Containing Protein 9 and Drives Glioma Progression. Neurosci. Bull. 36, 359–371 (2020). https://doi.org/10.1007/s12264-019-00436-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-019-00436-y

Keywords

Search

Navigation