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

  • Wenping Ma
  • Hongze Jin
  • Wenjie Liu
  • Xiaojuan Li
  • Xingang Zhou
  • Xinwu Guo
  • Runfa Tian
  • Qi Cui
  • Junjie Luo
  • Yueying Jiao
  • Youtao YuEmail author
  • Haifeng YangEmail author
  • Hongshan ZhaoEmail author
Original Article


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.


HOXB8 Glioma Aggressiveness SAMD9 Treatment 



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).

Conflict of interest

The authors declare no competing interests.

Supplementary material

12264_2019_436_MOESM1_ESM.pdf (1.9 mb)
Supplementary material 1 (PDF 1980 kb)


  1. 1.
    Ostrom QT, Gittleman H, Stetson L, Virk SM, Barnholtz-Sloan JS. Epidemiology of gliomas. Cancer Treat Res 2015, 163: 1–14.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 3.
    DeWeerdt S. The genomics of brain cancer. Nature 2018, 561: S54–S55.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.Google Scholar
  6. 6.
    Perry A, Wesseling P. Histologic classification of gliomas. Handb Clin Neurol 2016, 134: 71–95.CrossRefGoogle Scholar
  7. 7.
    Birk HS, Han SJ, Butowski NA. Treatment options for recurrent high-grade gliomas. CNS Oncol 2017, 6: 61–70.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 12.
    Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 2010, 10: 361–371.CrossRefGoogle Scholar
  13. 13.
    Quinonez SC, Innis JW. Human HOX gene disorders. Mol Genet Metab 2014, 111: 4–15.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 15.
    Domsch K, Papagiannouli F, Lohmann I. The HOX-apoptosis regulatory interplay in development and disease. Curr Top Dev Biol 2015, 114: 121–158.CrossRefGoogle Scholar
  16. 16.
    Bakalenko NI, Novikova EL, Nesterenko AY, Kulakova MA. Hox gene expression during postlarval development of the polychaete Alitta virens. Evodevo 2013, 4: 13.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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. Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Wenping Ma
    • 1
    • 2
    • 3
  • Hongze Jin
    • 4
  • Wenjie Liu
    • 5
  • Xiaojuan Li
    • 6
  • Xingang Zhou
    • 7
  • Xinwu Guo
    • 8
  • Runfa Tian
    • 2
  • Qi Cui
    • 1
  • Junjie Luo
    • 1
  • Yueying Jiao
    • 1
  • Youtao Yu
    • 9
    Email author
  • Haifeng Yang
    • 10
    Email author
  • Hongshan Zhao
    • 1
    Email author
  1. 1.Department of Medical Genetics, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
  2. 2.Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
  3. 3.Beijing Neurosurgical InstituteBeijingChina
  4. 4.The Second Affiliated Hospital of Zhejiang University School of MedicineChangxingChina
  5. 5.Department of Hepatobiliary Surgery, National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  6. 6.Department of RadiologyThe First Hospital of Harbin Medical UniversityHarbinChina
  7. 7.Department of PathologyBeijing Ditan Hospital, Capital Medical UniversityBeijingChina
  8. 8.Sansure Biotech Inc.ChangshaChina
  9. 9.Department of Intervention TherapyThe Fourth Medical Center of PLA General HospitalBeijingChina
  10. 10.Department of NeurosurgerySanbo Brain Hospital, Capital Medical UniversityBeijingChina

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