Advertisement

Cancer Immunology, Immunotherapy

, Volume 68, Issue 7, pp 1157–1169 | Cite as

Clinicopathological implications of TIM3+ tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients

  • Jinpeng Zhou
  • Yang Jiang
  • Haiying Zhang
  • Lian Chen
  • Peng Luo
  • Long Li
  • Junshuang Zhao
  • Fei Lv
  • Dan Zou
  • Ye ZhangEmail author
  • Zhitao JingEmail author
Original Article

Abstract

Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan–Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.

Keywords

Skull base chordoma TIM3 Galectin–9 CD8 FOXp3 miR-455-5p 

Abbreviations

ATCC

American Type Culture Collection

C-Cbl

C-Casitas B lineage lymphoma

CD8

Cluster of differentiation 8

CT

Computed tomography

CTLA-4

Cytolytic T lymphocyte-associated Ag-4

Gal9

Galectin-9

HE

Hematoxylin and eosin

KPS

Karnofsky performance status

LRFS

Local recurrence-free survival

MiRNAs

MicroRNAs

NC

Negative control

qPCR

Quantitative real-time polymerase chain reaction

SOX9

Sex-determining region Y (SRY)-box 9

TIM3

T-cell immunoglobulin and mucin-domain 3

Notes

Author contributions

ZJ and YZ conceived and designed the study; JZ and YJ performed the experiments and collected the data; HZ, JZ, LC, PL, LL, JZ, and YJ produced the figures and tables; all authors performed the analysis and analyzed the data. JZ, YJ, YZ, and ZJ interpreted results and wrote the manuscript. FL, DZ, and HZ modified the manuscript. All authors read and approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81101917, 81270036, 30901736), the Liaoning Province Natural Science Foundation (No. 20170541022), the Plan to Focus on Research and Development from Science and Technology project of Liaoning Province (No. 2017225029), the Science and Technology Plan Project of Shenyang City (No. 18-014-4-11), and the Fund for Scientific Research of The First Hospital of China Medical University (No. FHCMU-FSR).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

The study was approved by the Research Ethics Committee of the First Hospital of China Medical University and was in accordance with the ethical standards of the institutional committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study approval number is AF-SOP-07-01.

Informed consent

Informed consent was obtained from all individual participants included in the study. With approval from the National Science Foundation of China (81101917), we designed informed consent forms that were signed by eligible patients before recruitment into the study and admission to the hospital. The patients agreed to the use of their specimens and clinical data for research purposes only.

Cell line authentication

The human chordoma cell line UM-Chor1 was obtained as a gift from Professor Yazhuo Zhang, Department of Neurosurgery, Beijing Tiantan Hospital. The origin of UM-Chor1 was human clivus chordoma tissue. The American Type Culture Collection (ATCC) performed authentication of cell line UM-Chor1 via cytochrome C oxidase I assay and short tandem repeat analysis. We obtained a cell line authentication certificate from the ATCC.

Supplementary material

262_2019_2349_MOESM1_ESM.pdf (633 kb)
Supplementary material 1 (PDF 632 kb)

References

  1. 1.
    McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM (2001) Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12(1):1–11Google Scholar
  2. 2.
    Heffelfinger MJ, Dahlin DC, MacCarty CS, Beabout JW (1973) Chordomas and cartilaginous tumors at the skull base. Cancer 32(2):410–420Google Scholar
  3. 3.
    Salisbury JR (1993) The pathology of the human notochord. J Pathol 171(4):253–255.  https://doi.org/10.1002/path.1711710404 Google Scholar
  4. 4.
    Stacchiotti S, Sommer J (2015) Building a global consensus approach to chordoma: a position paper from the medical and patient community. Lancet Oncol 16(2):e71–e83.  https://doi.org/10.1016/s1470-2045(14)71190-8 Google Scholar
  5. 5.
    Chibbaro S, Cornelius JF, Froelich S, Tigan L, Kehrli P, Debry C, Romano A, Herman P, George B, Bresson D (2014) Endoscopic endonasal approach in the management of skull base chordomas—clinical experience on a large series, technique, outcome, and pitfalls. Neurosurg Rev 37(2):217–224.  https://doi.org/10.1007/s10143-013-0503-9 (discussion 224–215) Google Scholar
  6. 6.
    Di Maio S, Rostomily R, Sekhar LN (2012) Current surgical outcomes for cranial base chordomas: cohort study of 95 patients. Neurosurgery 70(6):1355–1360.  https://doi.org/10.1227/neu.0b013e3182446783 (discussion 1360) Google Scholar
  7. 7.
    Hines JP, Ashmead MG, Stringer SP (2014) Clival chordoma of the nasal septum secondary to surgical pathway seeding. Am J Otolaryngol 35(3):431–434.  https://doi.org/10.1016/j.amjoto.2013.12.018 Google Scholar
  8. 8.
    Koutourousiou M, Gardner PA, Tormenti MJ, Henry SL, Stefko ST, Kassam AB, Fernandez-Miranda JC, Snyderman CH (2012) Endoscopic endonasal approach for resection of cranial base chordomas: outcomes and learning curve. Neurosurgery 71(3):614–624.  https://doi.org/10.1227/neu.0b013e31825ea3e0 (discussion 624–615) Google Scholar
  9. 9.
    Jackson CM, Lim M, Drake CG (2014) Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res 20(14):3651–3659.  https://doi.org/10.1158/1078-0432.CCR-13-2057 Google Scholar
  10. 10.
    Dougan M, Dranoff G (2009) Immune therapy for cancer. Annu Rev Immunol 27:83–117.  https://doi.org/10.1146/annurev.immunol.021908.132544 Google Scholar
  11. 11.
    Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214.  https://doi.org/10.1016/j.cell.2015.03.030 Google Scholar
  12. 12.
    Garber ST, Hashimoto Y, Weathers SP, Xiu J, Gatalica Z, Verhaak RG, Zhou S, Fuller GN, Khasraw M, de Groot J, Reddy SK, Spetzler D, Heimberger AB (2016) Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neurooncology 18(10):1357–1366.  https://doi.org/10.1093/neuonc/now132 Google Scholar
  13. 13.
    Lim M, Xia Y, Bettegowda C, Weller M (2018) Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol.  https://doi.org/10.1038/s41571-018-0003-5 Google Scholar
  14. 14.
    Sounni NE, Noel A (2013) Targeting the tumor microenvironment for cancer therapy. Clin Chem 59(1):85–93.  https://doi.org/10.1373/clinchem.2012.185363 Google Scholar
  15. 15.
    Nirschl CJ, Drake CG (2013) Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res 19(18):4917–4924.  https://doi.org/10.1158/1078-0432.CCR-12-1972 Google Scholar
  16. 16.
    Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S, Katoh H (2006) Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94(2):275–280.  https://doi.org/10.1038/sj.bjc.6602934 Google Scholar
  17. 17.
    Shang B, Liu Y, Jiang SJ, Liu Y (2015) Prognostic value of tumor-infiltrating FOXp3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5:15179.  https://doi.org/10.1038/srep15179 Google Scholar
  18. 18.
    Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, Kim YJ, Kim JH, Park SY (2013) Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer 109(10):2705–2713.  https://doi.org/10.1038/bjc.2013.634 Google Scholar
  19. 19.
    Li G, Wang Z, Zhang C, Liu X, Cai J, Wang Z, Hu H, Wu F, Bao Z, Liu Y, Zhao L, Liang T, Yang F, Huang R, Zhang W, Jiang T (2017) Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. Oncoimmunology 6(8):e1328339.  https://doi.org/10.1080/2162402X.2017.1328339 Google Scholar
  20. 20.
    Zhu S, Lin J, Qiao G, Wang X, Xu Y (2016) Tim-3 identifies exhausted follicular helper T cells in breast cancer patients. Immunobiology 221(9):986–993.  https://doi.org/10.1016/j.imbio.2016.04.005 Google Scholar
  21. 21.
    Tan Y, Trent JC, Wilky BA, Kerr DA, Rosenberg AE (2017) Current status of immunotherapy for gastrointestinal stromal tumor. Cancer Gene Ther 24(3):130–133.  https://doi.org/10.1038/cgt.2016.58 Google Scholar
  22. 22.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415(6871):536–541.  https://doi.org/10.1038/415536a Google Scholar
  23. 23.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005) The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6(12):1245–1252.  https://doi.org/10.1038/ni1271 Google Scholar
  24. 24.
    Sharma P, Allison JP (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161(2):205–214.  https://doi.org/10.1016/j.cell.2015.03.030 Google Scholar
  25. 25.
    Ngiow SF, Teng MW, Smyth MJ (2011) Prospects for TIM3-targeted antitumor immunotherapy. Can Res 71(21):6567–6571.  https://doi.org/10.1158/0008-5472.CAN-11-1 Google Scholar
  26. 26.
    Ferris RL, Lu B, Kane LP (2014) Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. J Immunol 193(4):1525–1530.  https://doi.org/10.4049/jimmunol.1400557 Google Scholar
  27. 27.
    Liu Z, Han H, He X, Li S, Wu C, Yu C, Wang S (2016) Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma. Oncol Lett 11(3):1829–1834.  https://doi.org/10.3892/ol.2016.4142 Google Scholar
  28. 28.
    Li X, Chen Y, Liu X, Zhang J, He X, Teng G, Yu D (2017) Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Th1 responses in osteosarcoma patients. Int Immunopharmacol 44:153–159.  https://doi.org/10.1016/j.intimp.2017.01.006 Google Scholar
  29. 29.
    Komita H, Koido S, Hayashi K, Kan S, Ito M, Kamata Y, Suzuki M, Homma S (2015) Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors. Oncol Rep 34(4):2099–2105.  https://doi.org/10.3892/or.2015.4149 Google Scholar
  30. 30.
    Farazi TA, Spitzer JI, Morozov P, Tuschl T (2011) miRNAs in human cancer. J Pathol 223(2):102–115.  https://doi.org/10.1002/path.2806 Google Scholar
  31. 31.
    Le XF, Merchant O, Bast RC, Calin GA (2010) The roles of MicroRNAs in the cancer invasion-metastasis cascade. Cancer Microenviron 3(1):137–147.  https://doi.org/10.1007/s12307-010-0037-4 Google Scholar
  32. 32.
    Wang Z, Han J, Cui Y, Zhou X, Fan K (2013) miRNA-21 inhibition enhances RANTES and IP-10 release in MCF-7 via PIAS3 and STAT3 signalling and causes increased lymphocyte migration. Biochem Biophys Res Commun 439(3):384–389.  https://doi.org/10.1016/j.bbrc.2013.08.072 Google Scholar
  33. 33.
    Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, Liu MF, Wang ED (2010) MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Can Res 70(8):3119–3127.  https://doi.org/10.1158/0008-5472.CAN-09-4250 Google Scholar
  34. 34.
    Yang Q, Jiang W, Zhuang C, Geng Z, Hou C, Huang D, Hu L, Wang X (2015) MicroRNA-22 downregulation of galectin-9 influences lymphocyte apoptosis and tumor cell proliferation in liver cancer. Oncol Rep 34(4):1771–1778.  https://doi.org/10.3892/or.2015.4167 Google Scholar
  35. 35.
    Luo P, Wang X, Zhou J, Li L, Jing Z (2018) C-Cbl and Cbl-b expression in skull base chordomas is associated with tumor progression and poor prognosis. Hum Pathol 74:129–134.  https://doi.org/10.1016/j.humpath.2017.12.019 Google Scholar
  36. 36.
    Wang L, Wu Z, Tian K, Wang K, Li D, Ma J, Jia G, Zhang L, Zhang J (2017) Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients. J Neurosurg 127(6):1257–1267.  https://doi.org/10.3171/2016.9.JNS16559 Google Scholar
  37. 37.
    Fernandez-Miranda JC, Gardner PA, Snyderman CH, Devaney KO, Mendenhall WM, Suarez C, Rinaldo A, Ferlito A (2014) Clival chordomas: A pathological, surgical, and radiotherapeutic review. Head Neck 36(6):892–906.  https://doi.org/10.1002/hed.23415 Google Scholar
  38. 38.
    Jiang Y, Han S, Cheng W, Wang Z, Wu A (2017) NFAT1-regulated IL6 signalling contributes to aggressive phenotypes of glioma. Cell Commun Signal 15(1):54.  https://doi.org/10.1186/s12964-017-0210-1 Google Scholar
  39. 39.
    Zou MX, Peng AB, Lv GH, Wang XB, Li J, She XL, Jiang Y (2016) Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis. Am J Transl Res 8(7):3274–3287Google Scholar
  40. 40.
    Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, Taplin ME, Choueiri TK, Hodi FS, Freeman GJ, Signoretti S (2015) Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol 26(4):812–817.  https://doi.org/10.1093/annonc/mdv009 Google Scholar
  41. 41.
    Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, Kostron H, Stockhammer G, Ullrich A (2008) Axl and growth arrest specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14(1):130–138.  https://doi.org/10.1158/1078-0432.ccr-07-0862 Google Scholar
  42. 42.
    Remmele W, Schicketanz KH (1993) Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer. Pathol Res Pract 189(8):862–866.  https://doi.org/10.1016/s0344-0338(11)81095-2 Google Scholar
  43. 43.
    Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543.  https://doi.org/10.1073/pnas.0509182102 Google Scholar
  44. 44.
    Betel D, Koppal A, Agius P, Sander C, Leslie C (2010) Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 11(8):R90.  https://doi.org/10.1186/gb-2010-11-8-r90 Google Scholar
  45. 45.
    Wong N, Wang X (2015) miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 43(Database issue):D146–D152.  https://doi.org/10.1093/nar/gku1104 Google Scholar
  46. 46.
    Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120(1):15–20.  https://doi.org/10.1016/j.cell.2004.12.035 Google Scholar
  47. 47.
    Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C (2012) Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One 7(12):e51862.  https://doi.org/10.1371/journal.pone.0051862 Google Scholar
  48. 48.
    Han G, Chen G, Shen B, Li Y (2013) Tim-3: an activation marker and activation limiter of innate immune cells. Front Immunol 4:449.  https://doi.org/10.3389/fimmu.2013.00449 Google Scholar
  49. 49.
    Ocana-Guzman R, Torre-Bouscoulet L, Sada-Ovalle I (2016) TIM-3 regulates distinct functions in macrophages. Front Immunol 7:229.  https://doi.org/10.3389/fimmu.2016.00229 Google Scholar
  50. 50.
    Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, Nishi N, Fujimoto K, Tanji K, Shibata T, Tamo W, Matsumiya T, Yoshida H, Cui XF, Takanashi S, Hanada K, Okumura K, Yagihashi S, Wakabayashi K, Nakamura T, Hirashima M, Satoh K (2002) Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol 72(3):486–491Google Scholar
  51. 51.
    Yoshida H, Imaizumi T, Kumagai M, Kimura K, Satoh C, Hanada N, Fujimoto K, Nishi N, Tanji K, Matsumiya T, Mori F, Cui XF, Tamo W, Shibata T, Takanashi S, Okumura K, Nakamura T, Wakabayashi K, Hirashima M, Sato Y, Satoh K (2001) Interleukin-1beta stimulates galectin-9 expression in human astrocytes. Neuroreport 12(17):3755–3758Google Scholar
  52. 52.
    Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ, Kuchroo VK (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4(11):1102–1110.  https://doi.org/10.1038/ni988 Google Scholar
  53. 53.
    Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutierrez-Ramos JC, Coyle AJ, Strom TB (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4(11):1093–1101.  https://doi.org/10.1038/ni987 Google Scholar
  54. 54.
    Cheng G, Li M, Wu J, Ji M, Fang C, Shi H, Zhu D, Chen L, Zhao J, Shi L, Xu B, Zheng X, Wu C, Jiang J (2015) Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis. Int J Clin Exp Pathol 8(8):9452–9457Google Scholar
  55. 55.
    Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G, Zou W (2012) Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56(4):1342–1351.  https://doi.org/10.1002/hep.25777 Google Scholar
  56. 56.
    Duan Z, Shen J, Yang X, Yang P, Osaka E, Choy E, Cote G, Harmon D, Zhang Y, Nielsen GP, Spentzos D, Mankin H, Hornicek F (2014) Prognostic significance of miRNA-1 (miR-1) expression in patients with chordoma. J Orthop Res 32(5):695–701.  https://doi.org/10.1002/jor.22589 Google Scholar
  57. 57.
    Zhang H, Yang K, Ren T, Huang Y, Tang X, Guo W (2018) miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3. Cell Death Dis 9(6):680.  https://doi.org/10.1038/s41419-018-0738-z Google Scholar
  58. 58.
    Wei W, Zhang Q, Wang Z, Yan B, Feng Y, Li P (2016) miR-219-5p inhibits proliferation and clonogenicity in chordoma cells and is associated with tumor recurrence. Oncol Lett 12(6):4568–4576.  https://doi.org/10.3892/ol.2016.5222 Google Scholar
  59. 59.
    Zou MX, Guo KM, Lv GH, Huang W, Li J, Wang XB, Jiang Y, She XL (2018) Clinicopathologic implications of CD8(+)/FOXp3(+) ratio and miR-574-3p/PD-L1 axis in spinal chordoma patients. Cancer Immunol Immunother 67(2):209–224.  https://doi.org/10.1007/s00262-017-2080-1 Google Scholar
  60. 60.
    Zou MX, Huang W, Wang XB, Li J, Lv GH, Wang B, Deng YW (2015) Reduced expression of miRNA-1237-3p associated with poor survival of spinal chordoma patients. Eur Spine J 24(8):1738–1746.  https://doi.org/10.1007/s00586-015-3927-9 Google Scholar
  61. 61.
    Osaka E, Yang X, Shen JK, Yang P, Feng Y, Mankin HJ, Hornicek FJ, Duan Z (2014) MicroRNA-1 (miR-1) inhibits chordoma cell migration and invasion by targeting slug. J Orthop Res 32(8):1075–1082.  https://doi.org/10.1002/jor.22632 Google Scholar
  62. 62.
    Liu J, Zhang J, Li Y, Wang L, Sui B, Dai D (2016) MiR-455-5p acts as a novel tumor suppressor in gastric cancer by down-regulating RAB18. Gene 592(2):308–315.  https://doi.org/10.1016/j.gene.2016.07.034 Google Scholar
  63. 63.
    Yang Q, Hou C, Huang D, Zhuang C, Jiang W, Geng Z, Wang X, Hu L (2017) miR-455-5p functions as a potential oncogene by targeting galectin-9 in colon cancer. Oncol Lett 13(3):1958–1964.  https://doi.org/10.3892/ol.2017.5608 Google Scholar
  64. 64.
    Chen H, Garbutt CC, Spentzos D, Choy E, Hornicek FJ, Duan Z (2017) Expression and therapeutic potential of SOX9 in chordoma. Clin Cancer Res 23(17):5176–5186.  https://doi.org/10.1158/1078-0432.CCR-17-0177 Google Scholar
  65. 65.
    Fritzsching B, Fellenberg J, Moskovszky L, Sapi Z, Krenacs T, Machado I, Poeschl J, Lehner B, Szendroi M, Bosch AL, Bernd L, Csoka M, Mechtersheimer G, Ewerbeck V, Kinscherf R, Kunz P (2015) CD8(+)/FOXP3(+)-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology 4(3):e990800.  https://doi.org/10.4161/2162402X.2014.990800 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe First Hospital of China Medical UniversityShenyangChina
  2. 2.Department of Neurosurgery, Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  3. 3.International Education CollegeLiaoning University of Traditional Chinese MedicineShenyangChina
  4. 4.The First Laboratory of Cancer InstituteThe First Hospital of China Medical UniversityShenyangChina

Personalised recommendations