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Trks are novel oncogenes involved in the induction of neovascularization, tumor progression, and nodal metastasis in oral squamous cell carcinoma

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Abstract

The function of tropomyosin receptor kinase (Trk) family including TrkA, TrkB, and TrkC in cancer remains unknown. The role of Trks in oral squamous cell carcinoma (OSCC) was examined. Knockdown of Trks provided inhibition of growth or invasion and decrease of apoptosis in OSCC cells, which expressed Trks at high levels. VEGF expression was associated with TrkA and TrkB expression; a decrease of VEGF-C and VEGF-D was observed in OSCC cells with TrkB knockdown. TrkC did not affect the expression of VEGF family. An immunohistochemical analysis of 102 OSCCs showed that TrkB expression was related to microvessel density (MVD), lymph vessel density (LVD), and poor prognosis. TrkC expression was correlated with clinical stage, lymph node metastasis, MVD, LVD, and poor prognosis. TrkA expression was associated with VEGF expression, whereas TrkB expression was associated with the expressions of VEGF, VEGF-C and VEGF-D. No significant association was found between the expression of TrkC and genes of the VEGF family. Expression of Trks was not associated with RUNX3 silencing by methylation in OSCC cells. Trks expression was inversely correlated with RUNX3 expression in the OSCC cases. These results suggested that Trks enhances progression of OSCC through angiogenesis and lymphangiogenesis.

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Abbreviations

OSCC:

Oral squamous cell carcinoma

Trk:

Tropomyosin receptor kinase

NGF:

Nerve growth factor

BDNF:

Brain derived neurotrophic factor

NT3:

Neurotrophin3

RUNX3:

Runt-related transcription factor 3

VEGF:

Vascular endothelial growth factor

MVD:

Microvessel density

LVD:

Lymph vessel density

PI3K:

Phosphatidylinositol 3′-kinase

BMP:

Bone morphogenetic protein

TGF:

Transforming growth factor

References

  1. Chen YJ, Lin SC, Kao T, Chang CS, Hong PS, Shieh TM, Chang KW (2004) Genome-wide profiling of oral squamous cell carcinoma. J Pathol 204:326–332

    Article  PubMed  CAS  Google Scholar 

  2. Hunter KD, Parkinson EK, Harrison PR (2005) Profiling early head and neck cancer. Nat Rev Cancer 5:127–135

    Article  PubMed  CAS  Google Scholar 

  3. Lippman SM, Hong WK (2001) Molecular markers of the risk of oral cancer. N Engl J Med 344:1323–1326

    Article  PubMed  CAS  Google Scholar 

  4. Tanaka S, Sobue T (2005) Comparison of oral and pharyngeal cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO Mortality Database (1960–2000). Jpn J Clin Oncol 35:488–491

    Article  PubMed  CAS  Google Scholar 

  5. Hershkovich O, Oliva J, Nagler RM (2004) Lethal synergistic effect of cigarette smoke and saliva in an in vitro model: does saliva have a role in the development of oral cancer? Eur J Cancer 40:1760–1767

    Article  PubMed  CAS  Google Scholar 

  6. Dos Reis PP, Bharadwaj RR, Machado J, Macmillan C, Pintilie M, Sukhai MA, Perez-Ordonez B, Gullane P, Irish J, Kamel-Reid S (2008) Claudin 1 overexpression increases invasion and is associated with aggressive histological features in oral squamous cell carcinoma. Cancer 113:3169–3180

    Article  PubMed  Google Scholar 

  7. Thiele CJ, Li Z, McKee AE (2009) On Trk: the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res 15:5962–5967

    Article  PubMed  CAS  Google Scholar 

  8. Inoue K, Ito K, Osato M, Lee B, Bae SC, Ito Y (2007) The transcription factor Runx3 represses the neurotrophin receptor TrkB during lineage commitment of dorsal root ganglion neurons. J Biol Chem 282:24175–24184

    Article  PubMed  CAS  Google Scholar 

  9. Nakamura S, Senzaki K, Yoshikawa M, Nishimura M, Inoue K, Ito Y, Ozaki S, Shiga T (2008) Dynamic regulation of the expression of neurotrophin receptors by Runx3. Development 135:1703–1711

    Article  PubMed  CAS  Google Scholar 

  10. Sasahira T, Kurihara M, Yamamoto K, Bhawal U, Kirita T, Kuniyasu H (2011) Downregulation of runt-related transcription factor 3 (RUNX3) associated with poor prognosis of adenoid cystic and mucoepidermoid carcinomas of the salivary gland. Cancer Sci 102:492–497

    Article  PubMed  Google Scholar 

  11. Tessarollo L (1998) Pleiotropic functions of neurotrophins in development. Cytokine Growth Factor Rev 9:125–137

    Article  PubMed  CAS  Google Scholar 

  12. Yu X, Liu L, Cai B, He Y, Wan X (2008) Suppression of anoikis by the neurotrophic receptor TrkB in human ovarian cancer. Cancer Sci 99:543–552

    Article  PubMed  CAS  Google Scholar 

  13. Bouzas-Rodriguez J, Cabrera JR, Delloye-Bourgeois C, Ichim G, Delcros JG, Raquin MA, Rousseau R, Combaret V, Bénard J, Tauszig-Delamasure S, Mehlen P (2010) Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. J Clin Invest 120:850–858

    Article  PubMed  CAS  Google Scholar 

  14. Davidson B, Reich R, Lazarovici P, Nesland JM, Skrede M, Risberg B, Tropé CG, Flørenes VA (2003) Expression and activation of the nerve growth factor receptor TrkA in serous ovarian carcinoma. Clin Cancer Res 9:2248–2259

    PubMed  CAS  Google Scholar 

  15. Sclabas GM, Fujioka S, Schmidt C, Li Z, Frederick WA, Yang W, Yokoi K, Evans DB, Abbruzzese JL, Hess KR, Zhang W, Fidler IJ, Chiao PJ (2005) Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 11:440–449

    PubMed  CAS  Google Scholar 

  16. Yang ZF, Ho DW, Lam CT, Luk JM, Lum CT, Yu WC, Poon RT, Fan ST (2005) Identification of brain-derived neurotrophic factor as a novel functional protein in hepatocellular carcinoma. Cancer Res 65:219–225

    PubMed  CAS  Google Scholar 

  17. Satoh F, Mimata H, Nomura T, Fujita Y, Shin T, Sakamoto S, Hamada Y, Nomura Y (2001) Autocrine expression of neurotrophins and their receptors in prostate cancer. Int J Urol 8:S28–S34

    Article  PubMed  CAS  Google Scholar 

  18. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM (1994) Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14:759–767

    PubMed  CAS  Google Scholar 

  19. Chen-Tsai CP, Colome-Grimmer M, Wagner RF Jr (2004) Correlations among neural cell adhesion molecule, nerve growth factor, and its receptors, TrkA, TrkB, TrkC, and p75, in perineural invasion by basal cell and cutaneous squamous cell carcinomas. Dermatol Surg 30:1009–1016

    Article  PubMed  Google Scholar 

  20. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB, Brodeur GM (1993) Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328:847–854

    Article  PubMed  CAS  Google Scholar 

  21. Yamashiro DJ, Nakagawara A, Ikegaki N, Liu XG, Brodeur GM (1996) Expression of TrkC in favorable human neuroblastomas. Oncogene 12:37–41

    PubMed  CAS  Google Scholar 

  22. Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL (1994) Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci USA 91:12867–12871

    Article  PubMed  CAS  Google Scholar 

  23. Sasahira T, Oue N, Kirita T, Luo Y, Bhawal UK, Fujii K, Yasui W, Kuniyasu H (2008) Reg IV expression is associated with cell growth and prognosis of adenoid cystic carcinoma in the salivary gland. Histopathology 53:667–675

    Article  PubMed  CAS  Google Scholar 

  24. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109:113–124

    Article  PubMed  CAS  Google Scholar 

  25. Sasaki T, Fujii K, Yoshida K, Shimura H, Sasahira T, Ohmori H, Kuniyasu H (2006) Peritoneal metastasis inhibition by linoleic acid with activation of PPARγ in human gastrointestinal cancer cells. Virchows Arch 448:422–427

    Article  PubMed  CAS  Google Scholar 

  26. Sasaki T, Shimura H, Sasahira T, Fujii K, Kuniyasu H (2005) High concentration of deoxycholic acid abrogates in vitro transformation of IEC6 intestinal cells by azoxymethane. J Exp Clin Cancer Res 24:625–631

    PubMed  CAS  Google Scholar 

  27. Sasahira T, Akama Y, Fujii K, Kuniyasu H (2005) Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas. Virchows Arch 446:411–415

    Article  PubMed  CAS  Google Scholar 

  28. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    PubMed  CAS  Google Scholar 

  29. Sasahira T, Kirita T, Oue N, Bhawal UK, Yamamoto K, Fujii K, Yasui W, Kuniyasu H (2008) High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma. Cancer Sci 99:1806–1812

    PubMed  CAS  Google Scholar 

  30. Sasahira T, Kirita T, Bhawal UK, Ikeda M, Nagasawa A, Yamamoto K, Kuniyasu H (2007) The expression of receptor for advanced glycation end products is associated with angiogenesis in human oral squamous cell carcinoma. Virchows Arch 450:287–295

    Article  PubMed  CAS  Google Scholar 

  31. Sasahira T, Kirita T, Kurihara M, Yamamoto K, Bhawal UK, Bosserhoff AK, Kuniyasu H (2010) MIA-dependent angiogenesis and lymphangiogenesis are closely associated with progression, nodal metastasis and poor prognosis in tongue squamous cell carcinoma. Eur J Cancer 46:2285–2294

    Article  PubMed  CAS  Google Scholar 

  32. Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ (2006) Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 66:4249–4255

    Article  PubMed  CAS  Google Scholar 

  33. Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR (2004) TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6:347–360

    Article  PubMed  CAS  Google Scholar 

  34. Cristofaro B, Stone OA, Caporali A, Dawbarn D, Ieronimakis N, Reyes M, Madeddu P, Bates DO, Emanueli C (2010) Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia. Arterioscler Thromb Vasc Biol 30:1143–1150

    Article  PubMed  CAS  Google Scholar 

  35. Brzezianska E, Pastuszak-Lewandoska D, Lewinski A (2007) Rearrangements of NTRK1 oncogene in papillary thyroid carcinoma. Neuro Endocrinol Lett 28:221–229

    PubMed  CAS  Google Scholar 

  36. McGregor LM, McCune BK, Graff JR, McDowell PR, Romans KE, Yancopoulos GD, Ball DW, Baylin SB, Nelkin BD (1999) Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression. Proc Natl Acad Sci USA 96:4540–4545

    Article  PubMed  CAS  Google Scholar 

  37. Riedel F, Gotte K, Bergler W, Hormann K (2001) Inverse correlation of apoptotic and angiogenic markers in squamous cell carcinoma of the head and neck. Oncol Rep 8:471–476

    PubMed  CAS  Google Scholar 

  38. Larcher F, Robles AI, Duran H, Murillas R, Quintanilla M, Cano A, Conti CJ, Jorcano JL (1996) Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res 56:5391–5396

    PubMed  CAS  Google Scholar 

  39. Li Z, Jaboin J, Dennis PA, Thiele CJ (2005) Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death. Cancer Res 65:2070–2075

    Article  PubMed  CAS  Google Scholar 

  40. Jin W, Yun C, Kwak MK, Kim TA, Kim SJ (2007) TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling. Oncogene 26:7684–7691

    Article  PubMed  CAS  Google Scholar 

  41. Hanai J, Chen LF, Kanno T, Ohtani-Fujita N, Kim WY, Guo WH, Imamura T, Ishidou Y, Fukuchi M, Shi MJ, Stavnezer J, Kawabata M, Miyazono K, Ito Y (1999) Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter. J Biol Chem 274:31577–31582

    Article  PubMed  CAS  Google Scholar 

  42. Zaidi SK, Sullivan AJ, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2002) Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci USA 99:8048–8053

    Article  PubMed  CAS  Google Scholar 

  43. Chuang LS, Ito Y (2010) RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene 9:2605–2615

    Article  Google Scholar 

  44. Tsunematsu T, Kudo Y, Iizuka S, Ogawa I, Fujita T, Kurihara H, Abiko Y, Takata T (2009) RUNX3 has an oncogenic role in head and neck cancer. PLoS ONE 4:e5892

    Article  PubMed  Google Scholar 

  45. Jain RK, Munn LL, Fukumura D (2002) Dissecting tumour pathophysiology using intravital microscopy. Nat Rev Cancer 2:266–276

    Article  PubMed  CAS  Google Scholar 

  46. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported in part by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, Japan.

Conflict of interest

We declare that there is not any Financial Support or Relationships which may pose a conflict of interest in the contents of the submitted manuscript.

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Authors and Affiliations

  1. Department of Molecular Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Tomonori Sasahira, Ujjal K. Bhawal, Miyako Kurihara & Hiroki Kuniyasu

  2. Department of Oral and Maxillofacial Surgery, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Nobuhiro Ueda, Kazuhiko Yamamoto, Miyako Kurihara & Tadaaki Kirita

Authors
  1. Tomonori Sasahira
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  2. Nobuhiro Ueda
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Correspondence to Hiroki Kuniyasu.

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Sasahira, T., Ueda, N., Yamamoto, K. et al. Trks are novel oncogenes involved in the induction of neovascularization, tumor progression, and nodal metastasis in oral squamous cell carcinoma. Clin Exp Metastasis 30, 165–176 (2013). https://doi.org/10.1007/s10585-012-9525-x

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  • DOI: https://doi.org/10.1007/s10585-012-9525-x

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