Skip to main content

Advertisement

Log in

Tumor suppressor TSLC1 is implicated in cell proliferation, invasion and apoptosis in laryngeal squamous cell carcinoma by regulating Akt signaling pathway

  • Research Article
  • Published:
Tumor Biology

Abstract

Overwhelming evidence has demonstrated that TSLC1 (tumor suppressor in lung cancer 1), a novel tumor suppressor, is crucially implicated in various biological processes including progression, proliferation and apoptosis during tumorigenesis. However, the exact functions and molecular details of TSLC1 in laryngeal cancer remain ill-defined. Here, the expression of TSLC1 in laryngeal squamous cell carcinoma (LSCC) tissues and cells was detected, and the biological roles of TSLC1 in LSCC cells were investigated. The results showed that expressions of TSLC1 mRNA and protein were significantly reduced in LSCC tissues with low expression in 18 of 85 (21.18 %) and 16 of 85 (18.82 %), respectively. Additionally, statistical analysis revealed a significant correlation of TSLC1 expression with TNM staging and lymph node metastases (P < 0.05), but not related to age, gender and tumor differentiation (P > 0.05). Elevation of TSLC1 level inhibited cell proliferation, reduced cell invasion in vitro and induced cell apoptosis in Hep-2 cells, most importantly, TSLC1 upregulation decreased the level of pAkt, but not changed the level of total Akt in Hep-2 cells. Stepwise investigations demonstrated that overexpression of TSLC1 in Hep-2 cells increased caspase-3 activity and expressions of bax and p21 proteins but decreased the levels of bcl-2, MMP-2 and MMP-9 proteins. These data suggest that TSLC1 may exert essential roles in the progression and development of LSCC, and thus TSLC1 may be a potential molecular target for LSCC treatment.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.

    Article  PubMed  Google Scholar 

  2. Black RJ, Bray F, Ferlay J, Parkin DM. Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1990. Eur J Cancer. 1997;33(7):1075–107.

    Article  PubMed  CAS  Google Scholar 

  3. Morshed K, Polz-Dacewicz M, Szymanski M, Polz D. Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: clinico-pathological evaluation. Eur Arch Otorhinolaryngol. 2008;265 Suppl 1:S89–96.

    Article  PubMed  Google Scholar 

  4. Spector JG, Sessions DG, Chao KS, Haughey BH, Hanson JM, Simpson JR, et al. Stage I (T1 N0 M0) squamous cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation. Head Neck. 1999;21(8):707–17.

    Article  PubMed  CAS  Google Scholar 

  5. Spector JG, Sessions DG, Chao KS, Hanson JM, Simpson JR, Perez CA. Management of stage II (T2N0M0) glottic carcinoma by radiotherapy and conservation surgery. Head Neck. 1999;21(2):116–23.

    Article  PubMed  CAS  Google Scholar 

  6. Curran AJ, Jonathan CI, Gullane PJ. Cancer of larynx, paranasal sinuses and temporal bone. In: Lee KJ, editor. Essential otolaryngology. 7th ed. Upper Saddle River: Appleton & Lange; 1999. p. 549–72.

    Google Scholar 

  7. Murakami Y, Nobukuni T, Tamura K, Maruyama T, Sekiya T, Arai Y, et al. Localization of tumor suppressor activity important in nonsmall cell lung carcinoma on chromosome 11q. Proc Natl Acad Sci USA. 1998;95(14):8153–8.

    Article  PubMed  CAS  Google Scholar 

  8. Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP, et al. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet. 2001;27(4):427–30.

    Article  PubMed  CAS  Google Scholar 

  9. Yamada D, Yoshida M, Williams YN, Fukami T, Kikuchi S, Masuda M, et al. Disruption of spermatogenic cell adhesion and male infertility in mice lacking TSLC1/IGSF4, an immunoglobulin superfamily cell adhesion molecule. Mol Cell Biol. 2006;26(9):3610–24.

    Article  PubMed  CAS  Google Scholar 

  10. Shingai T, Ikeda W, Kakunaga S, Morimoto K, Takekuni K, Itoh S, et al. Implications of nectin-like molecule-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 in cell–cell adhesion and transmembrane protein localization in epithelial cells. J Biol Chem. 2003;278(37):35421–7.

    Article  PubMed  CAS  Google Scholar 

  11. Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res. 2003;63(19):6320–6.

    PubMed  CAS  Google Scholar 

  12. Steenbergen RD, Kramer D, Braakhuis BJ, Stern PL, Verheijen RH, Meijer CJ, et al. TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia. J Natl Cancer Inst. 2004;96(4):294–305.

    Article  PubMed  CAS  Google Scholar 

  13. Lung HL, Cheung AK, Xie D, Cheng Y, Kwong FM, Murakami Y, et al. TSLC1 is a tumor suppressor gene associated with metastasis in nasopharyngeal carcinoma. Cancer Res. 2006;66(19):9385–92.

    Article  PubMed  CAS  Google Scholar 

  14. Hui AB, Lo KW, Kwong J, Lam EC, Chan SY, Chow LS, et al. Epigenetic inactivation of TSLC1 gene in nasopharyngeal carcinoma. Mol Carcinog. 2003;38(4):170–8.

    Article  PubMed  CAS  Google Scholar 

  15. He G, Lei W, Wang S, Xiao R, Guo K, Xia Y, et al. Overexpression of tumor suppressor TSLC1 by a survivin-regulated oncolytic adenovirus significantly inhibits hepatocellular carcinoma growth. J Cancer Res Clin Oncol. 2012;138(4):657–70.

    Article  PubMed  CAS  Google Scholar 

  16. Yang G, He W, Cai M, Luo F, Kung H, Guan X, et al. Loss/down-regulation of tumor suppressor in lung cancer 1 expression is associated with tumor progression and is a biomarker of poor prognosis in ovarian carcinoma. Int J Gynecol Cancer. 2011;21(3):486–93.

    Article  PubMed  Google Scholar 

  17. Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM, et al. Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat. 2007;103(3):283–91.

    Article  PubMed  CAS  Google Scholar 

  18. You Y, Ma L, You M, Li X, Wang S, Li H, et al. TSLC1 gene silencing in cutaneous melanoma. Melanoma Res. 2010;20(3):179–83.

    PubMed  CAS  Google Scholar 

  19. Chen K, Wang G, Peng L, Liu S, Fu X, Zhou Y, et al. CADM1/TSLC1 inactivation by promoter hypermethylation is a frequent event in colorectal carcinogenesis and correlates with late stages of the disease. Int J Cancer. 2011;128(2):266–73.

    Article  PubMed  CAS  Google Scholar 

  20. Ando K, Ohira M, Ozaki T, Nakagawa A, Akazawa K, Suenaga Y, et al. Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation. Int J Cancer. 2008;123(9):2087–94.

    Article  PubMed  CAS  Google Scholar 

  21. Nowacki S, Skowron M, Oberthuer A, Fagin A, Voth H, Brors B, et al. Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma. Oncogene. 2008;27(23):3329–38.

    Article  PubMed  CAS  Google Scholar 

  22. Usami Y, Ito A, Ohnuma K, Fuku T, Komori T, Yokozaki H. Tumor suppressor in lung cancer-1 as a novel ameloblast adhesion molecule and its downregulation in ameloblastoma. Pathol Int. 2007;57(2):68–75.

    Article  PubMed  CAS  Google Scholar 

  23. Houshmandi SS, Surace EI, Zhang HB, Fuller GN, Gutmann DH. Tumor suppressor in lung cancer-1 (TSLC1) functions as a glioma tumor suppressor. Neurology. 2006;67(10):1863–6.

    Article  PubMed  CAS  Google Scholar 

  24. Liu HT, Wang N, Wang X, Li SL. Overexpression of Pim-1 is associated with poor prognosis in patients with esophageal squamous cell carcinoma. J Surg Oncol. 2010;102(6):683–8.

    Article  PubMed  CAS  Google Scholar 

  25. Muskhelishvili L, Latendresse JR, Kodell RL, Henderson EB. Evaluation of cell proliferation in rat tissues with BrdU, PCNA, Ki-67(MIB-5) immunohistochemistry and in situ hybridization for histone mRNA. J Histochem Cytochem. 2003;51(12):1681–8.

    Article  PubMed  CAS  Google Scholar 

  26. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–8.

    Article  PubMed  CAS  Google Scholar 

  27. Lu Z, Liu H, Xue L, Xu P, Gong T, Hou G. An activated Notch1 signaling pathway inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma cell line EC9706. Int J Oncol. 2008;32(3):643–51.

    PubMed  CAS  Google Scholar 

  28. Busam RD, Thorsell AG, Flores A, Hammarstrom M, Persson C, Obrink B, et al. Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B). J Biol Chem. 2011;286(6):4511–6.

    Article  PubMed  CAS  Google Scholar 

  29. Fukami T, Fukuhara H, Kuramochi M, Maruyama T, Isogai K, Sakamoto M, et al. Promoter methylation of the TSLC1 gene in advanced lung tumors and various cancer cell lines. Int J Cancer. 2003;107(1):53–9.

    Article  PubMed  CAS  Google Scholar 

  30. Ito A, Okada M, Uchino K, Wakayama T, Koma Y, Iseki S, et al. Expression of the TSLC1 adhesion molecule in pulmonary epithelium and its down-regulation in pulmonary adenocarcinoma other than bronchioloalveolar carcinoma. Lab Invest. 2003;83(8):1175–83.

    Article  PubMed  CAS  Google Scholar 

  31. Uchino K, Ito A, Wakayama T, Koma Y, Okada T, Ohbayashi C, et al. Clinical implication and prognostic significance of the tumor suppressor TSLC1 gene detected in adenocarcinoma of the lung. Cancer. 2003;98(5):1002–7.

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi Y, Iwai M, Kawai T, Arakawa A, Ito T, Sakurai-Yageta M, et al. Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer. 2011. doi:10.1007/s12282-011-0272-7.

  33. Heller G, Fong KM, Girard L, Seidl S, End-Pfutzenreuter A, Lang G, et al. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas. Oncogene. 2006;25(6):959–68.

    Article  PubMed  CAS  Google Scholar 

  34. Fukuhara H, Kuramochi M, Fukami T, Kasahara K, Furuhata M, Nobukuni T, et al. Promoter methylation of TSLC1 and tumor suppression by its gene product in human prostate cancer. Jpn J Cancer Res. 2002;93(6):605–9.

    Article  PubMed  CAS  Google Scholar 

  35. Allinen M, Peri L, Kujala S, Lahti-Domenici J, Outila K, Karppinen SM, et al. Analysis of 11q21–24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation. Genes Chromosomes Cancer. 2002;34(4):384–9.

    Article  PubMed  CAS  Google Scholar 

  36. Sussan TE, Pletcher MT, Murakami Y, Reeves RH. Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth properties and gene expression. Mol Cancer. 2005;4:28.

    Article  PubMed  Google Scholar 

  37. Qin L, Zhu W, Xu T, Hao Y, Zhang Z, Tian Y, et al. Effect of TSLC1 gene on proliferation, invasion and apoptosis of human hepatocellular carcinoma cell line HepG2. J Huazhong Univ Sci Technolog Med Sci. 2007;27(5):535–7.

    Article  PubMed  CAS  Google Scholar 

  38. Mao X, Seidlitz E, Truant R, Hitt M, Ghosh HP. Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces apoptosis and inhibits tumor growth. Oncogene. 2004;23(33):5632–42.

    Article  PubMed  CAS  Google Scholar 

  39. Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004;15(2):177–82.

    Article  PubMed  CAS  Google Scholar 

  40. Chen PN, Hsieh YS, Chiou HL, Chu SC. Silibinin inhibits cell invasion through inactivation of both PI3K-Akt and MAPK signaling pathways. Chem Biol Interact. 2005;156(2–3):141–50.

    Article  PubMed  CAS  Google Scholar 

  41. Shih YW, Shieh JM, Wu PF, Lee YC, Chen YZ, Chiang TA. Alpha-tomatine inactivates PI3K/Akt and ERK signaling pathways in human lung adenocarcinoma A549 cells: effect on metastasis. Food Chem Toxicol. 2009;47(8):1985–95.

    Article  PubMed  CAS  Google Scholar 

  42. Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010;333(1–2):169–80.

    Article  PubMed  CAS  Google Scholar 

  43. Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23(1):201–5.

    Article  PubMed  CAS  Google Scholar 

  44. Itoh N, Semba S, Ito M, Takeda H, Kawata S, Yamakawa M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer. 2002;94(12):3127–34.

    Article  PubMed  CAS  Google Scholar 

  45. Page C, Lin HJ, Jin Y, Castle VP, Nunez G, Huang M, et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 2000;20(1A):407–16.

    PubMed  CAS  Google Scholar 

  46. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.

    Article  PubMed  CAS  Google Scholar 

  47. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9(1):59–71.

    Article  PubMed  CAS  Google Scholar 

  48. Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem. 2003;253(1–2):269–85.

    Article  PubMed  CAS  Google Scholar 

  49. Rangaswami H, Bulbule A, Kundu GC. Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation. J Biol Chem. 2004;279(37):38921–35.

    Article  PubMed  CAS  Google Scholar 

  50. Takada Y, Kobayashi Y, Aggarwal BB. Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion. J Biol Chem. 2005;280(17):17203–12.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Baocai Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, B., Di, W., Wang, H. et al. Tumor suppressor TSLC1 is implicated in cell proliferation, invasion and apoptosis in laryngeal squamous cell carcinoma by regulating Akt signaling pathway. Tumor Biol. 33, 2007–2017 (2012). https://doi.org/10.1007/s13277-012-0460-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-012-0460-x

Keywords

Navigation