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The expression of COX-2, hTERT, MDM2, LATS2 and S100A2 in different types of non-small cell lung cancer (NSCLC)

Cellular & Molecular Biology Letters volume 14, pages 442–456 (2009)Cite this article

Abstract

Several studies have reported different expression levels of certain genes in NSCLC, mostly related to the stage and advancement of the tumours. We investigated 65 stage I-III NSCLC tumours: 32 adenocarcinomas (ADC), 26 squamous cell carcinomas (SCC) and 7 large cell carcinomas (LCC). Using the real-time reverse transcription polymerase chain reaction (RT-PCR), we analysed the expression of the COX-2, hTERT, MDM2, LATS2 and S100A2 genes and researched the relationships between the NSCLC types and the differences in expression levels. The differences in the expression levels of the LATS2, S100A2 and hTERT genes in different types of NSCLC are significant. hTERT and COX-2 were over-expressed and LATS2 under-expressed in all NSCLC. We also detected significant relative differences in the expression of LATS2 and MDM2, hTERT and MDM2 in different types of NSCLC. There was a significant difference in the average expression levels in S100A2 for ADC and SCC. Our study shows differences in the expression patterns within the NSCLC group, which may mimic the expression of the individual NSCLC type, and also new relationships in the expression levels for different NSCLC types.

Abbreviations

ADC:

adenocarcinoma

CDK2:

cyclin-dependent kinase 2

cDNA:

complementary DNA

COX-2:

cyclooxygenase 2

CT :

cycle threshold

DNA:

deoxyribonucleic acid

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

hTERT:

human telomerase reverse transcriptase

IHC:

immunohistochemistry

LATS2:

homolog of large tumour suppressor 2, Drosophilae

LCC:

large cell carcinoma

MDM2:

mouse double minute 2 homolog

mRNA:

messenger RNA

NSCLC:

non-small cell lung cancer

p21:

cyclin-dependent kinase inhibitor 1A

p53:

tumour protein p53

PCR:

polymerase chain reaction

pTNM:

pathological tumour-node-metastasis

RB:

retinoblastoma

RNA:

ribonucleic acid

rs :

Spearman’s rank correlation coefficient

RT-PCR:

real time PCR

S100A2:

S100 calcium binding protein A2

SCC:

squamous cell carcinoma

References

  1. Sekido, Y., Fong, K.M. and Minna, J.D. Molecular genetics of lung cancer. Annu. Rev. Med. 54 (2003) 73–87.

    Article  PubMed  CAS  Google Scholar 

  2. Wang, L., Soria, J.C., Kemp, B.L., Liu, D.D., Mao, L. and Khuri, F.R. hTERT expression is a prognostic factor of survival in patients with stage I non-small cell lung cancer. Clin. Cancer. Res. 8 (2002) 2883–2889.

    PubMed  CAS  Google Scholar 

  3. Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L., Coviello, G.M., Wright, W.E., Weinrich, S.L. and Shay, J.W. Specific association of human telomerase activity with immortal cells and cancer. Science 266 (1994) 2011–2015.

    Article  PubMed  CAS  Google Scholar 

  4. Hiyama, K., Hiyama, E., Ishioka, S., Yamakido, M., Inai, K., Gazdar, A.F., Piatyszek, M.A. and Shay, J.W. Telomerase activity in small-cell and nonsmall-cell lung cancers. J. Natl. Cancer. Inst. 87 (1995) 895–902.

    Article  PubMed  CAS  Google Scholar 

  5. Lantuéjoul, S., Salon, C., Soria, J.C. and Brambilla, E. Telomerase expression in lung preneoplasia and neoplasia. Int. J. Cancer. 120 (2007) 1835–1841.

    Article  PubMed  CAS  Google Scholar 

  6. Komiya, T., Kawase, I., Nitta, T., Yasumitsu, T., Kikui, M., Fukuoka, M., Nakagawa, K. and Hirashima, T. Prognostic significance of hTERT expression in non-small cell lung cancer. Int. J. Oncol. 16 (2000) 1173–1177.

    PubMed  CAS  Google Scholar 

  7. Lantuejoul, S., Soria, J.C., Moro-Sibilot, D., Morat, L., Veyrenc, S., Lorimier, P., Brichon, P.Y., Sabatier, L., Brambilla, C. and Brambilla, E. Differential expression of telomerase reverse transcriptase (hTERT) in lung tumours. Br. J. Cancer 90 (2004) 1222–1229.

    Article  PubMed  CAS  Google Scholar 

  8. Tazawa, R., Xu, X.-M., Wu, K.K. and Wang, L.-H. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem. Biophys. Res. Commun. 203 (1994) 190–199.

    Article  PubMed  CAS  Google Scholar 

  9. Castelao, J.E., Bart, III R.D., DiPerna, C.A., Sievers, E.M. and Bremner, R.M. Lung cancer and cyclooxygenase-2. Ann. Thorac. Surg. 76 (2003) 1327–1335.

    Article  PubMed  Google Scholar 

  10. Laga, A.C., Zander, D.S. and Cagle, P.T. Prognostic significance of cyclooxygenase 2 expression in 259 cases of non-small cell lung cancer. Arch. Pathol. Lab. Med. 129 (2005) 1113–1117.

    PubMed  CAS  Google Scholar 

  11. Wolff, H., Saukkonen, K., Anttila, S., Karjalainen, A., Vainio, H. and Ristimaki, A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res. 58 (1998) 4997–5001.

    PubMed  CAS  Google Scholar 

  12. Hida, T., Yatabe, Y., Achiwa, H., Muramatsu, H., Kozaki, K., Nakamura, S., Ogawa, M., Mitsudomi, T., Sugiura, T. and Takahashi, T. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res. 58 (1998) 3761–3764.

    PubMed  CAS  Google Scholar 

  13. Hastürk, S., Kemp, B., Kalapurakal, S.K., Kurie, J.M., Hong, W.K. and Lee, J.S. Expression of cyclooxygenase-1 and cyclooxygenase-2 in bronchial epithelium and nonsmall cell lung carcinoma. Cancer 94 (2002) 1023–1031.

    Article  PubMed  CAS  Google Scholar 

  14. Ermert, L., Dierkes, C. and Ermert, M. Immunohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clin. Cancer Res. 9 (2003) 1604–1610.

    PubMed  CAS  Google Scholar 

  15. Fang, H.Y., Lin, T.S., Lin, J.P., Wu, Y.C., Chow, K.C. and Wang, L.S. Cyclooxygenase-2 in human non-small cell lung cancer. Eur. J. Surg. Oncol. 29 (2003) 171–177.

    Article  PubMed  CAS  Google Scholar 

  16. Brabender, J., Park, J., Metzger, R., Schneider, P.M., Lord, R.V., Holscher, A.H., Danenberg, K.D. and Danenberg, P.V. Prognostic significance of cyclooxygenase 2 mRNA expression in non-small cell lung cancer. Ann. Surg. 235 (2002) 440–443.

    Article  PubMed  Google Scholar 

  17. Achiwa, H., Yatabe, Y., Hida, T., Kuroishi, T., Kozaki, K., Nakamura, S., Ogawa, M., Sugiura, T., Mitsudomi, T. and Takahashi, T. Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin. Canc. Res. 5 (1999) 1001–1005.

    CAS  Google Scholar 

  18. Lu, C., Soria, J.C., Tang, X., Xu, X.C., Wang, L., Mao, L., Lotan, R., Kemp, B., Bekele, B.N., Feng, L., Hong, W.K. and Khuri, F.R. Prognostic factors in resected stage I non-small-cell lung cancer: a multivariate analysis of six molecular markers. J. Clin. Oncol. 22 (2004) 4575–4583.

    Article  PubMed  Google Scholar 

  19. Gorgoulis, V.G., Zacharatos, P., Kotsinas, A., Mariatos, G., Liloglou, T., Vogiatzi, T., Foukas, P., Rassidakis, G., Garinis, G., Ioannides, T., Zoumpourlis, V., Bramis, J., Michail, P.O., Asimacopoulos, P.J., Field, J.K. and Kittas, C. Altered expression of the cell cycle regulatory molecules pRb, p53 and MDM2 exert a synergetic effect on tumor growth and chromosomal instability in non-small cell lung carcinomas (NSCLCs). Mol. Med. 3 (2000) 208–237.

    Google Scholar 

  20. Eymin, B., Leduc, C., Coll, J.L., Brambilla, E. and Gazzeri, S. p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene 22 (2003) 1822–1835.

    Article  PubMed  CAS  Google Scholar 

  21. Sun, Y. p53 and its downstream proteins as molecular targets of cancer. Mol. Carcinog. 45 (2006) 409–415.

    Article  PubMed  CAS  Google Scholar 

  22. Sdek, P., Ying, H., Chang, D.L.F., Qiu, W., Zheng, H., Touitou, R., Allday, M.J. and Xiao, Z.-X.J. MDM2 promotes proteasome-dependent ubiquitinindependent degradation of retinoblastoma protein. Mol. Cell 20 (2005) 699–708.

    Article  PubMed  CAS  Google Scholar 

  23. Uchida, C., Miwa, S., Kitagawa, K., Hattori, T., Isobe, T., Otani, S., Oda, T., Sugimura, H., Kamijo, T., Ookawa, K., Yasuda, H. and Kitagawa, M. Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. EMBO J. 24 (2005) 160–169.

    Article  PubMed  CAS  Google Scholar 

  24. Giono, L.E. and Manfredi, J.J. Mdm2 is required for inhibition of Cdk2 activity by p21, thereby contributing to p53-dependent cell cycle arrest. Mol. Cell. Biol. 27 (2007) 4166–4178.

    Article  PubMed  CAS  Google Scholar 

  25. Duan, W., Gao, L., Wu, X., Zhang, Y., Otterson, G.A. and Villalona-Calero, M.A. Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells. Exp. Cell. Res. 312 (2006) 3370–3378.

    Article  PubMed  CAS  Google Scholar 

  26. Momand, J., Jung, D., Wilczynski, S. and Niland, J. The MDM2 gene amplification database. Nucleic Acids Res. 26 (1998) 3453–3459.

    Article  PubMed  CAS  Google Scholar 

  27. Wang, Y.C., Lin, R.K., Tan, Y.H., Chen, J.T., Chen, C.Y. and Wang, Y.C. Wild-type p53 overexpression and its correlation with MDM2 and p14ARF alterations: an alternative pathway to non-small-cell lung cancer. J. Clin. Oncol. 23 (2005) 154–164.

    Article  PubMed  CAS  Google Scholar 

  28. Ko, J.L., Cheng, Y.W., Chang, S.L., Su, J.M., Chen, C.Y. and Lee, H. MDM2 mRNA expression is a favorable prognostic factor in non-small-cell lung cancer. Int. J. Cancer 89 (2000) 265–270.

    Article  PubMed  CAS  Google Scholar 

  29. Li, Y., Pei, J., Xia, H., Ke, H., Wang, H. and Tao, W. Lats2, a putative tumor suppressor, inhibits G1/S transition. Oncogene 22 (2003) 4398–4405.

    Article  PubMed  CAS  Google Scholar 

  30. McPherson, J.P., Tamblyn, L., Elia, A., Migon, E., Shehabeldin, A., Matysiak-Zablocki, E., Lemmers, B., Salmena, L., Hakem, A., Fish, J., Kassam, F., Squire, J., Bruneau, B.G., Hande, M.P. and Hakem, R. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J. 23 (2004) 3677–3688.

    Article  PubMed  CAS  Google Scholar 

  31. Ke, H., Pei, J., Ni, Z., Xia, H., Qi, H., Woods, T., Kelekar, A. and Tao, W. Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L). Exp. Cell. Res. 298 (2004) 329–338.

    Article  PubMed  CAS  Google Scholar 

  32. Aylon, Y., Michael, D., Shmueli, A., Yabuta, N., Nojima, H. and Oren, M. A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev. 20 (2006) 2687–2700.

    Article  PubMed  CAS  Google Scholar 

  33. Voorhoeve, P.M., le Sage, C., Schrier, M., Gillis, A.J., Stoop, H., Nagel, R., Liu, Y.P., van Duijse, J., Drost, J., Griekspoor, A., Zlotorynski, E., Yabuta, N., De Vita, G., Nojima, H., Looijenga, L.H. and Agami, R. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124 (2006) 1169–1181.

    Article  PubMed  CAS  Google Scholar 

  34. Abe, Y., Ohsugi, M., Haraguchi, K., Fujimoto, J. and Yamamoto, T. LATS2-Ajuba complex regulates gamma-tubulin recruitment to centrosomes and spindle organization during mitosis. FEBS Lett. 580 (2006) 782–788.

    Article  PubMed  CAS  Google Scholar 

  35. Mueller, A., Schafer, B.W., Ferrari, S., Weibel, M., Makek, M., Hochli, M. and Heizmann, C.W. The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. J. Biol. Chem. 280 (2005) 29186–29193.

    Article  PubMed  CAS  Google Scholar 

  36. Tsai, W.C., Tsai, S.T., Jin, Y.T. and Wu, L.W. Cyclooxygenase-2 is involved in S100A2-mediated tumor suppression in squamous cell carcinoma. Mol. Cancer Res. 4 (2006) 539–547.

    Article  PubMed  CAS  Google Scholar 

  37. Feng, G., Xu, X., Youssef, E.M. and Lotan, R. Diminished expression of S100A2, a putative tumor suppressor, at early stage of human lung carcinogenesis. Cancer Res. 61 (2001) 7999–8004.

    PubMed  CAS  Google Scholar 

  38. Smith, S.L., Gugger, M., Hoban, P., Ratschiller, D., Watson, S.G., Field, J.K., Betticher, D.C. and Heighway, J. S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas. Br. J. Cancer 91 (2004) 1515–1524.

    PubMed  CAS  Google Scholar 

  39. Wang, H., Zhang, Z., Li, R., Ang, K.K., Zhang, H., Caraway, N.P., Katz, R.L. and Jiang, F. Overexpression of S100A2 protein as a prognostic marker for patients with stage I non small cell lung cancer. Int. J. Cancer 116 (2005) 285–290.

    Article  PubMed  CAS  Google Scholar 

  40. Diederichs, S., Bulk, E., Steffen, B., Ji, P., Tickenbrock, L., Lang, K., Zänker, K.S., Metzger, R., Schneider, P.M., Gerke, V., Tomas, M., Berdel, W.E., Serve, H. and Müller-Tidow, C. S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer. Cancer Res. 64 (2004) 5564–5569.

    Article  PubMed  CAS  Google Scholar 

  41. Nishimura, G., Yanoma, S., Mizuno, H., Kawakami, K. and Tsukuda, M. A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Jpn. J. Cancer Res. 90 (1999) 1152–1162.

    PubMed  CAS  Google Scholar 

  42. Lönnroth, C., Andersson, M. and Lundholm, K. Indomethacin and telomerase activity in tumor growth retardation. Int. J. Oncol. 18 (2001) 929–937.

    PubMed  Google Scholar 

  43. Deng, W.G., Kawashima, H., Wu, G., Jayachandran, G., Xu, K., Minna, J.D., Roth, J.A. and Ji, L. Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells. Cancer Res. 67 (2007) 709–717.

    Article  PubMed  CAS  Google Scholar 

  44. Ashcroft, M. and Vousden, K.H. Regulation of p53 stability. Oncogene 18 (1999) 7637–7643.

    Article  PubMed  CAS  Google Scholar 

  45. Takahashi, Y., Miyoshi, Y., Takahata, C., Irahara, N., Taguchi, T., Tamaki, Y. and Noguchi, S. Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin. Cancer Res. 15 (2005) 1380–1385.

    Article  Google Scholar 

  46. Takahashi, Y., Miyoshi, Y., Morimoto, K., Taguchi, T., Tamaki, Y. and Noguchi, S. Low LATS2 mRNA level can predict favorable response to epirubicin plus cyclophosphamide, but not to docetaxel, in breast cancers. J. Cancer Res. Clin. Oncol. 133 (2007) 501–509.

    Article  PubMed  CAS  Google Scholar 

  47. Duale, N., Lindeman, B., Komada, M., Olsen, A.K., Andreassen, A., Soderlund, E.J. and Brunborg, G. Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles. Mol. Cancer 6 (2007) 53.

    Article  PubMed  CAS  Google Scholar 

  48. Jiang, Z., Li, X., Hu, J., Zhou, W., Jiang, Y., Li, G. and Lu, D. Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. Neurosci. Res. 56 (2006) 450–458.

    Article  PubMed  CAS  Google Scholar 

  49. Jiménez-Velasco, A., Román-Gómez, J., Agirre, X., Barrios, M., Navarro, G., Vázquez, I., Prósper, F., Torres, A. and Heiniger, A. Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia. Leukemia 19 (2005) 2347–2350.

    Article  PubMed  CAS  Google Scholar 

  50. Matsubara, D., Niki, T., Ishikawa, S., Goto, A., Ohara, E., Yokomizo, T., Heizmann, C.W., Aburatani, H., Moriyama, S., Moriyama, H., Nishimura, Y., Funata, N. and Fukayama, M. Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes. Cancer Sci. 96 (2005) 844–857.

    Article  PubMed  CAS  Google Scholar 

  51. Soria, J.C., Xu, X., Liu, D.D., Lee, J.J., Kurie, J., Morice, R.C., Khuri, F., Mao, L., Hong, W.K. and Lotan, R. Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers. J. Natl. Cancer Inst. 95 (2003) 165–168.

    Article  PubMed  CAS  Google Scholar 

  52. Chen, H.H., Yu, C.H., Wang, J.T., Liu, B.Y., Wang, Y.P., Sun, A., Tsai, T.C. and Chiang, CP. Expression of human telomerase reverse transcriptase (hTERT) protein is significantly associated with the progression, recurrence and prognosis of oral squamous cell carcinoma in Taiwan. Oral Oncol. 43 (2007) 122–129.

    Article  PubMed  CAS  Google Scholar 

  53. Yim, H.W., Slebos, R.J., Randell, S.H., Umbach, D.M., Parsons, A.M., Rivera, M.P., Detterbeck, F.C. and Taylor, J.A. Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells. Cancer Lett. 246 (2007) 24–33.

    Article  PubMed  CAS  Google Scholar 

  54. Mittelstrass, K., Sauter, W., Rosenberger, A., Illig, T., Timofeeva, M., Klopp, N., Dienemann, H., Meese, E., Sybrecht, G., Woelke, G., Cebulla, M., Degen, M., Morr, H., Drings, P., Groeschel, A., Kreymborg, K.G., Haeussinger, K., Hoeffken, G., Schmidt, C., Jilge, B., Schmidt, W., Ko, Y.D., Taeuscher, D., Chang-Claude, J., Wichmann, H.E., Bickeboeller, H. and Risch, A. Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene. BMC Cancer 23 (2008) 113.

    Article  CAS  Google Scholar 

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  1. Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000, Ljubljana, Slovenia

    Mojca Stražišar, Vid Mlakar & Damjan Glavač

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  1. Mojca Stražišar
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  2. Vid Mlakar
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Correspondence to Damjan Glavač.

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Stražišar, M., Mlakar, V. & Glavač, D. The expression of COX-2, hTERT, MDM2, LATS2 and S100A2 in different types of non-small cell lung cancer (NSCLC). Cell Mol Biol Lett 14, 442–456 (2009). https://doi.org/10.2478/s11658-009-0011-7

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Cellular & Molecular Biology Letters

ISSN: 1689-1392

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