Perimembrane Aurora-A expression is a significant prognostic factor in correlation with proliferative activity in non-small-cell lung cancer (NSCLC)

Eiji Ogawa, Kazumasa Takenaka, Hiromichi Katakura, Masashi Adachi, Yosuke Otake, Yoshinobu Toda, Hirokazu Kotani, Toshiaki Manabe, Hiromi Wada, Fumihiro Tanaka, Eiji Ogawa, Kazumasa Takenaka, Hiromichi Katakura, Masashi Adachi, Yosuke Otake, Yoshinobu Toda, Hirokazu Kotani, Toshiaki Manabe, Hiromi Wada, Fumihiro Tanaka

Abstract

Purpose: Aurora-A, also known as STK15/BTAK, is a member of the protein serine/threonine kinase family, and experimental studies have revealed that Aurora-A plays critical roles in cell mitosis and in carcinogenesis. However, no clinical studies on Aurora-A expression in non-small-cell lung cancer (NSCLC) have been reported. Thus, the present study was conducted to assess the clinical significance of Aurora-A status.

Experimental design: A total of 189 consecutive patients with resected pathologic (p-)stage I-IIIA, NSCLC were retrospectively reviewed, and immunohistochemical staining was used to detect Aurora-A expression.

Results: Aurora-A expression was negative in 31 patients (16.4%); among Aurora-A positive patients, 124 patients showed pure diffuse cytoplasmic Aurora-A expression and the other 34 patients showed perimembrane Aurora-A expression. Perimembrane Aurora-A tumors showed the highest proliferative index (PI) (mean PIs for negative, diffuse cytoplasmic, and perimembrane tumors: 49.2, 41.7, and 63.5, respectively; P < .001). Five-year survival rates of Aurora-A negative, diffuse cytoplasmic, and perimembrane patients were 67.8%, 66.7%, and 47.6%, respectively, showing the poorest postoperative survival in perimembrane patients (P = .033). Subset analyses revealed that perimembrane Aurora-A expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. A multivariate analysis confirmed that perimembrane Aurora-A expression was an independent and significant factor to predict a poor prognosis.

Conclusions: Perimembrane Aurora-A status was a significant factor to predict a poor prognosis in correlation with enhanced proliferative activity in NSCLC.

Figures

Fig. 1.
Fig. 1.
Aurora-A expression in non-small-cell carcinoma (NSCLC) as detected with imuunohistochemical staining. A Negative staining. B diffuse cytoplasmic staining. C Peri-membrane staining.
Fig. 2.
Fig. 2.
Survival curves of patients who underwent complete resection for pathologic (p-) stage I–IIIA non-small-cell lung cancer. Comparison according to Aurora-A expression status.

References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1378/chest.111.6.1710', 'is_inner': False, 'url': 'https://doi.org/10.1378/chest.111.6.1710'}, {'type': 'PubMed', 'value': '9187198', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9187198/'}]}
    2. Mountain CF. Revisions in the international system for lung cancer. Chest 1997; 111:1710–7
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '2842549', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/2842549/'}]}
    2. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 1998; 96:440–7
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S1010-7940(00)00490-5', 'is_inner': False, 'url': 'https://doi.org/10.1016/s1010-7940(00)00490-5'}, {'type': 'PubMed', 'value': '10925222', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10925222/'}]}
    2. Tanaka F, Yanagihara K, Otake Y, et al. Surgery for non-small cell lung cancer: postoperative survival based on the revised tumor-node-metastasis classification and its time trend. Eur J Cardiothorac Surg 2000; 18:147–55
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1056/NEJMoa040938', 'is_inner': False, 'url': 'https://doi.org/10.1056/nejmoa040938'}, {'type': 'PubMed', 'value': '15118073', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15118073/'}]}
    2. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129–39
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1126/science.1099314', 'is_inner': False, 'url': 'https://doi.org/10.1126/science.1099314'}, {'type': 'PubMed', 'value': '15118125', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15118125/'}]}
    2. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497–500
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/0092-8674(95)90374-7', 'is_inner': False, 'url': 'https://doi.org/10.1016/0092-8674(95)90374-7'}, {'type': 'PubMed', 'value': '7720077', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/7720077/'}]}
    2. Goover DM, Leibowitz MH, McLean DA, Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 1995; 81:95–105
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/emboj/17.11.3052', 'is_inner': False, 'url': 'https://doi.org/10.1093/emboj/17.11.3052'}, {'type': 'PMC', 'value': 'PMC1170645', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1170645/'}, {'type': 'PubMed', 'value': '9606188', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9606188/'}]}
    2. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17:3052–65
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/2496', 'is_inner': False, 'url': 'https://doi.org/10.1038/2496'}, {'type': 'PubMed', 'value': '9771714', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9771714/'}]}
    2. Zhou H, Kuang J, Zhong L, et al. Tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998; 20:189–93
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12124350', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12124350/'}]}
    2. Goepfert TM, Adigun YE, Zhong L, Gay J, Medina D, Brinkley WR. Centrosome amplification and overexpression of Aurora A are early events in rat mammary carcinogenesis. Cancer Res 2002; 62:4115–22
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/sj.cr.7290152', 'is_inner': False, 'url': 'https://doi.org/10.1038/sj.cr.7290152'}, {'type': 'PubMed', 'value': '12737516', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12737516/'}]}
    2. Ke YW, Dou Z, Zhang J, Yao XB. Function and regulation of Aurora/Ip11p kinase family in cell division. Cell Res. 2003; 13:69–81
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.biocel.2005.02.021', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.biocel.2005.02.021'}, {'type': 'PubMed', 'value': '15896667', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15896667/'}]}
    2. Balanos-Garcia VM. Aurora kinases. Int J Biochem Cell Biol 2005; 37:1572–7
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15547718', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15547718/'}]}
    2. Klein A, Reichardt W, Jung V, Zang KD, Meese E, Urbschat S. Overexpression and amplification of STK15 in human gliomas. Int J Oncol 2004; 25:1789–94
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/0008-5472.CAN-03-3968', 'is_inner': False, 'url': 'https://doi.org/10.1158/0008-5472.can-03-3968'}, {'type': 'PubMed', 'value': '15126347', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15126347/'}]}
    2. Neben K, Korshunov A, Benner A, et al. Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. Cancer Res 2004; 64:3103–11
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1054/bjoc.2000.1684', 'is_inner': False, 'url': 'https://doi.org/10.1054/bjoc.2000.1684'}, {'type': 'PMC', 'value': 'PMC2363814', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2363814/'}, {'type': 'PubMed', 'value': '11259099', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11259099/'}]}
    2. Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer 2001; 84:824–31
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/1078-0432.CCR-04-0806', 'is_inner': False, 'url': 'https://doi.org/10.1158/1078-0432.ccr-04-0806'}, {'type': 'PubMed', 'value': '15534106', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15534106/'}]}
    2. Tong T, Zhong Y, Kong J, et al. Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma. Clin Cancer Res 2004; 10:7304–10
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/1078-0432.CCR-04-1627', 'is_inner': False, 'url': 'https://doi.org/10.1158/1078-0432.ccr-04-1627'}, {'type': 'PubMed', 'value': '15756006', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15756006/'}]}
    2. Tanaka E, Hashimoto Y, Ito T, et al. The clinical significance of Aurora-A/STK15/BTAK expression in human esophageal squamous cell carcinoma. Clin Cancer Res 2005; 11:1827–34
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12631597', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12631597/'}]}
    2. Li D, Zhu J, Firozi PF, et al. Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 2003; 9:991–7
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12684414', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12684414/'}]}
    2. Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ. Activation and over expression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 2003; 9:1420–6
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/ijc.1200', 'is_inner': False, 'url': 'https://doi.org/10.1002/ijc.1200'}, {'type': 'PubMed', 'value': '11291073', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11291073/'}]}
    2. Miyoshi Y, Iwao K, Egawa C, Noguchi S. Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 2001; 92:370–3
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1002/cncr.11879', 'is_inner': False, 'url': 'https://doi.org/10.1002/cncr.11879'}, {'type': 'PubMed', 'value': '14692019', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14692019/'}]}
    2. Royce ME, Xia W, Sahin AA, et al. STK15/Aurora-A expression in primary breast tumors is correlated with nuclear grade but not with prognosis. Cancer 2004; 100:12–9
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '12208897', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12208897/'}]}
    2. Sen S, Zhou H, Zhang RD, et al. Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 2002; 94:1320–9
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/1078-0432.CCR-1057-03', 'is_inner': False, 'url': 'https://doi.org/10.1158/1078-0432.ccr-1057-03'}, {'type': 'PubMed', 'value': '15041727', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15041727/'}]}
    2. Jeng YM, Peng SY, Lin CY, Hsu HC. Over expression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 2004; 10:2065–71
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '10561347', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10561347/'}]}
    2. Tanaka F, Kawano Y, Li M, et al. Prognostic significance of apoptotic index in completely resected non-small-cell lung cancer. J Clin Oncol 1999; 17:2728–36
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PMC', 'value': 'PMC5926087', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5926087/'}, {'type': 'PubMed', 'value': '10363582', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10363582/'}]}
    2. Tanaka F, Yanagihara K, Ohtake Y, et al. p53 status predicts the efficacy of postoperative oral administration of tegafur for completely resected non-small cell lung cancer. Jpn J Cancer Res (Cancer Sci) 1999; 90:432–8
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '11705856', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/11705856/'}]}
    2. Tanaka F, Otake Y, Yanagihara K, et al. Evaluation of angiogenesis in non-small cell lung cancer : comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res 2001; 7:3410–5
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/emboj/17.11.3052', 'is_inner': False, 'url': 'https://doi.org/10.1093/emboj/17.11.3052'}, {'type': 'PMC', 'value': 'PMC1170645', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1170645/'}, {'type': 'PubMed', 'value': '9606188', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/9606188/'}]}
    2. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17:3052–65
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/S0955-0674(99)80015-5', 'is_inner': False, 'url': 'https://doi.org/10.1016/s0955-0674(99)80015-5'}, {'type': 'PubMed', 'value': '10047524', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/10047524/'}]}
    2. Zimmerman W, Sparks CA, Doxsey SJ. Amorphous no longer: the centrosome comes into focus. Curr Opin Cell Biol 1999; 11:122–8
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/emboj/cdf409', 'is_inner': False, 'url': 'https://doi.org/10.1093/emboj/cdf409'}, {'type': 'PMC', 'value': 'PMC126178', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc126178/'}, {'type': 'PubMed', 'value': '12198151', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/12198151/'}]}
    2. Chen SS, Chang PC, Cheng YW, Tang FM, Lin YS. Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function. EMBO J 2002; 21:4491–9
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1074/jbc.M406802200', 'is_inner': False, 'url': 'https://doi.org/10.1074/jbc.m406802200'}, {'type': 'PubMed', 'value': '15469940', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15469940/'}]}
    2. Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J, Cheng JQ. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 2004; 279:52175–82
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/ng1279', 'is_inner': False, 'url': 'https://doi.org/10.1038/ng1279'}, {'type': 'PubMed', 'value': '14702041', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/14702041/'}]}
    2. Katayama H, Sasai K, Kawai H, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 2004; 36:55–62
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/0008-5472.CAN-04-0651', 'is_inner': False, 'url': 'https://doi.org/10.1158/0008-5472.can-04-0651'}, {'type': 'PubMed', 'value': '15087379', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15087379/'}]}
    2. Miao X, Sun T, Wang Y, Zhang X, Tan W, Lin D. Functional STK15 Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma. Cancer Res 2004; 64:2680–3
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '15466974', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15466974/'}]}
    2. Dicioccio RA, Song H, Waterfall C, et al. STK15 polymorphisms and association with risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev 2004; 13:1589–94
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/carcin/bgh231', 'is_inner': False, 'url': 'https://doi.org/10.1093/carcin/bgh231'}, {'type': 'PubMed', 'value': '15271853', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15271853/'}]}
    2. Egan KM, Newcomb PA, Ambrosone CB, et al. STK15 polymorphism and breast cancer risk in a population-based study. Carcinogenesis 2004; 25:2149–53
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/carcin/bgh244', 'is_inner': False, 'url': 'https://doi.org/10.1093/carcin/bgh244'}, {'type': 'PubMed', 'value': '15271856', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15271856/'}]}
    2. Sun T, Miao X, Wang J, Tan W, Zhou Y, Yu C, Lin D. Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma. Carcinogenesis 2004; 25:2225–30
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1158/0008-5472.CAN-04-2149', 'is_inner': False, 'url': 'https://doi.org/10.1158/0008-5472.can-04-2149'}, {'type': 'PMC', 'value': 'PMC2536656', 'is_inner': False, 'url': 'http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2536656/'}, {'type': 'PubMed', 'value': '15867347', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15867347/'}]}
    2. Kimura MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H. Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk. Cancer Res 2005; 65:3548–54
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1093/carcin/bgi085', 'is_inner': False, 'url': 'https://doi.org/10.1093/carcin/bgi085'}, {'type': 'PubMed', 'value': '15802297', 'is_inner': True, 'url': 'http://pubmed.ncbi.nlm.nih.gov/15802297/'}]}
    2. Ewart-Toland A, Dai Q, Gao YT, et al. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 2005; 6:1368–73

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj