Abstract
Background
Cyclin dependent kinases (CDK) are key factors in promoting the initiation and development of tumors. These kinases are important for maintenance of mitochondrial biogenesis and imbalance in their expression in old age may lead to the oxidative stress. Lung cancer (LC), and head and neck squamous cell carcinoma (HNSCC) are two very prominent cancers in older Indians. Both the cancers are showing increasing trend in older population. The present study assessed serum concentration of one of the kinases; CDK4 in older LC and HNSCC patients.
Methods
The study included 100 subjects each of LC and HNSCC; and older subjects without cancer or any major health problems as controls. Serum CDK4 concentration was estimated using real-time label-free Surface plasmon resonance (SPR) and was verified by western blot.
Results
Significant elevation in serum CDK4 was observed in cases with LC and HNSCC compared to controls. HNSCC patients with higher CDK4 expression had distinctly shorter survival than patients with comparatively lower CDK4 expression. No such difference was observed in LC patients. The germ line mutation study of this gene in Exon-2 was performed and none was observed among cases and controls.
Conclusion
It can be concluded that older patients with HNSCC and lung cancer have raised serums CDK4 levels, which has the potential to emerge as a biomarker in clinical practice.
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Abbreviations
- CDK4:
-
Cyclin-dependent kinase 4
- LC:
-
Lung cancer
- SCLC:
-
Small cell lung cancer
- NSCLC:
-
Non-small cell lung cancer
- HNSCC:
-
Head and neck squamous cell carcinoma
- SPR:
-
Surface plasmon resonance
References
Pal SK, Katheria V, Hurria A. Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. CA Cancer J Clin. 2010;60:120–32.
Centers for Disease Control and Detection: Deaths: National Vital Statistics Reports, Final Data for 2012. NVSR http://www.cdc.gov/nchs/data/nvsr/nvsr63/nvsr63_09.pdf 63:9. 85 (PHS); 2015.
Mohanti BK, Nachiappan P, Pandey RM, Sharma A, Bahadur S, Thakar A. Analysis of 2167 head and neck cancer patients’ management, treatment compliance and outcomes from a regional cancer centre, Delhi, India. J Laryngol Otol. 2007;121:49–56.
Deshpande A, Sicinski P, Hinds PW. Cyclins and cdks in development and cancer: a perspective. Oncogene. 2005;24:2909–15.
Mehan MR, Ayers D, Thirstrup D, Xiong W, Ostroff RM, Brody EN, et al. Protein signature of lung cancer tissues. PLoS One. 2012;7:e35157.
Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol. 1998;18:753–61.
Miliani de Marval PL, Macias E, Macias CJ. Enhanced malignant tumorigenesis in Cdk4 transgenic mice. Oncogene. 2004;23:1863–73.
Ortega S, Malumbres M, Ortega BM. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta. 2002;1602:73–87.
Wei G, Lonardo F, Ueda T, Kim T, Huvos AG, Healey JH, et al. CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. Int J Cancer. 1999;80:199–204.
Perry A, Anderl K, Borell TJ, Kimmel DW, Wang CH, O’Fallon JR, et al. Detection of p 16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas. Am J Clin Pathol. 1999;112:801–9.
An HX, Beckmann MW, Reifenberger G, Bender HG, Niederacher D. Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation. Am J Pathol. 1999;154:113–8.
Thoms HC, Dunlop MG, Stark LA. CDK4 inhibitors and apoptosis: a novel mechanism requiring nucleolar targeting of RelA. Cell Cycle. 2007;6:1293–7.
Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J. Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol Med. 2009;39:793–9.
Lindberg D, Hessman O, Akerström G, Westin G. Cyclin-dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors. Neuroendocrinology. 2007;86:112–8.
Wikman H, Nymark P, Väyrynen A, Jarmalaite S, Kallioniemi A, Salmenkivi K, et al. CDK4 is a probable target gene in a novel amplicon at 12q13.3–q14.1 in lung cancer. Genes Chromosomes Cancer. 2005;42:193–9.
Dobashi Y, Goto A, Fukayama M, Abe A, Ooi A. Overexpression of cdk4/cyclin D1, a possible mediator of apoptosis and an indicator of prognosis in human primary lung carcinoma. Int J Cancer. 2004;110:532–41.
Fang W, Li X, Jiang Q, Liu Z, Yang H, Wang S, et al. Transcriptional patterns, biomarkers and pathways characterizing nasopharyngeal carcinoma of Southern China. J Transl Med. 2008;6:6–32.
Sabir M, Baig RM, Mahjabeen I, Kayani MA. Novel germline CDK4 mutations in patients with head and neck cancer. Hered Cancer Clin Pract. 2012;10:11–20.
Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818–28.
Wu A, Wu B, Guo J, Luo W, Wu D, Yang H, et al. Elevated expression of CDK4 in lung cancer. J Transl Med. 2011;9:38–51.
Fulop T, Franceschi C, Hirokawa K, et al. Handbook on immunosenescence: basic understanding and clinical applications. Berlin: Springer; 2009.
Lingfei K, Pingzhang Y, Zhengguo L, Jianhua G, Yaowu Z. A study on p16, pRb, cdk4 and cyclinD1 expression in non-small cell lung cancers. Cancer Lett. 1998;130:93–101.
Shyam NDVN, Rao NN, Narang RDS, George J, Bommu SR, Kiran G. Immunohistochemical characterization of cyclin dependent kinase-4 in different histological grades of oral leukoplakia and oral squamous cell carcinoma. J Oral Maxillofac Pathol. 2014;18:36–41.
Acknowledgements
Authors acknowledge National Programme for Health Care of the Elderly for providing funds for the research work and to AIIMS and Indian Council of Medical Research for fellowships of Joyita Banerjee, Rashmita Pradhan, Vishal Sahu, and Abhishek Gupta.
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12094_2016_1565_MOESM1_ESM.tif
Fig S1. Expression and Purification of CDK4 protein. a) 10% SDS-PAGE gel showing expression of CDK4 in Rasetta 2 strain of E Coli: Lane 1: Uninduced Culture Lane 2: Induced Culture b) 10% SDS-PAGE shows an eluent obtained from Ni-NTA column chromatography Lane 1: Marker, Lane 2: Unbound Fraction, Lane 4-9 are elutant purified fraction of CDK4
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Banerjee, J., Pradhan, R., Gupta, A. et al. CDK4 in lung, and head and neck cancers in old age: evaluation as a biomarker. Clin Transl Oncol 19, 571–578 (2017). https://doi.org/10.1007/s12094-016-1565-2
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DOI: https://doi.org/10.1007/s12094-016-1565-2