Lung cancer is the most prevalent type of cancer which causes greater than millions worldwide cancer-related death [1, 2]. About 85−90% of lung cancer is caused due to tobacco smoking resulting in bronchogenic carcinoma [3, 4].
It has been classified into four distinct histological types, namely, small cell lung carcinoma (SCLC) and three non-small cell lung carcinoma (NSCLC) types; adenocarcinoma (ADC), squamous cell carcinoma (SQC), and large cell carcinoma (LCC) . This type of cancer develops its proliferation through alterations in oncogenes, such as EGFR and tumor suppressor genes, such as TP53, RB1, CDKN2A/p16[1, 6]. Smoking is the most important root of all lung cancer types but small-cell lung cancer and squamous-cell carcinoma are more strongly caused by tobacco smoke. However, in patients who have never smoked in their life, adenocarcinoma is the most frequent type.
Epigenetic changes have also a profound impact in development of lung cancer. In the DNA promoter sequence of protein-coding genes, hypermethylation of cytosine in clusters of CpG dinucleotides can cause loss of gene expression. Research indicated that more than 80 genes are hypermethylated including tumour suppressor genes, e.g. p16INK4a in this type of cancer. Early detection of methylated DNA in sputum or blood of a patient can be an effective biomarker for diagnosis of lung cancer at initial stages. DNA promotor methylation and histone deacetylation are reversible processes; therefore, pharmacological inhibition can be used as therapeutic strategy to cure this disorder as this strategy may reverse gene silencing which will be beneficial in curing lung cancer .
Several different signalling pathways play significant roles in lung cancer therapy, for example, Growth promoting pathways (Epidermal Growth Factor Receptor/Ras/ PhosphatidylInositol 3-Kinase),Growth inhibitory pathways (p53/Rb/P14ARF, STK11), Apoptotic pathways (Bcl-2/Bax/Fas/FasL),DNA repair and immortalisation genes. Among these pathways, we have selected p16INK4/cyclin D1/Rb pathway for this particular study.
Expression profiling of eleven genes involved in this pathway was done by utilizing several databases like BioGPS, HPRD and GeneCards. Two candidate genes were short listed based on (i) Molecular Function, (ii) Biological process and (iii) Cellular location. Furthermore, common functional partners of selected pathway genes through STRING database were evaluated and it was found that three dimensional structures of these short listed proteins P16-INK4A and RB1 are not reported to have been resolved yet. Therefore, in current study, 3-D structures are predicted using a computational methodology i.e., homology modeling. Furthermore, Protein-protein docking was performed for proteins encoded by these genes.