To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14ARF and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma).
These studies suggest that p16 is capable of mediating apoptosis in NSCLC cell lines expressing wild-type p53, through a direct down-regulation of Rb and an indirect down-regulation of the anti-apoptotic protein bcl-2.
We have found that ectopic p16(INK4) expression increased cellular sensitivity of human non-small-cell-lung-cancer (NSCLC) A549 cells to a selective growth-inhibitory effect induced by the topoisomerase-I inhibitor 11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11) in vitro.
We conclude that, in a sub-set of NSCLCs, (i) abnormal p16 expression contributes to tumor growth mainly by increasing the proliferative activity in the initial stages of carcinogenesis; (ii) the association with aneuploidy merely reflects the impact of aberrant p16 on proliferative activity; and (iii) other putative TSGs possibly reside within the 9p21-23 region that possibly co-operate in certain cases with CDKN2A in the development of NSCLCs.
The results suggest that NaB blocks the growth of both cell lines by induction of cyclin-dependent kinase inhibitors (in particular, p21(waf1) in NCI-H23 and p27(kip1) and p16(ink4) in NCI-H460) through a p53-dependent or p53-independent mechanism, and open up interesting perspectives for the use of NaB as an alternative or additional strategy in the treatment of non-small cell lung carcinoma.
Thus, inactivation of the p16 gene is a common event in all non-small cell lung cancer, but the mechanism of gene alteration differs between smokers and nonsmokers.
Although loss of p16INK4a function remains tightly correlated with pRB expression, loss of other regulatory elements in NSCLC such as p53 mutation and cyclin D1 over-expression appear independent of loss of the p16INK4a gene product.
It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF).
We have tested this hypothesis by examining the genomic status of the unique exon 1beta of p14ARF in 53 human cell lines and 86 primary non-small cell lung carcinomas and correlated this with previously characterized alterations of p53.
We have determined telomerase activity and p16 expression in a series of 98 prospectively collected NSCLC specimens obtained from patients who had undergone surgery without other treatment.
The presented results prompt the conclusion that hypermethylation of p16 is the major mechanism for p16 gene inactivation in early stage NSCLC and could be a useful molecular marker for the prognosis.
Methylation techniques have shown that these epigenetic changes commonly occur at the same frequency in numerous genes, both well-known ( FHIT, APC, p16 ) and recently discovered ( TMS1, RASSF1 ) in non-small cell lung cancer and in breast cancer.
To identify the molecular basis for this p16 immunohistochemical negativity further, we performed a genetic and epigenetic study of p16(INK4a) status in a series of 115 NSCLC samples parallel to the clinicopathologic and prognostic analyses.
Here, we examined 5' CpG island methylation status and expression of the p14(ARF), p16(INK4a) and RASSF1A tumor suppressor genes, and investigated the relationship of these factors with the mRNA expression of DNA methyltransferases (DNMTs) and/or methyl-CpG-binding proteins (MBPs) in 30 lung cancer cell lines including 12 small cell lung cancers (SCLCs) and 18 non-small cell lung cancers (NSCLCs).
Our study indicated that aberrant methylation of p16 may be an excellent biomarker for early diagnosis and follow-up of NSCLC patients, and MSP is a reliable method for these purposes.