We evaluated the antitumor activity of the Bax gene and green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand (GFP/TRAIL) fusion gene driven by the human telomerase reverse transcriptase promoter both separately and combined in the human ovarian cancer lines SKOV3ip and DOV13 and human lung cancer line H1299.
We termed this lung cancer system TTS (TTF1 gene under the control of human telomerase reverse transcriptase promoter and human surfactant protein A1 promoter).
These results indicate that (a) the HBEC model system is a powerful new approach to assess the contribution of individual and combinations of genetic alterations to lung cancer pathogenesis; (b) a combination of four genetic alterations, including human telomerase reverse transcriptase overexpression, bypass of p16/RB and p53 pathways, and mutant K-RAS(V12) or mutant EGFR, is still not sufficient for HBECs to completely transform to cancer; and (c) EGFR tyrosine kinase inhibitors inhibit the growth of preneoplastic HBEC cells, suggesting their potential for chemoprevention.
The sensitivity and specificity in lung cancer diagnosis were 89.0% and 72.7% for hTERT mRNA, and 71.3% and 80.0% for EGFR mRNA, respectively. hTERT mRNA was superior to other tumor markers in lung cancer diagnosis.
We verified the tumor-specific binding activity of AP-2beta for the hTERT promoter in vitro and in vivo and detected high expression levels of AP-2beta in lung cancer cells.
The quantity of plasma DNA was determined using quantitative Real-Time PCR with amplification of the human telomerase reverse transcriptase (hTERT) gene in 151 patients that suffer from lung cancer and 79 healthy controls.
These data demonstrate a potential association between the TERT-CLPTM1L variant and levels of bulky DNA adducts measured by (32)P-postlabeling and hence a basis for susceptibility to the development of lung cancer.
Our data demonstrated that hTERT promoter-driven IFN-beta expression was the tumor-specific, decreased the cell viability of tumor cells but not normal cells, and induced tumor cell apoptosis via activation of caspase pathway and release of cytochrome c. AAV-mediated IFN-beta expression driven by hTERT promoter significantly suppressed the growth of colorectal cancer and lung cancer xenograft in mice and resulted in tumor cells death in vivo.
DQA1*03 and the minor allele for a polymorphism, rs2736100, in TERT, another lung cancer susceptibility locus identified in recent GWASs on Europeans and Americans, were indicated to independently contribute to ADC risk with per allele OR of 1.43 (95% CI = 1.31-1.56, P = 7.8 x 10(-16)).
In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.
We constructed a recombinant adenovirus containing the human sodium iodide symporter (hNIS) gene directed by the hTERT promoter, characterized the ability of infected cells in uptaking iodide, and explored the therapeutic efficacy of (131)I in a lung cancer cell line in vitro.
The combined analyses identified six well-replicated SNPs with independent effects and significant lung cancer associations (P < 5.0 × 10(-8)) located in TP63 (rs4488809 at 3q28, P = 7.2 × 10(-26)), TERT-CLPTM1L (rs465498 and rs2736100 at 5p15.33, P = 1.2 × 10(-20) and P = 1.0 × 10(-27), respectively), MIPEP-TNFRSF19 (rs753955 at 13q12.12, P = 1.5 × 10(-12)) and MTMR3-HORMAD2-LIF (rs17728461 and rs36600 at 22q12.2, P = 1.1 × 10(-11) and P = 6.2 × 10(-13), respectively).
Human telomerase reverse transcriptase (hTERT) gene amplification was detected in pleural effusions of patients with lung cancer (n = 69) and in patients with benign lung disease (n = 46) when using a quantitative polymerase chain reaction (qPCR) technique.
Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P<0.001), respectively, in two independent sample sets (n=82; n=150).
Genetic factors included six variants implicated in a previous a genome-wide association study (GWAS) of NPC and three variants residing near the CHRNA3 and TERT genes that were linked to lung cancer risk in Asian populations.