APOPTOSIS GENE EXPRESSION PROFILE IN EARLY-STAGE NON SMALL CELL LUNG CANCER
Metodieva SN1, Cherneva RV, Nikolova DN, Genchev GD, Petrov DB, Toncheva DI
*Corresponding Author: Svetlana Nikolova Metodieva, Department of Medical Genetics, Medical University Sofia, 2 Zdrave str, 1431 Sofia, Bulgaria; Tel.: +359-2-952-0357; Fax: +359- 2-952-0357; E-mail: svetlana.metodieva@yahoo.com
page: 47

DISCUSSION

Apoptosis occurs via an extrinsic and an intrinsic pathway. The extrinsic pathway is initiated by binding of cell surface death receptors (via death domains) to adaptor proteins [e.g., Fas-associated via death domain (FADD)] in a death-induced signaling complex. The intrinsic pathway acts through generation of mitochondrial permeability transition leading to the establishment of the ‘apoptosome’ protein complex. Both pathways converge into a common cascade that consists of proteolytic enzymes-caspases [11]. The down regulated genes and their role regarding the two apoptotic pathways are presented in Figure 1. The extrinsic pathway is initiated via activation of the cell surface death receptors by members of the TNF superfamily. Expression analysis of our NSCLC samples suggests deregulation of TNFmediated cell death via down regulation of the TNF ligand TNFSF8 and of DAPK1, calciumcalmodulin regulated protein kinase [12] involved in mitochondrial-based pro-apoptotic events [13]. While the role of TNFSF8 in lung tumorigenesis is not clear, the down regulation of DAPK1 is consistent with previous findings [14] and is probably caused by aberrant methylation [15-17]. Among the substantially down regulated genes were CASP8 and CASP10, initiator caspases which transmit apoptotic signals [18]. Their death-effector domains interact with that of the adaptor FADD, which is involved in TNF-related apoptosis [19]. Loss of CASP8 through gene hypermethylation [20] allows for cellular survival in the stromal microenvironment, and promotes metastases [21]. BCL10, another proapoptotic gene, which along with CASP8 is involved in activation of NFkB signaling [22], was the most significantly down regulated gene in our NSCLC samples. The intrinsic pathway is composed of various pro- and anti-apoptotic members of the BCL2 family. In NSCLC, we found slight but constant down regulation of the BCL2 family member MCL1, which may induce apoptosis by overexpression of its short isoform [23]. HRK, another BCL2-related activator of apoptosis, was under expressed in AC histotype but not in the SCC. Our results suggest that deregulation of apoptosis in early-stage NSCLC is associated with down regulation of factors of TNF-mediated cell death (including TNFSF8, and the kinase DAPK1), caspase cascade (via initiator caspases CASP8 and CASP10), and the CARD domain containing mediator BCL10. A larger group of patients is needed in order to confirm the above results, while their clinical significance as potential prognostic and predictive markers should be validated in future studies.



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