Altered expression of several genes in highly metastatic subpopulations ofa human pulmonary adenocarcinoma cell line

Non-small cell lung cancer is associated with approximately 85% mortality d ue to its high metastatic potential. Therapeutic efforts have failed to pro duce a significant improvement in prognosis. In this situation, a better un derstanding of the key factors of metastasis may be useful for designing ne w molecular targets of therapy. In order to identify these factors, we comp ared the expression profiles of two subpopulations of an adenocarcinoma cel l line with a high metastatic potential, PC9/f9 and PC9/fl4, with the paren t cell line, PC9, using a cDNA array. The expression of 15 genes was found to be significantly enhanced or reduced in the highly metastatic subpopulat ions. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen act ivator inhibitor-1 (PAI-1) and interleukin-1 (IL-1 alpha) were upregulated in the highly metastatic subpopulations, while the expression of carcino em bryonic antigen (CEA), caspase-5, Fas li.-and, Prk/FNK, cyclin E, cyclin B1 , Ki-67, proliferating cell nuclear antigen (PCNA), Smad4, macrophage proin flammatory human chemokine-3 alpha (MIP-3 alpha)/LARC, Met and CD44 were do wnregulated. Data from the literature suggest that the altered expression o f MMP-2, PAI-1, IL-1 alpha, CEA, caspase-5. Fas ligand, Prk/FNK and Smad4 p romotes the highly metastatic phenotype. The differential expression of the se genes was confirmed by Northern blot analysis, standard reverse transcri ption-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. This analysis in subpopulations of a lung cancer cell line indicated that the highly metastatic potential of lung cancer may be induced not by an alt eration in the expression of a single gene, but by the accumulation of alte rations in the expression of several genes involved in extracellular matrix (ECM) adhesion disruption, ECM degradation, escape from apoptosis, and res istance to transfonning growth factor-beta (1) (TGF-beta (1)). Strate-ies f or inhibiting metastasis of pulmonary adenocarcinoma should be designed acc ordingly. (C) 2001 Elsevier Science Ltd. All rights reserved.