Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients

Metallothioneins (MT) are intracellular, low molecular weight proteins (6–7 kDa) involved in binding of metal ions, scavenging of free radicals, cell proliferation and apoptosis and resistance to certain chemotherapeutics. Four basic families of MT proteins are distinguished: MT-I, MT-II, MT-III, MT-IV, within each of them different isoforms occur. The study aimed at examining the expression level of nine MT isoforms: MT-1A, -1B, -1E, -1F, -1G, -1H, -1X, MT-2A and MT-IV by using real-time PCR and MT-I/II expression by immunohistochemical (IHC) technique in 69 cases of non-small cell lung cancer (NSCLC) and 12 non-malignant lung tissues (NMLT) and to correlate them with patients clinicopathological data and Ki-67 antigen expression. Out of all the analyzed cases, 62 (89.9%) demonstrated an increased MT-I/II expression. MT-1B, 1F, -1G, -1H and MT-1X were significantly up-regulated, whereas MT-1E was significantly down-regulated in NSCLC as compared to NMLT. Only in two cases MT-IV mRNA expression was noted. Significant positive correlations were observed between each particular MT isoform expressions. Higher MT-1F and MT-1A mRNA expression was associated with larger primary tumor size (P = 0.0362 and P < 0.0001, respectively). Moreover, up-regulated MT-1F mRNA expression was associated with higher grade of malignancy of NSCLC (P = 0.0085). Higher MT-1B mRNA expression was associated with squamocellular and adenocarcinoma subtype of NSCLC (P = 0.0358). Univariate analysis showed, that up-regulated MT-1F and MT-2A mRNA predicted poor patients' survival (P = 0.0206 and P = 0.0097, respectively). The levels of MT-1F and MT-2A mRNA could be considered as new markers of poor prognosis of NSCLC patients.