Relation between prognosis and expression of metastasis-associated protein 1 in stage I non-small cell lung cancer

Interactive CardioVascular and Thoracic Surgery, Feb 2011

Metastasis-associated protein 1 (MTA1 protein) has been reported to be correlated with the biological behavior and prognosis of several malignant carcinomas. We hypothesized that stage I non-small cell lung cancer (NSCLC) patients with MTA1 protein overexpression would be more likely to have a poor prognosis. Therefore, we tested the expression of MTA1 protein in 60 stage I NSCLC and 30 paracarcinous normal lung tissues using the streptavidin-perosidase method. The Kaplan–Meier method was used to calculate the survival rate, and Cox regression analysis was performed to identify prognostic risk factors. MTA1 protein overexpression was detected in 22 stage I NSCLC tissues in this study. Tumor differentiation and tumor diameter were significantly associated with MTA1 protein overexpression, while not correlated with age, sex, pathological type or smoking status. The five-year survival rate of patients with MTA1 protein overexpression was significantly lower than that of those without expression (40.9% vs. 84.1%; P<0.001). The results of multivariate analysis confirmed that MTA1 protein overexpression was an independent prognostic factor (risk ratio=5.23, P=0.007). These findings demonstrated MTA1 might be a prognostic factor in NSCLC.

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Relation between prognosis and expression of metastasis-associated protein 1 in stage I non-small cell lung cancer

Yang Yu 1 Zhou Wang 1 Ming-Yue Zhang 0 Xiang-Yan Liu 1 Hua Zhang 1 0 Department of Thoracic Surgery, Affiliated Hospital of Weifang Medical University , 425 Yu He Road, Weifang 261031, China 1 Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Shandong University , 324 Jing Wu Road, Jinan 250021, China Metastasis-associated protein 1 (MTA1 protein) has been reported to be correlated with the biological behavior and prognosis of several malignant carcinomas. We hypothesized that stage I non-small cell lung cancer (NSCLC) patients with MTA1 protein overexpression would be more likely to have a poor prognosis. Therefore, we tested the expression of MTA1 protein in 60 stage I NSCLC and 30 paracarcinous normal lung tissues using the streptavidin-perosidase method. The Kaplan-Meier method was used to calculate the survival rate, and Cox regression analysis was performed to identify prognostic risk factors. MTA1 protein overexpression was detected in 22 stage I NSCLC tissues in this study. Tumor differentiation and tumor diameter were significantly associated with MTA1 protein overexpression, while not correlated with age, sex, pathological type or smoking status. The five-year survival rate of patients with MTA1 protein overexpression was significantly lower than that of those without expression (40.9% vs. 84.1%; P-0.001). The results of multivariate analysis confirmed that MTA1 protein overexpression was an independent prognostic factor (risk ratios5.23, Ps0.007). These findings demonstrated MTA1 might be a prognostic factor in NSCLC. 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved. 1. Introduction Lung cancer is one of the most common lethal malignancies worldwide. The occurrence rate of stage I non-small cell lung cancer (NSCLC) is nearly 20%. The overall fiveyear survival rate of stage I NSCLC is as high as 71.7%, but 3040% patients still have a poor prognosis because of postoperative metastasis or regional recurrence w1x. Therefore, investigation of the mechanism of tumor metastasis and regional recurrence has been an important research field. Up to now, various metastasis-associated genes have been studied and isolated. Among them, metastasis-associated gene 1 was isolated, and expression of metastasisassociated protein 1 (MTA1 protein) was correlated with the invasive and metastatic potential in many cancer cells. Expression of MTA1 protein is correlated with tumor invasion, and metastasis has also been reported in many cases. This study was designed to investigate the expression MTA1 protein and its relationship to the prognosis of stage I NSCLC. 2. Materials and methods 2.1. Patients A total of 60 patients with stage I NSCLC (operated between March 2003 and June 2005, confirmed by histolog 2.2. Methods ical examination) were enrolled in this study. Our study was approved by the Ethics Committee in our hospital, and we obtained the consent from the patients. All patients underwent complete resection of lung cancer with systemic lymph node dissection (according to the Naruke lymph node profile, Fig. 1) w2x, at the Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, between March 2003 and June 2005. The specimens (cancer tissues and corresponding adjacent normal tissues, which were 5 cm away from cancer tissues) were immersed in 10% neutral-buffered formaldehyde immediately after resection, and they were then embedded in a paraffin block. The study group consisted of 24 men and 36 women, ranging in age from 42 to 74 years. On the basis of the tumor-node-metastasis (TNM) classification of the International Union Against Cancer 1997, 13 patients had IA disease, 47 patients had IB disease. There were 38 adenocarcinomas and 22 squamous cell carcinomas; 22 well-differentiated cases, 20 moderately differentiated cases and 18 poorly differentiated cases. Seventeen patients had tumors -3 cm, 43 patients had tumors )3 cm. There were no serious perioperative complications such as fistula, empyema, respiratory failure, death, etc. All patients in this study did not receive adjuvant therapies including chemotherapy or radiotherapy. Immunohistochemical staining for MTA1 protein was performed using the streptavidin-perosidase (SP) method. Y. Yu et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) 166169 Fig. 1. Lymph node groups. 1, Highest mediastinal nodes; 2, upper paratracheal nodes; 3, pre-vascular and retrotracheal nodes; 4, lower paratracheal nodes; 5, subaortic nodes (A-P window); 6, para-aortic nodes; 7, subcarinal nodes; 8, paraesophageal nodes; 9, pulmonary ligament; 10, Hilar nodes; 11, interlobar nodes; 12, lobar nodes; 13, segmental nodes; 14, subsegmental nodes. Slides were deparaffinized and rehydrated with xylene and graded alcohol. Optimal antigen retrieval was carried out in citrate buffer (pHs6.0) for 10 min with a steam oven to enhance the immunoreactivity. The nuclear protein expression was scored semiquantitatively by the combination of intensity and proportion of the stained tumor nuclei as follows: (), 010% tumor nuclei stained; (q), more than 10% tumor nuclei stained w3x. Two independent observers did the semiquantitative scoring of the expression levels of MTA1 protein, and both observers reexamined the immunostained slides to determine a consensus score (Fig. 2). 2.3. Follow-up There was 100% follow-up on all patients after discharge. The site and time of tumor relapse were recorded. Patients Fig. 2. MTA1 protein was immunohistochemically stained in the cancer cell nuclei using SP method, and its intensity was graded as (), (q). The upper two figures showed negative MTA1 protein expression in squamous cell lung cancer and lung adenocarcinoma, the lower two figures showed positive MTA1 protein expression in squamous cell lung cancer and lung adenocarcinoma (original magnification =400). MTA1, metastasis-associated protein 1; SP, streptavidin-perosidase. who died of postoperative relapse were included in the prognostic analysis. The median follow-up period was 50 months (range: 1264 months). 2.4. Statistical analysis All statistic analyses were performed with SPSS 13.0 statistical software. The KaplanMeier method was used to calculate the survival rate, and the log-rank test was performed to compare the survival difference. Cox regression multivariate analysis was performed to judge independent prognostic factors. Differences were considered significant when the P-value was -0.05. 3. Results 3.1. MTA1 protein expression in cancer and adjacent normal lung tissues Of the 90 specimens analyzed, 22 (36.7%) of the cancer tissues showed overexpression of the MTA1 protein; and none of the 30 adjacent normal lung specimens expressed MTA1 protein. The difference was statistically significant (P-0.01) (Table 1). 3.2. Correlations between MTA1 protein expression and clinicopathologic characters MTA1 protein overexpression was significantly associated with histological differentiation (x2s7.89, P-0.005), tumor diameter (x2s6.33, P-0.05). However, no statistically significant correlations with gender, age, smoking status and pathological grouping were demonstrated (Table 2). Y. Yu et al. / Interactive CardioVascular and Thoracic Surgery 12 (2011) 166169 MTA1 protein (q) MTA1 protein () *Log-rank analysis. MTA1, metastasis-associated protein 1. 3.3. Correlations between MTA1 protein expression and stage I NSCLC prognosis Follow-up data were available for all patients. Tumor relapse or metastasis developed during follow-up in 23 (38.3%) of the 60 patients, 16 of whom had MTA1 protein overexpression and seven of whom did not (P-0.005). KaplanMeier analysis revealed that the overall five-year survival rate was 68.3%, and patients with MTA1 protein overexpression had a five-year survival rate of 40.9% compared to 84.1% of those without MTA1 protein expression (Figs. 3 and 4). The results of multivariate analysis confirmed that tumor differentiation degree and MTA1 protein expression were independent prognostic factors (Table 3). 4. Discussion Lung cancer is one of the most common intrathoracic malignancies, and most patients may have an advanced stage of disease at the time of definitive diagnosis. Early discovery, early diagnosis and early treatment are always the focus in the treatment lung cancer. Although stage I NSCLC is relatively local and lymph nodes are histologically negative, patients may also sometimes suffer tumor relapse or even metastasis. Metastasis-associated gene 1 is one of the recently identified candidate metastasis-associated genes, and it encodes a putative protein of 715 amino acids residues Table 2. Correlations between metastasis-associated protein 1 expression and clinicopathologic characters Clinicopathologic characters MTA1 protein expression Positive Negative 1.26 )0.05 0.43 )0.05 0.27 )0.05 7.89 -0.01 6.63 -0.05 2.35 )0.05 *Log-rank analysis. MTA1, metastasis-associated protein 1. Fig. 3. The KaplanMeier method was used to calculate the survival rate. A KaplanMeier survival curve for all patients is shown. with a predicted molecular weight of 82 kDa. It was isolated by differential cDNA library screening using the rat mammary adenocarcinoma metastatic system w4x, and the studies in the following several years indicate that the expression of MTA1 protein was correlated with the invasive and metastatic potential of many malignancies. But the mechanism it effects the tumor growth is still unknown. It may influence the tumor growth through the following two mechanisms: (1) combination of the MTA1 gene with the histone deacetylase can remodel the chromatin structure and realise down regulating metastasis-associated genes transcription w5, 6x. (2) MTA1 gene can change the cytokeratin protein filament system, and then the cells will possess more invasive and metastatic phenotype w7x. Many studies reported that MTA1 protein was associated with the invasive and metastatic potential of several human cancers w810x. Overexpression of MTA1 protein in these tumors may enhance metastases to lymph nodes, increase 95% CI for HR 1.57517.338 0.3212.483 0.67744.048 1.83315.507 0.2721.885 0.2661.878 0.4517.228 MTA1, metastasis-associated protein 1; B, regression coefficient; S.E., standard error; Wald, Wald value; P, P-value; HR, Hazard ratio; CI, confidence interval. Fig. 4. Survival curve for patients with overexpression and no expression of MTA1 protein, respectively. MTA1, metastasis-associated protein 1. cell motility, and potentiate growth w11x. To our knowledge, there were few data available regarding the correlation between MTA1 protein expression and NSCLC. Sasaki et al. w12x tested the MTA1 mRNA level in stage IIIV NSCLC using the reverse-transcription polymerase chain reaction method, and reported that the MTA1 gene expression was significantly associated with the tumor invasive ability, and had no significant correlations with gender and age. The findings of our study showed that the overexpression of MTA1 protein in stage I NSCLC tissues was high. However, we found no expression of MTA1 protein in normal lung tissues. Also, MTA1 protein overexpression was significantly associated with tumor differentiation and tumor diameter, especially in poorly differentiated tumors and tumors with a diameter )3 cm. However, the overexpression of MTA1 protein had no significant correlations with gender, age, smoking status and pathological grouping. Toh et al. w13x and Hamatsu et al. w14x have reported correlations between MTA1 protein expression and the prognosis of patients with esophageal carcinoma and hepatomas. In our study, the statistical results of survival rate demonstrated that the five-year survival rate of patients with MTA1 protein overexpression was significantly lower than that of the patients without MTA1 protein expression. The overall five-year survival rate of the 60 stage I NSCLC patients was 68.3%, and patients with MTA1 protein overexpression had a five-year survival rate of 40.9% compared to 84.1% of those without MTA1 protein expression (P-0.05; log-rank test). The results of Cox regression multivariate analysis confirmed that MTA1 protein expression was an independent prognostic factor wrisk ratio (RR)s5.23, Ps0.007x. As no patients received postoperative adjunctive therapy, we did not take postoperative adjunctive therapy into analysis. This study is a retrospective study, so we concluded that MTA1 protein overexpression was usually associated with tumor diameter, but tumor diameter was not an independent prognostic factor. In summary, the findings of our present study showed a significant association between MTA1 protein overexpression and tumor relapse or metastasis. These results suggest that MTA1 might be a predictor of relapsing phenotype and a prognostic factor in stage I NSCLC. The association between MTA1 protein overexpression and tumor behavior warrants further study.


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Yang Yu, Zhou Wang, Ming-Yue Zhang, Xiang-Yan Liu, Hua Zhang. Relation between prognosis and expression of metastasis-associated protein 1 in stage I non-small cell lung cancer, Interactive CardioVascular and Thoracic Surgery, 2011, 166-169, DOI: 10.1510/icvts.2010.243741