Non-small cell lung cancer (NSCLC) is the most predominant type of lung cancer and the leading cause of cancer death worldwide . Deletions or insertions in exon 19 and point mutations in exons 18 and 21 in the epidermal growth factor receptor are special diagnostic value in advanced-stage non-small cell lung cancer patients [17, 18]. Expression of oncofetal protein IMP3 correlates with distant metastases regardless of histological subtype of lung adenocarcinoma . Promoter methylation was associated with clinicopathologic characteristics and may be served as a potentially increased risk factor for pleural indentation of NSCLC . These groups have used different sets of markers to predict the prognosis and survival of patients with NSCLC with some success. However, there is little by using a combination of metastasis-related markers. Epithelial-mesenchymal transition (EMT) is considered to be one of the major molecular mechanisms inducing tumour invasion and metastasis. Some study showed that centrally located tumour cells stained positively for epithelial markers, but it was absent at the invasive front of the tumour in lung cancer [21–23]. So the expression of EMT-related proteins which related to metastasis may better reflect and predict the prognosis and survival in patients with NSCLC. In our study the aim was to evaluate changes in EMT-related proteins and to investigate their association with prognosis in lung adenocarcinoma.
As the epithelial markers, E-cadherin and cytokeratin expression is strongly related to positive serosal involvement, infiltrating type, poorly differentiated histology [13, 24]. Thyroid transcription factor-1 (TTF-1) is a transcription factor that is expressed in approximately 75% of lung adenocarcinoma. Several studies demonstrated an independent lower risk of death for lung adenocarcinoma patients whose tumor expresses positive TTF1 staining . Recently one paper suggested that TTF-1 is an important EMT-related marker. It inhibits EMT and restores epithelial phenotype in lung adenocarcinoma cells . As a result, a novel aspect of TTF-1 is that losing expression of TTF-1 made tumor cells generating EMT and then resulting in the worse prognosis of patients. The above reports and our findings indicate that loss of E-cadherin, cytokeratin and TTF1 expression is an important indicator of EMT. The regulators involving mesenchumal differentiation such as β-catenin, Snail, Twist are considered to regulate EMT by strong repression of E-cadherin expression [11, 27, 28]. Our study showed that the acquisition of mesenchymal protein expression tended to correlate with loss of epithelial protein expression. CD44 has been identified as a specific marker of cancer stem cells. In addition, CD44 plays an important role in tumor cells undergoing an EMT-like process and associated with cancer progression [29, 30]. In the present study we have demonstrated that the expression of various EMT-related proteins is associated with a poor prognosis in lung adenocarcinoma. Our results support previous reports where the expression of various EMT-related molecule were associated with neoplastic progression and poor survival in some malignancies.
Characteristics of EMT include complete loss of epithelial polarity, loss of epithelial markers and acquisition of mesenchymal markers. In addition to processes involving complete EMT, many processes occurring during development and in adult organisms involve only a transient loss of epithelial polarity without full acquisition of mesenchymal characteristics. We have defined as partial EMT [31, 32]. Partial EMT has been suggested to occur in some metastatic cancers and the number of EMT-related proteins’ alteration may reflect the degree of EMT in a way . So in our study, we divided the patients into two groups according to the number of EMT-related proteins’ alteration. The results showed that the patients with higher number of EMT-related proteins’ alteration had a significantly shorter overall survival. In multivariate analyses the number of EMT-related proteins’ alteration was significant independent prognostic indicators for overall survivals. This finding suggests that higher number of EMT-related proteins’ alteration may be significantly related to tumor progression and metastasis.
There is increasing evidence to support the role of postoperative adjuvant chemotherapy in locally advanced-stage lung cancer. However, the effect of adjuvant chemotherapy in early-stage adenocarcinoma remains to be determined . In the study we analyzed the predictive ability of the number of EMT-related proteins’ alteration in patients with early-stage lung adenocarcinoma. For early-stage lung adenocarcinoma (stage I and II) there is a trend toward worse overall survival in patients with a higher number of EMT-related proteins’ alteration. The number of EMT-related proteins’ alteration was significant independent prognostic indicators for overall survivals for early-stage adenocarcinoma in multivariate analyses. The results suggest that the number of EMT-related proteins’ alteration may be able to identify the poor prognostic cases in early-stage lung adenocarcinoma. Adjuvant therapy may be considered in patients with early-stage lung adenocarcinoma when patients have a higher number of EMT-related proteins’ alteration.