Abstract
To investigate the role of thyroid transcription factor-1 (TTF-1) and tumor differentiation in resected lung adenocarcinoma. A total of 520 patients with clinical early stage lung adenocarcinoma who underwent surgical resection were reviewed retrospectively. Clinical data and outcomes were evaluated with an average follow-up of 117 months. The results were validated via lung cancer cell line studies. The clinical parameters did not differ between relapse and nonrelapse patients. Exceptions were tumor differentiation, lymphovascular space invasion, F18-fluorodeoxyglucose maximum standard uptake value, tumor size, and pathological stage (p < 0.001). Poor tumor differentiation was the independent prognostic factor (odds ratio: 2.937, p = 0.026). The expression of TTF-1 was correlated with tumor differentiation in resected lung adenocarcinoma patients (p < 0.001). Five-year survival was 60.0% for score 1 TTF-1 expression patients, 80.1% for score 2 TTF-1 expression patients, and 86.1% for score 3 TTF-1 expression group patients. The lung cancer cell line study of knockdown and overexpression of TTF-1 revealed TTF-1 mediated High Mobility Group AT-Hook 2 (HMGA2) protein involved with epithelium-mesenchymal transformation. The chromatin immunoprecipitation revealed TTF-1 regulated HMGA2 via direct binding. TTF-1/HMGA2 axis was associated with tumor differentiation and mediated the aggressiveness of the tumor and prognosis.
Highlights
Lung cancer remains the leading cause of cancer-related death
We retrospectively evaluated the records of patients who underwent surgical resection for clinical early stage (I&II) lung adenocarcinoma from January 2002 to June 2010 in Tri-Service General Hospital, Taiwan
Patients developed with relapse had a poor prognosis with a short Overall survival (OS). 5-year OS was 38.4% in the relapse groups, and 97.3% in the nonrelapse groups respectively (p < 0.001) (Fig. 1A)
Summary
Lung cancer remains the leading cause of cancer-related death. Despite advances in therapeutic drugs and newly developed target therapies, long-term survival is still unsatisfactory. Tumors graded as poorly differentiated are found to be an independent prognostic factor in patients with stage I non-small-cell lung cancer (NSCLC)[3,4], but the mechanism is not clear. The expression of TTF-1 is restricted to alveolar type II cells[8] It has been found in all types of lung cancer but is reported frequently in adenocarcinoma[9,10]. Some studies have shown that differentiation grade is not a prognostic factor for lung cancer survival[12,13]. The mechanisms which control tissue-specific expression of TTF-1, tumor differentiation, and their prognostic significance are not fully understood. We aimed to clarify the role of TTF-1 in tumor differentiation and the aggressiveness of lung adenocarcinoma
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