WNT/β-catenin pathway activation via Wnt1 overexpression and Axin1 downregulation correlates with cadherin-catenin complex disruption and increased lymph node involvement in micropapillary-predominant lung adenocarcinoma

Background: Micropapillary-predominant adenocarcinoma (MPA) of the lung is associated with extensive lymph node involvement and rapid terminal metastasis. However, this subtype has been recognized for only a few years, and there have been few studies of the molecular mechanisms associated with its highly invasive behaviors. Methods: The present study utilized immunohistochemical staining of surgically resected tissue blocks of MPA and lepidic-predominant lung adenocarcinoma to quantify the expression of specific biological markers in the WNT/beta-catenin pathway and evaluate their influence on the lymph nodes invasion of these two types of lung adenocarcinomas. Results: Our findings revealed that disruption of the cell membrane cadherin-catenin complex, which weakens the tumor cell adherence of MPA, was caused by the dissociation of beta-catenin from the cadherin-catenin complex and the subsequent accumulation of beta-catenin in the cytoplasm. This caused abnormal activation of the WNT/beta-catenin pathway. We also found that Wnt-1-specific overexpression and Axin1 inhibition in MPA could explain the redistribution and cytoplasmic retention of beta-catenin. Collectively, these findings suggest that an abnormality in the WNT/beta-catenin pathway could enhance the invasiveness of MPA through the overexpression of Wnt-1 and downregulation of Axin1 molecules. Conclusions: Our data support the need for further research regarding the WNT/beta-catenin pathway and the need to develop novel targeted therapies for restoration of tumor cell adherence and improvement of the prognosis of MPA.