Abstract
Anaplastic thyroid carcinoma (ATC) is one of the most invasive human cancers and has a poor prognosis. Molecular targets of ATC that determine its highly aggressive nature remain unidentified. This study investigated L1 cell adhesion molecule (L1CAM) expression and its role in tumorigenesis of ATCs. Expression of L1CAM in thyroid cancer was evaluated by immunohistochemical analyses of tumor samples from patients with thyroid cancer. We investigated the role of L1CAM in proliferation, migration, invasion, and chemoresistance using short hairpin RNA (shRNA) knockdown experiments in human ATC cell lines. Finally, we evaluated the role of L1CAM on tumorigenesis with ATC xenograft assay in a nude mouse model. L1CAM expression was not detectable in normal follicular epithelial cells of the thyroid or in differentiated thyroid carcinoma. In contrast, analysis of ATC samples showed specifically higher expression of L1CAM in the invasive area of the tumor. Specific knockdown of L1CAM in the ATC cell lines, FRO and 8505C, caused a significant decrease in the proliferative, migratory, and invasive capabilities of the cells. Suppression of L1CAM expression in ATC cell lines increased chemosensitivity to gemcitabine or paclitaxel. Finally, in an ATC xenograft model, depletion of L1CAM markedly reduced tumor growth and increased the survival of tumor-bearing mice. We report that L1CAM is highly expressed in the samples taken from patients with ATCs. L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs. Therefore, we suggest that L1CAM may be an important therapeutic target in patients with ATCs.
Highlights
Anaplastic thyroid carcinoma (ATC) is the most aggressive and invasive type of human thyroid cancer with a median survival of 4 to 6 months
We report that L1 cell adhesion molecule (L1CAM) is highly expressed in the samples taken from patients with ATCs
L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs
Summary
Anaplastic thyroid carcinoma (ATC) is the most aggressive and invasive type of human thyroid cancer with a median survival of 4 to 6 months. Recent studies have shown that the accumulation of multiple genetic mutations in various genes, such as RAS [1], BRAF [2], TP53 [3], b-catenin [4], PTEN [5], and PIK3CA [6], contributes to ATC tumorigenesis. L1 cell adhesion molecule (L1CAM) is a member of the immunoglobulin superfamily of cell adhesion molecules [7]. It is expressed in developing neuronal cells, renal epithelial cells, hematopoietic cells, endothelial cells, and intestinal crypt cells [8,9,10]. Recent clinical observations have shown that L1CAM expression correlates with tumor progression and metastasis in ovarian carcinoma [11] and colorectal carcinoma [12].
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