Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma

Abstract

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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.

L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma

“…Interestingly, there was a definite inverse relationship between these 2 features, indicating that L1 might be related with loss of differentiation in retinoblastoma. This finding was in line with previous reports on the expression of L1 in poorly differentiated cancers in other organs [13, 17]. Furthermore, in 4 human retinoblastoma tumor samples from patients who underwent enucleation despite multiple cycles of intravenous chemotherapy, diffuse L1 expression was observed, supporting the role of L1 in the chemoresistance of retinoblastoma.…”

L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer

“…These observations suggested that overexpression of L1cam might be a common incidence in gastric cancer and could serve as an independent prognostic indicator to identify patients with different outcomes. In line with our study, up-regulation of L1cam was also found in other tumors, such as ovarian cancer, colorectal cancer, anaplastic thyroid carcinoma and intrahepatic cholangiocarcinoma [14,16,17,25]. However, further study is needed to confirm if L1cam could be used as a universal biomarker of prognosis for neoplasm.…”

RAF kinase inhibitor-independent constitutive activation of Yes-associated protein 1 promotes tumor progression in thyroid cancer

“…37, 38 Furthermore, our group has recently reported that L1CAM has an important role in determining tumor behavior and chemosensitivity in anaplastic thyroid cancers. 39 On the basis of these findings, we postulated that L1CAM and YAP1 might have synergistic effects on epithelial to mesenchymal changes, resulting in the invasion of adjacent normal tissues. Compatible with our idea, IHC staining demonstrated membrane localization of L1CAM in shCOM tumor cells.…”