The cell adhesion molecule L1 promotes gallbladder carcinoma progression in vitro and in vivo

Abstract

Abstract. Recent studies have demonstrated that the cell adhesion molecule, L1, is expressed in several malignant tumor types and its expression correlates with tumor progression and metastasis. However, the role of L1 in gallbladder carcinoma (GBC) remains unclear. Here, we demonstrate that L1 is expressed in GBC cells and plays an important role in the growth, motility, invasiveness, and adhesiveness of GBC cells. Specific depletion or overexpression of L1 in the GBC cell lines JCRB1033 and SNU-308, respectively, was achieved by lentivirus-mediated transduction and expression of an L1 mRNA-specific short hairpin RNA or full-length human L1. Stable depletion of L1 led to a significant decrease in GBC cell proliferation, migration and invasion, as well as decreased intracellular signaling through AKT and FAK. Overexpression of L1 in GBC cells enhanced these cellular activities. In a GBC xenograft nude mouse model, suppression of L1 markedly reduced tumor growth and increased the survival of tumorbearing mice whereas L1 overexpression stimulated tumorigenicity. Taken together, these results suggest that L1 plays a crucial role in GBC progression and may be a novel therapeutic target in GBC treatment. IntroductionGallbladder carcinoma (GBC) is the most common malignancy of the biliary tract. Although occurrence is rare compared to other gastrointestinal tract neoplasms such as gastric and colorectal cancers, GBC has a distinctly higher incidence in certain demographic groups and geographic areas (1,2). The prevalence of GBC in China, Thailand and Northern India is much higher than in the United States and Europe (3). Surgical resection is currently the most effective and potentially curative treatment for GBC. However, many patients present late in the course of the disease when surgical intervention is no longer effective; most patients with advanced GBC experience frequent recurrence after surgery. Therefore, the overall survival rate remains quite poor (4). Although the most important risk factor for the development of GBC is cholelithiasis (up to 95% of GBCs are associated with gallstones) (5), the molecular mechanisms involved in early carcinogenesis and the factors affecting disease progression remain unclear. Therefore, the identification of factors crucial for GBC progression is necessary for development of new therapeutic strategies.L1 is a transmembrane glycoprotein of 200-220 kDa that belongs to the immunoglobulin superfamily of cell adhesion molecules. It consists of six immunoglobulin-like domains and five fibronectin type III repeats in the extracellular region, a single-pass transmembrane domain and a cytoplasmic tail (6). L1 was originally described as a neural cell adhesion molecule and has been shown to initiate a variety of dynamic motile processes, including cerebellar cell migration and neurite extension in the central nervous system (7,8). L1 is also expressed in other cell types such as endothelial cells, certain epithelial cells, reticular fibroblasts, and cells of lymphoid and myelomonocyt...

TWIST1 drives cisplatin resistance and cell survival in an ovarian cancer model, via upregulation of GAS6, L1CAM, and Akt signalling

“…Given that both GAS6 and L1CAM have been linked to Akt signalling2728, and that TWIST2-mediated activation of Akt has been previously implicated in acquired cisplatin resistance22, we hypothesized that Akt may also be a key factor downstream from TWIST1, GAS6, and L1CAM . We also hypothesized that knockdown of GAS6 or L1CAM in TWIST1 overexpressing cells could inhibit upregulation and activation of Akt.…”

“…It was found to be an indicator of poor survival in endometrial carcinoma and correlated with progression, stage, grade, and poor survival in ovarian cancer4344. Finally, like GAS6, L1CAM has been shown to signal through the PI3K/Akt pathway, and drives progression and invasion in gallbladder carcinoma28. We therefore examined whether knockdown of GAS6 or L1CAM would impact cisplatin treatment efficacy.…”

L1 Cell Adhesion Molecule Promotes Migration and Invasion via JNK Activation in Extrahepatic Cholangiocarcinoma Cells with Activating KRAS Mutation

“…The differential effects of L1CAM knockdown in these two cell lines may represent that L1CAM signaling pathway in the TFK-1 cells is different from that in EGI-1 cells. In fact, we previously observed that L1CAM overexpression in gallbladder carcinoma SNU308 or ICC cells with wild type KRAS increased cell proliferation, migration and invasion through activation of FAK and AKT signaling (Jung et al, 2011; Min et al, 2010). To elucidate the functional role of L1CAM in the ECC cells with wild type KRAS , the effect of L1CAM overexpression in TFK-1 cells needs to be examined.…”

“…L1CAM was originally identified as a neural cell adhesion molecule that plays an essential role in the development of the nervous system (Grumet and Edelman, 1988). Subsequently, L1CAM has been found to be aberrantly expressed in a variety of malignant tumors, including ovarian cancer, melanoma, breast cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, neuroblastoma, and cholangiocarcinoma, and its expression correlates with a poor prognosis and metastasis (Altevogt et al, 2016; Chen et al, 2013; Jung et al, 2011; Li et al, 2009; Min et al, 2010; Samatov et al, 2016; Weidle et al, 2009). Studies on the cellular functions of L1CAM have demonstrated its promotion of cellular proliferation, migration, invasion, and chemoresistance (Kiefel et al, 2012; Raveh et al, 2009).…”

A chimeric antibody to L1 cell adhesion molecule shows therapeutic effect in an intrahepatic cholangiocarcinoma model

“…Anti-L1CAM mAb has displayed therapeutic activity in a mouse model for ovarian carcinoma (Arlt et al, 2006; Wolterink et al, 2010). Previously, we found that L1CAM is involved in tumor progression of ICC, ECC, and gallbladder carcinoma; we generated a murine mAb, A10-A3 (IgG1) binding to the Ig1 domain of L1CAM (Li et al, 2009; Min et al, 2010; Choi et al, 2011; Jung et al, 2011; Wei et al, 2011). In the present study, we constructed the cA10-A3 containing the constant regions of human IgG1, confirmed its ADCC activity in vitro , and evaluated its therapeutic activity in a Choi-CK xenograft model.…”