ABSTRACT
Objective To investigate the clinical significance and prognostic value of PKD3 expression in human hepatocellu-lar carcinoma (HCC)after hepatectomy.Methods We analyzed mRNA expression of L1CAM in 1 10 HCCs by quantitative real-time PCR (qRT-PCR)and western blot,and the relationship among the overall survival of HCCs.Results The relative protein and mRNA expression level of L1CAM was up-regulated in HCCs comparing with adjacent non tumor liver tissues (P <0.01).L1CAM expression in the well-differentiated group was higher than that in the poor-differentiated group (P < 0.01 ).The expression of L1CAM mRNA was significantly correlated with tumor differentiation and TNM stage (P <0.05).The prognosis of patients with high expression L1CAM was poor (P <0.01).Conclusion L1CAM expression is related to occurrence and development of HCCs and may predict the prognosis of HCCs after hepatectomy.
ABSTRACT
Homophilic interaction of the L1 family of cell adhesion molecules plays a pivotal role in regulating neurite outgrowth and neural cell networking in vivo. Functional defects in L1 family members are associated with neurological disorders such as X-linked mental retardation, multiple sclerosis, low-IQ syndrome, developmental delay, and schizophrenia. Various human tumors with poor prognosis also implicate the role of L1, a representative member of the L1 family of cell adhesion molecules, and ectopic expression of L1 in fibroblastic cells induces metastasis-associated gene expression. Previous studies on L1 homologs indicated that four N-terminal immunoglobulin-like domains form a horseshoe-like structure that mediates homophilic interactions. Various models including the zipper, domain-swap, and symmetry-related models are proposed to be involved in structural mechanism of homophilic interaction of the L1 family members. Recently, cryo-electron tomography of L1 and crystal structure studies of neurofascin, an L1 family protein, have been performed. This review focuses on recent discoveries of different models and describes the possible structural mechanisms of homophilic interactions of L1 family members. Understanding structural mechanisms of homophilic interactions in various cell adhesion proteins should aid the development of therapeutic strategies for L1 family cell adhesion molecule-associated diseases.
Subject(s)
Humans , Cell Adhesion , Crystallography, X-Ray , Escherichia coli , Immunoglobulins/chemistry , Neural Cell Adhesion Molecule L1/chemistry , Neurites/chemistry , Protein Conformation , Protein Interaction Domains and MotifsABSTRACT
Intrahepatic cholangiocarcinoma (ICC), a malignant tumor derived from the intrahepatic bile duct epithelium, has a poor prognosis and is refractory to conventional chemotherapy and radiation therapy. Thus, there is an urgent need to develop new effective therapeutic strategies for this disease. We previously found that L1 cell adhesion molecule (L1CAM) plays an important role in tumor progression of ICC, and we generated a murine mAb, A10-A3 (IgG1), that binds to the Ig1 domain of L1CAM. In the present study, we further characterized A10-A3, constructed a chimeric A10-A3 antibody (cA10-A3) containing the constant regions of human IgG1, and evaluated the therapeutic potential in a human ICC xenograft nude mice model. The affinities (K D) of A10-A3 and cA10-A3 for soluble L1CAM were 1.8 nM and 1.9 nM, respectively, as determined by competition ELISA. A10-A3 inhibited L1CAM homophilic binding and was slowly internalized into the tumor cells, but it did not significantly inhibit proliferation of ICC cells in vitro. cA10-A3 mediated antibody-dependent cell-mediated cytotoxicity in vitro and displayed anti-tumor activity in the ICC animal model. These results suggest that the humanized A10-A3 antibody may have potential as an anticancer agent for the treatment of ICC.