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L1CAM belongs to the L1 protein family and is a transmembrane protein member, with approximately the length of 200-220 kDa. It is encoded by the L1CAM gene. L1CAM was first identified in 1984 by M. Schachner, a scientist who found the protein in post-mitotic mice neurons. L1CAM is now widely studied, in that it is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. Furthermore, due to its function, L1CAM also plays a key role in treatment-resistant cancers. General investigation in to L1CAM also revealed that mutations in the L1 protein are the cause of three neurological syndromes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).
It has been implicated that L1CAM plays a role in the development and progression of gastric cancer. A study investigated the clinical significance of L1CAM and EPCAM in the development, progression and prognosis of gastric cancer. It has been concluded that expression of L1CAM correlated with age, tumor location, size of tumors, Lauren’s classification, depth of invasion, lymph node and distant metastases, regional lymph node stage, Tumor-Node-Metastasis (TNM) stage and prognosis. These findings suggest that expression of L1CAM along with EPCAM in gastric cancer have a strong link with lymph node and distant metastasis, and poor prognosis, meaning that L1CAM and EPCAM proteins could be useful markers for tumor progression and prognosis prediction(Fig. 1).
Fig. 1. Funtions of L1CAM. (Shani et al, 2009)
By cleaving of the neuronal isoform of the L1CAM, along with stimulation of the cognate L1-dependent signaling pathways, could produce a nuclear import of an L1 fragment that contains the intracellular domain, the transmembrane domain, and part of the extracellular domain. Researchers have revealed that the LXXLL and FXXLF motifs in the extracellular and transmembrane domain of this L1CAM fragment have a role in mediating the interaction with the nuclear ERα and ERβ, PPARγ, and RXRβ. Interaction of the L1CAM fragment with these nuclear receptors disturbed by mutations of the LXXLL motif in the transmembrane domain and of the FXXLF motif in the extracellular domain could result in impairment of motor coordination, learning and memory, as well as synaptic connectivity in the cerebellum in the mouse model. This suggests that the interaction of nuclear L1CAM and distinct nuclear receptors is related to synaptic contact formation and plasticity.
It has been discovered that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Investigator also found that CE7R+ T cells (memory derived T cells (TCM) that were genetically modified to express an anti-L1-CAM CAR (chimeric antigen receptor)) were able to target primary ovarian cancer cells. Intraperitoneal administration of CE7R+ TCM induced a considerable regression of xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. These findings indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells can provide a novel and effective immunotherapy strategy for advanced ovarian cancer.
Researchers have also demonstrated that the L1CAM was expressed in androgen-insensitive and highly metastatic human prostate cancer cell lines. This correlation could also be validated in serum samples of prostate cancer patients. Knockdown of L1CAM expression in prostate cancer cells considerably decreased their aggressive behaviors in vitro and tumor formation in a metastatic murine model. Targeting of L1CAM expression in vivo effectively inhibited prostate cancer growth in mouse bone. These findings taken together provide basis for L1CAM playing a major role in prostate cancer metastasis and translational application of siRNA-based L1CAM-targeted therapy.
Previous studies in vitro have supported the hypothesis that L1CAM cell adhesion molecule (L1CAM) is a target for ethanol (EtOH) developmental neurotoxicity. L1CAM functions through signal transduction leading to phosphorylation and dephosphorylation of tyrosines on its cytoplasmic domain, along with trafficking through lipid rafts (LRs). Researchers hypothesed that L1CAM is a target for EtOH neurotoxicity in vivo. Findings suggest that EtOH at all doses decreased the relative amount of Y1176 dephosphorylation and the relative amount of L1CAM phosphorylated on other tyrosines. These results proved that L1CAM is indeed a target for EtOH developmental neurotoxicity in vivo.