TypeⅡVLDLR Is Overexpressed In Different Cancers And Promotes Cancer Cells Invasive Migration By Stabilizingβ-Catenin

The very low density lipoprotein receptor (VLDLR) which belongs to the low density lipoprotein receptor (LDLR) family was initially cloned on the basis of its homology to the LDLR. This receptor exhibits domain structures similar to those of the LDLR, except it has an extra repeat of the cysteine-rich ligand-binding domain. The tissue distribution of VLDLR is most abundantly expressed in heart, skeletal muscle and adipose tissue, the VLDLR is originally considered to specifically bind to VLDL and played important roles for apolipoprotein E (apoE) metabolism. Interest in VLDLR has focused mainly on its possible role in extrahepatic tissues active in fatty acid metabolism and its role as an energy source. However, the physiological and pathological importance of this receptor has not been clearly identified. Previous studies has found that VLDLR is a multiple function receptor due to binding numerous ligands besides lipoproteins, including lipoprotein lipase (LPL), receptor-associated protein (RAP), thrombospondin-1, urokinase plasminogen activator/plasminogen activator inhibitor-1 complex (uPA/PAI-1) and several other proteinase-serpin complexes, causing endocytosis and affecting many cellular functions.Furthermore, a signaling function for the VLDLR has also been recognized, as demonstrated by the ability of reelin to modulate neuronal migration, neurodevelopment, and other physiological processes in the central nervous system. Binding of reelin to VLDLR induces tyrosine phosphorylation of Disable-1 (Dab-1) in neurons. In addition to neuronal migration via reelin, in vitro studies revealed that the VLDLR modulates cell migration via a pathway that depends on uPA. That receptor-bound uPA plays a pivotal role in tumor invasion and metastasis via the generation of plasmin and subsequent degradation of the extracellular matrix in various processes like cancer cell invasion, stromal remodelling, and angiogenesis. So the VLDLR appears to regulate biological processes by binding or intenalization of ligands, or by transducing extracellular signals across the cell membrane.VLDLR consists of two subtypes because of alternative splicing, namely the full-length VLDLR and typeⅡVLDLR (VLDLRⅡ) which lacks the O-linked sugar domain encode by the 16th exon. The tissue distribution of two VLDLR subtypes are different, the full-length VLDLR mainly expressed in heart and muscles with high lipid metabolism, whereas VLDLRⅡis a-105 kD protein that mainly expressed in kidney, spleen, adrenal gland and testis. The previous research has also shown that VLDLRⅡis predominantly expressed in the gastroenterological cancer, breast cancer, and lung cancer and so on. Other report indicates that the O-linked sugar domain of VLDLR has been demonstrated to be responsible for cell growth inhibition, and this growth inhibition is ligand-independed. These studies suggest that VLDLRⅡactivities may be related to certain cellular functions other than its involvement in lipoprotein metabolism, and has been speculated to promote the tumor cells to proliferate and metastasis.P-Catenin is part of the cadherin-catenin complex that mediates cell-cell adhesion and is a critical member of the canonical Wnt signaling pathway that is active normally in embryogenesis. It also is believed that aberrant Wnt signaling is a characteristic shared by numerous human tumors. Recent studies have revealed that Wnt signal transduction plays a pivotal role in human tumor development, where it mediates the transcription of numerous downstream target genes associated with increased growth and invasion. Chen et al reported that VLDLR is a negative regulator of the Wnt signaling pathway. But in the past research, we have indicated that increased p-Catenin accumulation is found in the human gastric adenocarcinoma cell line SGC7901, accompanied by an increase in VLDLRⅡexpression. These previous results suggest that the molecular mechanism underlying the role of VLDLR II in tumor cell proliferation and migration may be related to the stability of P-Catenin and the subsequent activation of the transcription of certain target genes. However, in tumor tissue levels, whether the mount ofβ-Catenin has a correlation with VLDLRⅡexpression need to be elucidated.In the current study, we examined the expression of VLDLRⅡin different carcinoma samples by immunohistochemistry (IHC) and Western blot, and investigated whether the expression of VLDLRⅡare different between normal and malignant tissues. Then we further analyzed potential correlations of VLDLRⅡexpression levels with various clinicopathologic tumor features, as well as with P-Catenin expression levels. Then, we further elucidated whether VLDLRⅡexpression modulates accumulation ofβ-Catenin, and affects migration and invasion of breast cancer cell line MCF-7 and 1590. Our data showed that overexpression of VLDLRⅡcould promote migration and invasion of breast cancer cells by accumulating and stabilizingβ-Catenin. Importantly, inhibiting P-Catenin signaling pathway clearly abrogated the effect of VLDLR II enhanced migration and invasion.In conclusion, VLDLRⅡmay mediate the relative signal pathway, and affect cancer cell function. Our study detected the relationship between VLDLRⅡand cellular invasive migration and the Wnt/β-Catenin signal pathway, which provided encyclopedic views of VLDLRⅡfunction and new recognition of lipoprotein receptor as a cellular Swiss army knife.