Li Y, Lu W, He X, Schwartz AL, Bu G.. LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering β-catenin subcellular distribution. Oncogene 23: 9129-9135

Harvard University, Cambridge, Massachusetts, United States
Oncogene (Impact Factor: 8.46). 01/2005; 23(56):9129-35. DOI: 10.1038/sj.onc.1208123
Source: PubMed


The Wnt signaling pathway plays key roles in both embryogenesis and tumorigenesis. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6), a novel member of the expanding LDL receptor family, functions as an indispensable co-receptor for the Wnt signaling pathway. Although the role of LRP6 in embryonic development is now well established, its role in tumorigenesis is unclear. We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues. Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased. This is accompanied by a significant increase in Wnt/beta-catenin signaling and cell proliferation. Finally, we demonstrate that LRP6 expression promotes tumorigenesis in vivo. These results thus indicate that LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling.

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    • "LRP6 is a well-known activator of beta-catenin, leading to pro-proliferation, pro-metastasis and anti-apoptosis in several cancer types including HCC [21,28,29]. Here, we demonstrated that overexpression of miR-126-3p led to down-regulation of LRP6 and its downstream beta-catenin in vitro and in vivo studies. "
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    ABSTRACT: Background The deregulation of microRNAs has been reported to play a pivotal role in hepatocellular carcinoma (HCC). MiR-126-3p has been reported to be associated with poor prognosis in HCC. However the underlying mechanism of miR-126-3p in HCC remains unclear.Methods The expression levels of miR-126-3p in HCC tissues and cells were detected by RT-PCR. Transwell assay and capillary tube formation assay were applied to assess the metastasis and angiogenesis in vitro. Nude mice subcutaneous tumor model was used to perform in vivo study. Dual- luciferase reporter assay was conducted to confirm the direct binding of miR-126-3p and target genes. The changes of biomarker protein levels were examined by western blot and Immunohistochemistry.ResultsWe observed that the miR-126-3p expression levels in HCC tissues and cells were significantly down-regulated. Through gain- and loss- of function studies, we showed that miR-126-3p dramatically inhibited HCC cells from migrating and invading extracellular matrix gel and suppressed capillary tube formation of endothelial cells in vitro. Furthermore, overexpression of miR-126-3p significantly reduced the volume of tumor and microvessel density in vivo. LRP6 and PIK3R2 were identified as targets of miR-126-3p. Silencing LRP6 and PIK3R2 had similar effects of miR-126-3p restoration on metastasis and angiogenesis individually in HCC cells. Furthermore, the miR-126-3p level was inversely correlated with LRP6 and PIK3R2 in HCC tissues. In addition, the rescue experiments indicated that the metastasis and angiogenesis functions of miR-126-3p were mediated by LRP6 and PIK3R2.Conclusion Our results demonstrates that deregulation of miR-126-3p contributes to metastasis and angiogenesis in HCC. The restoration of miR-126-3p expression may be a promising strategy for HCC therapy.
    Full-text · Article · Sep 2014 · Journal of Translational Medicine
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    • "Aberrant LRP6 expression alters Wnt ligand binding and receptor activation, and extracellular antagonists are associated with stem cell self-renewal and differentiation as well as cancer development and progression 15. Specifically, LRP6 protein binding to the Frizzled family member, leads to the activation of the Wnt pathway 16 and the subsequent stabilization and nuclear translocation of β-catenin 17. Pharmacological inhibition of the LRP6 Wnt-binding domains leads to the suppression of the Wnt pathway and its downstream gene regulatory mechanisms 18. "
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    ABSTRACT: Objectives: Low-density lipoprotein receptor-related protein 6 (LRP6) modulates Wnt signaling transduction. Altered LRP6 expression leads to abnormal Wnt protein activation, cell proliferation and tumorigenesis. This study investigated the association between LRP6 single-nucleotide polymorphisms (SNPs) and non-small-cell lung cancer (NSCLC) in a Chinese population. Methods: A total of 500 NSCLC patients and 500 healthy controls were recruited for assessment of four LRP6 SNPs using the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time of flight mass spectrometry. The association between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. Results: The frequency of the LRP6 rs10845498 genotype was 60.9% (A/A), 35.5% (AG) and 3.6% (GG) in patients with lung squamous cell carcinoma (SCC) and 69.2% (A/A), 27.2% (A/G) and 3.6% (GG) in controls. Logistic regression analysis revealed that the LRP6 rs10845498 A/A major allele was associated with a reduced risk in developing lung SCC (OR = 0.69; 95% CI, 0.48-1.00; P=0.04), and tobacco smokers had a 2.21 fold greater risk in developing SCC than nonsmokers (p<0.01, 95% CI, 1.72-2.85), and tobacco smokers who carried an "A" allele (AA+AG) in rs6488507 had a 2.34-fold greater risk in developing NSCLC than other patients (p< 0.01, 95%CI, 1.74-3.13). Conclusions: The LRP6 rs10845498 SNP is associated with a reduced risk of lung SCC, while tobacco smoke increases the risk. LRP6 rs6488507 polymorphism synergistically increased the risk of NSCLC in tobacco smokers. Further studies are needed to elucidate the functional impact of LRP6 expression and activity in NSCLC.
    Preview · Article · May 2014 · International journal of medical sciences
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    • "Li et al. found that LRP6 is significantly expressed in human colon cancer, breast cancer, lung cancer, fibrosarcoma, and kidney tumors. Overexpression of LRP6 promotes cell proliferation and tumorigenesis [18]. Liu et al. found that LRP6 expression is frequently upregulated in breast cancer, and might define a class of breast cancer subtype and may be considered as a putative target for therapy [19]. "
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    ABSTRACT: MicroRNAs have emerged as important regulators of carcinogenesis. In the current study, we observed that microRNA-202 (miR-202) is downregulated in hepatocellular carcinoma (HCC) cells and tissues, indicating a significant correlation between miR-202 expression and HCC progression. Overexpression of miR-202 in HCC cells suppressed cell proliferation and tumorigenicity, while downregulation of miR-202 enhanced the cells' proliferative capacity. Furthermore, we identified low-density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-202. MiR-202 suppresses the expression of LRP6 by binding to the 3'- untranslated region (UTR) of its mRNA. Finally, we found that silencing the expression of LRP6 is the essential biological function of miR-202 during HCC cell proliferation. Collectively, our findings reveal that miR-202 is a potential tumor suppressive miRNA that participates in carcinogenesis of human HCC by suppressing LRP6 expression.
    Preview · Article · Apr 2014 · FEBS letters
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