Upregulation of the Wnt Co-Receptor LRP6 Promotes Hepatocarcinogenesis and Enhances Cell Invasion

Abstract

BackgroundActivation of the Wnt/β-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/β-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC.Methodology/Principal FindingsUsing real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of β-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/β-catenin signaling pathway, as shown by the TCF/β-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice.Conclusions/SignificanceOur findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt/β-catenin signaling pathway in human HCCs and suggest it may play a role in hepatocarcinogenesis.

Identification of microRNA-487b as a negative regulator of liver metastasis by regulation of KRAS in colorectal cancer

“…6). LRP6 has been shown to function as an oncogene by promoting cell growth, invasion and migration, and is expected to be a target for cancer therapy (40)(41)(42)(43)(44)(45). Notably, there is evidence that ERK1/2 in the RAS/MAPK pathway could facilitate WNT/β-catenin signaling via LRP6 phosphorylation on serine-1490 (S1490) and threonine-1572 (T1572) at both mature (transmenbrane LRP6) and immature state during its Golgi network-based maturation process (46,47).…”

Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β‐catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells

“…As an essential Wnt-co-receptor, LRP6 is overexpressed in several types of cancer [Lindvall et al, 2009; Liu et al, 2010; Yang et al, 2011; Liu et al, 2012b; Tung et al, 2012], and represents a promising therapeutic target for the development of novel anticancer drugs [King et al, 2012]. It has been demonstrated that LRP6 deficiency in human TNBC MDA-MB-231 cells resulted in significantly decreases of Wnt/β-catenin signaling, cell proliferation, and tumor growth in vivo [Liu et al, 2010], and that blocking Wnt/β-catenin signaling by N-myc downstream regulated gene-1 (NDRG1), a tumor metastasis suppressor which interacts with LRP6 and represses Wnt/β-catenin signaling, led to drastic suppression of metastatic phenotypes of mammary tumor cells in vitro and in vivo [Liu et al, 2012b].…”

Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention

“…The LRP6 R611C mutation promoted PDGF stimulated VSMC proliferation and [86], dedifferentiation and neointimal thickening via the non-canonical Wnt signaling pathway [85]. Recent studies have shown that overexpression of LRP6 enhances cell proliferation and induces tumorigenesis in fibrosarcoma [102], hepatocellular carcinoma [103], and breast [104,105] and colorectal [106] cancer. In conclusion, aberrant activation of LRP6 gene plays a major role in pathophysiology of both diseases and may be as one of the genetic links between CVD and cancer.…”