A Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers

Raisch, Jennifer; Côté-Biron, Anthony; Rivard, Nathalie

doi:10.3390/cancers11081162

Cited by 52 publications

(45 citation statements)

References 138 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LRP6 is a transmembrane protein involved in receptor-mediated endocytosis of lipoproteins and protein ligands [ 32 ]. This protein forms a complex with transmembrane receptor members of the Frizzled family and acts as a co-receptor in the classical Wnt/β-catenin signaling cascade [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Circ_0000527 promotes the progression of retinoblastoma by regulating miR-646/LRP6 axis

Zhang¹,

Wu²,

Li³

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

Background: Researches validate that circular RNAs (circRNAs) are dysregulated in a variety of malignancies and play an important role in regulating the malignant phenotype of tumor cells. Nevertheless, the role of circ_0000527 in retinoblastoma (RB) and its regulatory mechanisms remain largely unknown. Methods: Real-time PCR (RT-PCR) was used to detect circ_0000527 and miR-646 expression in RB tissues and cells. The LRP6 expression in RB cells was detected by Western blot. The relationship between circ_0000527 expression and the clinicopathological parameters of RB patients was analyzed. Cell proliferation, apoptosis and metastasis were monitored by cell counting kit-8 (CCK-8), flow cytometry, and Transwell assay. The dual-luciferase reporter gene assay and RIP assay were employed to verify the targeting relationship between circ_0000527 and miR-646, miR-646 and LRP6. Results: Circ_0000527 was highly expressed in both RB and RB cell lines, whose high expression level and degree of differentiation were significantly correlated with the increase in cTNM staging level. Overexpression of circ_0000527 contributed to RB cell proliferation, migration, invasion and suppressed cell apoptosis, while knocking down circ_0000527 inhibited the above malignant biological behavior. The underlying mechanism suggested that functioning as a endogenous competitive RNA, circ_0000527 directly targeted miR-646 and positively regulated LRP6 expression. Conclusion: Circ_0000527 enhances the proliferation and metastasis of RB cells by modulating the miR-646/LRP6 axis.

show abstract

Section: Discussionmentioning

confidence: 99%

Circ_0000527 promotes the progression of retinoblastoma by regulating miR-646/LRP6 axis

Zhang¹,

Wu²,

Li³

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…As TRAP1 modulates β-Catenin phosphorylation/degradation without being part of its degradation complex [ 18 ], the hypothesis that TRAP1 regulates upstream levels of Wnt canonical pathway activation was further investigated. More specifically, we studied the relationship between TRAP1 and Wnt LRP5/6 receptors, which are known to be widely expressed in colon epithelial and CRC cells [ 15 , 21 , 22 ]. The protein expression of LRP5/6 receptors and specific β-Catenin-dependent TCF target genes were evaluated in low versus high TRAP1 background in HCT116 and HEK293T cells ( Figure 3 A) and in patient-derived spheroids ( Figure 3 B) [ 14 , 18 , 23 ].…”

Section: Resultsmentioning

confidence: 99%

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Lettini

Condelli

Pietrafesa

et al. 2020

IJMS

View full text Add to dashboard Cite

Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.

show abstract

“…In particular, the Wnt/β-catenin pathway controls proliferation and survival and is required for the maintenance of intestinal stem cells. Wnt factors signals through Frizzled receptors and LRP5/LRP6 coreceptors to downregulate Glycogen Synthase Kinase 3β (GSK3b) activity, resulting in increased nuclear β-catenin [3][4][5] . In the absence of Wnt ligand, β-catenin is destabilized by a destruction complex composed of casein kinase 1 alpha (CK1a), GSK3b, Axin and adenomatous polyposis coli (APC) proteins.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the Roles of Low-Density Lipoprotein Receptor-Related Protein 6 in Intestinal Homeostasis, Regeneration and Oncogenesis

Raisch

Côté-Biron

Langlois

et al. 2021

Preprint

View full text Add to dashboard Cite

Intestinal epithelial self-renewal is tightly regulated by signaling pathways controlling stem cell proliferation, determination and differentiation. In particular, Wnt/β-catenin signaling controls crypt cell division and survival and is required for maintenance of the intestinal stem cell niche. Most colorectal cancers are also initiated by mutations activating the Wnt/β-catenin pathway. Wnt signals are transduced through Frizzled receptors and LRP5/LRP6 coreceptors to downregulate GSK3β activity, resulting in increased nuclear β-catenin. Herein, we explored if LRP6 expression is required for maintenance of intestinal homeostasis, regeneration and oncogenesis. Mice with an intestinal epithelial cell-specific deletion of Lrp6 (Lrp6IEC-KO) were generated and their phenotype analyzed. No difference in intestinal architecture or in proliferative and stem cell numbers was found in Lrp6IEC-KO mice in comparison to controls. Nevertheless, using ex vivo intestinal organoid cultures, we found that LRP6 expression was critical for crypt cell proliferation and stem cell maintenance. When exposed to dextran sodium sulfate, Lrp6IEC-KO mice developed more severe colitis than control mice. However, loss of LRP6 did not affect tumorigenesis in Apc Min/+ mice nor growth of human colorectal cancer cells. By contrast, Lrp6 silencing diminished anchorage-independent growth of BRafV600E-transformed IEC. Thus, LRP6 controls intestinal stem cell functionality and is necessary for BRAF-induced IEC oncogenesis.

show abstract

A Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers

Cited by 52 publications

References 138 publications

Circ_0000527 promotes the progression of retinoblastoma by regulating miR-646/LRP6 axis

Circ_0000527 promotes the progression of retinoblastoma by regulating miR-646/LRP6 axis

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

Unveiling the Roles of Low-Density Lipoprotein Receptor-Related Protein 6 in Intestinal Homeostasis, Regeneration and Oncogenesis

Contact Info

Product

Resources

About