Pattern of LRP6 gene expression in tumoral tissues of colorectal cancer

Rismani, Elham; Fazeli, Mohammad Sadegh; Mahmoodzadeh, Habibollah; Movassagh, Aghdas; Azami, Sina; Karimipoor, Morteza; Teimoori‐Toolabi, Ladan

doi:10.3233/cbm-160175

Cited by 21 publications

(17 citation statements)

References 26 publications

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“…Moreover, LRP6 activates the Wnt/β-catenin pathway, promoting the genesis and development of tumors (36,37). LRP6 is expressed at high levels in CRC (38) and is involved in the regulation of its malignant development in vitro and in vivo (23,39). In the present, it was demonstrated that miR-629 directly targeted LRP6 and suppressed the Wnt/β-catenin pathway, thereby controlling proliferation, apoptosis, migration, and invasion of CRC cells in vitro and tumor growth in vivo.…”

Section: Discussionmentioning

confidence: 53%

Downregulation of microRNA‑629‑5p in colorectal cancer and prevention of the malignant phenotype by direct targeting of low‑density lipoprotein receptor‑related protein 6

Yan

Zhao

et al. 2019

Int J Mol Med

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Aberrant expression of numerous microRNAs (miRNAs/miRs) in colorectal cancer (cRc) significantly affects disease progression. Recently, miR-629-5p (miR-629) was identified as a tumor-promoting miRNA in the malignant processes of a number of human cancers. However, few studies have been conducted regarding expression profiles and detailed roles of miR-629 in CRC. In the present study, reverse transcription-quantitative polymerase chain reaction was used to assess miR-629 expression in cRc tissues and cell lines. cell Counting Kit-8 assay, flow cytometry and Transwell assays were performed to determine the in vitro effects of miR-629 on CRC cell proliferation, apoptosis, and metastasis, respectively. Xenograft models were employed to determine the in vivo effects of miR-629 on tumor growth in nude mice. Molecular mechanisms underlying the activity of miR-629 in CRC cells were explored. miR-629 expression decreased in cRc tissues and cell lines. The decreased aberrant miR-629 expression was significantly associated with tumor size, lymphatic metastasis and tumor-node-metastasis stage of cRc, and was a predictor of poor prognosis. Restoring miR-629 expression attenuated cRc cell proliferation, migration and invasion; promoted cell apoptosis in vitro; and inhibited tumor growth in vivo. Low-density lipoprotein receptor-related protein 6 (LRP6) was a direct target gene of miR-629 in CRC cells. Furthermore, the effect of LRP6 knockdown was similar to that of miR-629 overexpression in CRC cells. Restoration of LRP6 expression neutralized the effects of miR-629 in CRC cells. miR-629 suppressed the activation of the Wnt/β-catenin pathway through LRP6 regulation both in vitro and in vivo. In conclusion, miR-629 suppressed the development and progression of CRC by directly targeting LRP6 and inhibiting the Wnt/β-catenin pathway both in vitro and in vivo. Therefore, miR-629 may be a novel prognostic biomarker and therapeutic target in CRC.

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Section: Discussionmentioning

confidence: 53%

Downregulation of microRNA‑629‑5p in colorectal cancer and prevention of the malignant phenotype by direct targeting of low‑density lipoprotein receptor‑related protein 6

Yan

Zhao

et al. 2019

Int J Mol Med

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“…Besides that, in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC, Broderick et al (2017) found no significant enrichment of LRP6 mutations in CRC [61,62]. Nevertheless, LRP6 is overexpressed in many CRC cell lines in comparison to normal epithelial cells, and 61% of malignant tissues isolated from sporadic CRC patients harbor higher LRP6 levels (Table 1) [53]. This increased LRP6 expression in CRC may result from hypermethylation of the Necdin promoter—a transcriptional repressor of the LRP6 gene [63].…”

Section: Lrp6 and Carcinoma Developmentmentioning

confidence: 99%

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

Raisch

Côté-Biron

Rivard

2019

Cancers

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The WNT/β-catenin signaling pathway controls stem and progenitor cell proliferation, survival and differentiation in epithelial tissues. Aberrant stimulation of this pathway is therefore frequently observed in cancers from epithelial origin. For instance, colorectal and hepatic cancers display activating mutations in the CTNNB1 gene encoding β-catenin, or inactivating APC and AXIN gene mutations. However, these mutations are uncommon in breast and pancreatic cancers despite nuclear β-catenin localization, indicative of pathway activation. Notably, the low-density lipoprotein receptor-related protein 6 (LRP6), an indispensable co-receptor for WNT, is frequently overexpressed in colorectal, liver, breast and pancreatic adenocarcinomas in association with increased WNT/β -catenin signaling. Moreover, LRP6 is hyperphosphorylated in KRAS-mutated cells and in patient-derived colorectal tumours. Polymorphisms in the LRP6 gene are also associated with different susceptibility to developing specific types of lung, bladder and colorectal cancers. Additionally, recent observations suggest that LRP6 dysfunction may be involved in carcinogenesis. Indeed, reducing LRP6 expression and/or activity inhibits cancer cell proliferation and delays tumour growth in vivo. This review summarizes current knowledge regarding the biological function and regulation of LRP6 in the development of epithelial cancers—especially colorectal, liver, breast and pancreatic cancers.

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“…Mutations in genes associated with the Wnt/β‐catenin pathway result in functionally abnormal proteins with altered protein structures and protein interactions. The LRP6 gene encodes a transmembrane cell‐surface protein that is a major component of the Wnt receptor complex in the Wnt/β‐catenin signalling cascade 25 . LRP6 contains a large extracellular domain that binds to Wnt proteins.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation of LRP6 identified by whole‐exome sequencing in a Chinese family with non‐syndromic tooth agenesis

Wang

Liu

Zheng

et al. 2020

Orthod Craniofacial Res

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Objective The aim of this study was to explore the genetic basis of non‐syndromic tooth agenesis (TA) in a Chinese family of five individuals using whole‐exome sequencing (WES) analysis. Settings and sample population Five participants/Family‐based study of a non‐syndromic TA proband. Methods The proband, proband's mother and grandmother displayed congenital tooth deficiency. Genomic DNA was extracted from the peripheral blood or saliva samples of the proband, her parents and her grandmother, and WES was utilized to identify the causal genetic mutation. The identified mutation was further verified by Sanger sequencing and analysed using bioinformatics tools. Results A novel missense mutation, c.G711T (p.L237F), was identified in the low‐density lipoprotein receptor‐related protein 6 (LRP6) gene in all affected individuals. Bioinformatics analysis predicted the mutation to be deleterious, with the mutant LRP6 protein displaying a tertiary structural change that might disturb the Wnt/β‐catenin signalling pathway. Conclusions The identification of the mutation in the LRP6 gene and autosomal dominant inheritance with TA in the generations is consistent with the mutation being responsible for TA in the family, and furthers the association of LRP6 with nonsyndromic TA.

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Pattern of LRP6 gene expression in tumoral tissues of colorectal cancer

Abstract: Due to the profound overexpression of LRP6 in sporadic and rectal types of cancer compared to normal colonic ones, antagonist related approaches can be promising for targeted therapies of cancer.

Cited by 21 publications

References 26 publications

Downregulation of microRNA‑629‑5p in colorectal cancer and prevention of the malignant phenotype by direct targeting of low‑density lipoprotein receptor‑related protein 6

Downregulation of microRNA‑629‑5p in colorectal cancer and prevention of the malignant phenotype by direct targeting of low‑density lipoprotein receptor‑related protein 6

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

A novel missense mutation of LRP6 identified by whole‐exome sequencing in a Chinese family with non‐syndromic tooth agenesis

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