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Knockout of CTNNB1 by CRISPR-Cas9 technology inhibits cell proliferation through the Wnt/β-catenin signaling pathway

Guan L, Zhu S, Han Y, Yang C, Liu Y, Qiao L, et al.

Biotechnol Lett, 2018 Mar;40(3):501-508.
PMID: 29249062 DOI: 10.1007/s10529-017-2491-2

OBJECTIVE: To study the effects of CTNNB1 gene knockout by CRISPR-Cas9 technology on cell adhesion, proliferation, apoptosis, and Wnt/β-catenin signaling pathway.
RESULTS: CTNNB1 gene of HEK 293T cells was knocked out by CRISPR-Cas9. This was confirmed by sequencing and western blotting. Methylthiazolyl-tetrazolium bromide assays indicated that deletion of β-catenin significantly weakened adhesion ability and inhibited proliferation rate (P catenin did not affect apoptosis of HEK 293T cells, which was analyzed by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining. In addition, expression level of GSK-3β, CCND1, and CCNE1 detected by qPCR and expression level of N-Cadherin and cyclin D1 detected by western blotting were significantly decreased (P catenin detected by western blotting was significantly increased (P catenin signaling pathway and significantly inhibited adhesion and proliferation of HEK 293T cells.

Matched MeSH terms: beta Catenin/genetics*
No difference in the occurrence of mismatch repair defects and APC and CTNNB1 genes mutation in a multi-racial colorectal carcinoma patient cohort

Tan LP, Ng BK, Balraj P, Lim PK, Peh SC

Pathology, 2007 Apr;39(2):228-34.
PMID: 17454753

BACKGROUND AND AIMS: Colorectal cancers of different subtypes involve different pathogenic pathways like the Wnt and the mutator pathways. In this study, we screened 73 colorectal cancer cases from a multi-racial group for genetic and expression profile defects with the aim of correlating these with patients' clinicopathological characteristics.
METHODS: Mutation screening of the entire coding region of APC and exon 3 of CTNNB1, loss of heterozygosity (LOH) of APC, and microsatellite instability (MSI) status were assessed for 44 patients with available paired frozen normal and tumour tissues. In addition, 29 cases with available paraffin embedded tumour blocks were screened for mutation in exon 3 of CTNNB1, the APC mutation cluster region (codon 1286-1513), and hMLH1, hMSH2, hMSH6 protein expressions by immunohistochemistry method.
RESULTS: In our study, 15/73 cases showed APC mutations (20.5%), 1/73 cases had CTNNB1 mutation (1.4%), 5/32 cases had APC LOH (15.6%), and 16/70 (22.9%) cases revealed at least some form of mismatch repair (MMR) defect. Tumour grade (poor differentiation) was found to correlate significantly with right-sided tumour and mucinous histology (p = 0.01879 and 0.00320, respectively). Patients of younger age (below 45 years) more often had tumours of mucinous histology (p = 0.00014), while patients of older age (above 75 years) more often had tumours on the right side of the colon (p = 0.02448). Tumours of the mucinous histology subtype often had MMR defects (p = 0.02686). There was no difference in the occurrence of APC and CTNNB1 mutations and MMR defects found within our multi-racial colorectal cancer patient cohort.
CONCLUSION: Our findings support the notion that racial factor may not be related to the occurrence of MMR defects and APC and CTNNB1 mutations in our multi-racial patient cohort.

Matched MeSH terms: beta Catenin/genetics*
Fulltext Brewers' rice induces apoptosis in azoxymethane-induced colon carcinogenesis in rats via suppression of cell proliferation and the Wnt signaling pathway

Tan BL, Esa NM, Rahman HS, Hamzah H, Karim R

BMC Complement Altern Med, 2014;14:304.
PMID: 25129221 DOI: 10.1186/1472-6882-14-304

Brewers' rice is locally known as temukut, is a byproduct of the rice milling process, and consists of broken rice, rice bran, and rice germ. Unlike rice bran, the health benefit of brewers' rice has yet to be fully studied. Our present study aimed to identify the chemopreventive potential of brewers' rice with colonic tumor formation and to examine further the mechanistic action of brewers' rice during colon carcinogenesis.

Matched MeSH terms: beta Catenin/genetics
Fulltext Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations

Teo AE, Garg S, Shaikh LH, Zhou J, Karet Frankl FE, Gurnell M, et al.

N Engl J Med, 2015 Oct 08;373(15):1429-36.
PMID: 26397949 DOI: 10.1056/NEJMoa1504869

Recent discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type. (Funded by grants from the National Institute for Health Research Cambridge Biomedical Research Centre and others.).

Matched MeSH terms: beta Catenin/genetics*
Emerging strategies for sensitization of therapy resistant tumors toward cancer therapeutics by targeting the Bcl-2 family, TGF-β, Wnt/β-Catenin, RASSF and miRNA regulated signaling pathways

Veerasamy T, Eugin Simon S, Tan KO

Int J Biochem Cell Biol, 2021 08;137:106016.
PMID: 34082133 DOI: 10.1016/j.biocel.2021.106016

Conventional chemotherapy relies on the cytotoxicity of chemo-drugs to inflict destructive effects on tumor cells. However, as most tumor cells develop resistance to chemo-drugs, small doses of chemo-drugs are unlikely to provide significant clinical benefits in cancer treatment while high doses of chemo-drugs have been shown to impact normal human cells negatively due to the non-specific nature and cytotoxicity associated with chemo-drugs. To overcome this challenge, sensitizations of tumor cells with bioactive molecules that specifically target the pro-survival and pro-apoptosis signaling pathways of the tumor cells are likely to increase the therapeutic impacts and improve the clinical outcomes by reducing the dependency and adverse effects associated with using high doses of chemo-drugs in cancer treatment. This review focuses on emerging strategies to enhance the sensitization of tumor cells toward cancer therapies based on our understanding of tumor cell biology and underlying signaling pathways.

Matched MeSH terms: beta Catenin/genetics
Fulltext Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Zhou J, Azizan EAB, Cabrera CP, Fernandes-Rosa FL, Boulkroun S, Argentesi G, et al.

Nat Genet, 2021 Sep;53(9):1360-1372.
PMID: 34385710 DOI: 10.1038/s41588-021-00906-y

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.

Matched MeSH terms: beta Catenin/genetics*
Fulltext Brewers' rice modulates oxidative stress in azoxymethane-mediated colon carcinogenesis in rats

Tan BL, Norhaizan ME, Huynh K, Yeap SK, Hazilawati H, Roselina K

World J Gastroenterol, 2015 Aug 7;21(29):8826-35.
PMID: 26269672 DOI: 10.3748/wjg.v21.i29.8826

To investigate the mechanistic action of brewers' rice in regulating the Wnt/nuclear factor-kappa B (NF-κB)/Nrf2-signaling pathways during colon carcinogenesis in male Sprague-Dawley rats.

Matched MeSH terms: beta Catenin/genetics
Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways

Wee LH, Morad NA, Aan GJ, Makpol S, Wan Ngah WZ, Mohd Yusof YA

Asian Pac J Cancer Prev, 2015;16(15):6549-56.
PMID: 26434873

The PI3K-Akt-mTOR, Wnt/β-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, Wnt/β-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with IC50 values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, β-catenin, Gsk3β, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, Wnt/β catenin signaling pathways and induction of apoptosis pathway.

Matched MeSH terms: beta Catenin/genetics