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The emerging role of non-coding RNAs in the Wnt/β-catenin signaling pathway in Prostate Cancer

Kazmi I, Altamimi ASA, Afzal M, Majami AA, AlGhamdi AS, Alkinani KB, et al.

Pathol Res Pract, 2024 Feb;254:155134.
PMID: 38277746 DOI: 10.1016/j.prp.2024.155134

Prostate cancer (PCa) is an important worldwide medical concern, necessitating a greater understanding of the molecular processes driving its development. The Wnt/-catenin signaling cascade is established as a central player in PCa pathogenesis, and recent research emphasizes the critical involvement of non-coding RNAs (ncRNAs) in this scenario. This in-depth study seeks to give a thorough examination of the complex relationship between ncRNAs and the Wnt/β-catenin system in PCa. NcRNAs, such as circular RNAs (circRNAs), long ncRNAs (lncRNAs), and microRNAs (miRNAs), have been recognized as essential regulators that modulate numerous facets of the Wnt/β-catenin network. MiRNAs have been recognized as targeting vital elements of the process, either enhancing or inhibiting signaling, depending on their specific roles and targets. LncRNAs participate in fine-tuning the Wnt/β-catenin network as a result of complicated interplay with both upstream and downstream elements. CircRNAs, despite being a relatively recent addition to the ncRNA family, have been implicated in PCa, influencing the Wnt/β-catenin cascade through diverse mechanisms. This article encompasses recent advances in our comprehension of specific ncRNAs that participate in the Wnt/β-catenin network, their functional roles, and clinical relevance in PCa. We investigate their use as screening and predictive indicators, and targets for treatment. Additionally, we delve into the interplay between Wnt/β-catenin and other signaling networks in PCa and the role of ncRNAs within this complex network. As we unveil the intricate regulatory functions of ncRNAs in the Wnt/β-catenin cascade in PCa, we gain valuable insights into the disease's pathogenesis. The implementation of these discoveries in practical applications holds promise for more precise diagnosis, prognosis, and targeted therapeutic approaches, ultimately enhancing the care of PCa patients. This comprehensive review underscores the evolving landscape of ncRNA research in PCa and the potential for innovative interventions in the battle against this formidable malignancy.

Matched MeSH terms: Wnt Signaling Pathway/genetics
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 Wnt/β-catenin signaling pathway and significantly inhibited adhesion and proliferation of HEK 293T cells.

Matched MeSH terms: Wnt Signaling Pathway/genetics*
Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma

Siar CH, Nagatsuka H, Han PP, Buery RR, Tsujigiwa H, Nakano K, et al.

J Oral Pathol Med, 2012 Apr;41(4):332-9.
PMID: 22077561 DOI: 10.1111/j.1600-0714.2011.01104.x

Canonical and non-canonical Wnt signaling pathways modulate diverse cellular processes during embryogenesis and post-natally. Their deregulations have been implicated in cancer development and progression. Wnt signaling is essential for odontogenesis. The ameloblastoma is an odontogenic epithelial neoplasm of enamel organ origin. Altered expressions of Wnts-1, -2, -5a, and -10a are detected in this tumor. The activity of other Wnt members remains unclarified.

Matched MeSH terms: Wnt Signaling Pathway/genetics
Fulltext Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

Kared H, Tan SW, Lau MC, Chevrier M, Tan C, How W, et al.

Nat Commun, 2020 02 10;11(1):821.
PMID: 32041953 DOI: 10.1038/s41467-020-14442-6

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.

Matched MeSH terms: Wnt Signaling Pathway/genetics
Fulltext LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal

Shaikh LH, Zhou J, Teo AE, Garg S, Neogi SG, Figg N, et al.

J Clin Endocrinol Metab, 2015 Jun;100(6):E836-44.
PMID: 25915569 DOI: 10.1210/jc.2015-1734

CONTEXT: Aldosterone synthesis and cellularity in the human adrenal zona glomerulosa (ZG) is sparse and patchy, presumably due to salt excess. The frequency of somatic mutations causing aldosterone-producing adenomas (APAs) may be a consequence of protection from cell loss by constitutive aldosterone production.
OBJECTIVE: The objective of the study was to delineate a process in human ZG, which may regulate both aldosterone production and cell turnover.
DESIGN: This study included a comparison of 20 pairs of ZG and zona fasciculata transcriptomes from adrenals adjacent to an APA (n = 13) or a pheochromocytoma (n = 7).
INTERVENTIONS: Interventions included an overexpression of the top ZG gene (LGR5) or stimulation by its ligand (R-spondin-3).
MAIN OUTCOME MEASURES: A transcriptome profile of ZG and zona fasciculata and aldosterone production, cell kinetic measurements, and Wnt signaling activity of LGR5 transfected or R-spondin-3-stimulated cells were measured.
RESULTS: LGR5 was the top gene up-regulated in ZG (25-fold). The gene for its cognate ligand R-spondin-3, RSPO3, was 5-fold up-regulated. In total, 18 genes associated with the Wnt pathway were greater than 2-fold up-regulated. ZG selectivity of LGR5, and its absence in most APAs, were confirmed by quantitative PCR and immunohistochemistry. Both R-spondin-3 stimulation and LGR5 transfection of human adrenal cells suppressed aldosterone production. There was reduced proliferation and increased apoptosis of transfected cells, and the noncanonical activator protein-1/Jun pathway was stimulated more than the canonical Wnt pathway (3-fold vs 1.3-fold). ZG of adrenal sections stained positive for apoptosis markers.
CONCLUSION: LGR5 is the most selectively expressed gene in human ZG and reduces aldosterone production and cell number. Such conditions may favor cells whose somatic mutation reverses aldosterone inhibition and cell loss.

Matched MeSH terms: Wnt Signaling Pathway/genetics*
Fulltext Comprehensive genomic and immunological characterization of Chinese non-small cell lung cancer patients

Zhang XC, Wang J, Shao GG, Wang Q, Qu X, Wang B, et al.

Nat Commun, 2019 04 16;10(1):1772.
PMID: 30992440 DOI: 10.1038/s41467-019-09762-1

Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.

Matched MeSH terms: Wnt Signaling Pathway/genetics
A targeted approach to genome-wide studies reveals new genetic associations with central corneal thickness

Benson MD, Khor CC, Gage PJ, Lehmann OJ

Mol Vis, 2017;23:952-962.
PMID: 29296075

Purpose: To evaluate the ability of a targeted genome-wide association study (GWAS) to identify genes associated with central corneal thickness (CCT).
Methods: A targeted GWAS was used to investigate whether ten candidate genes with known roles in corneal development were associated with CCT in two Singaporean populations. The single nucleotide polymorphisms (SNPs) within a 500 kb interval encompassing each candidate were analyzed, and in light of the resulting data, members of the Wnt pathway were subsequently screened using similar methodology.
Results: Variants within the 500 kb interval encompassing three candidate genes, DKK1 (rs1896368, p=1.32×10-3), DKK2 (rs17510449, p=7.34×10-4), and FOXO1 (rs7326616, p=1.56×10-4 and rs4943785, p=1.19×10-3), were statistically significantly associated with CCT in the Singapore Indian population. DKK2 was statistically significantly associated with CCT in a separate Singapore Malaysian population (rs10015200, p=2.26×10-3). Analysis of Wnt signaling pathway genes in each population demonstrated that TCF7L2 (rs3814573, p=1.18×10-3), RYK (rs6763231, p=1.12×10-3 and rs4854785, p=1.11×10-3), and FZD8 (rs640827, p=5.17×10-4) were statistically significantly associated with CCT.
Conclusions: The targeted GWAS identified four genes (DKK1, DKK2, RYK, and FZD8) with novel associations with CCT and confirmed known associations with two genes, FOXO1 and TCF7L2. All six participate in the Wnt pathway, supporting a broader role for Wnt signaling in regulating the thickness of the cornea. In parallel, this study demonstrated that a hypothesis-driven candidate gene approach can identify associations in existing GWAS data sets.

Matched MeSH terms: Wnt Signaling Pathway/genetics*