ArticleGenes & cancer2016
MUC4 is negatively regulated through the Wnt/β-catenin pathway via the Notch effector Hath1 in colorectal cancer.
Article in Genes & cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- Synergistic Profiling of Programmed Cell Death and Immune Responses Identifies a Novel Prognostic Index for Cervical Cancer.ACS omega · 2026Article
- Molecular genetic analysis of colorectal carcinoma with an aggressive extraintestinal immunohistochemical phenotype.Scientific reports · 2024Article
- Article
- Article
- Relationship Between MUC4 Variants and Metastatic Recurrence in Colorectal Cancer.International journal of general medicine · 2023Article
- Article
- The role of membrane mucin MUC4 in breast cancer metastasis.Endocrine-related cancer · 2021Review
- Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Article
- Review
- Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance.Molecular cancer · 2020Article
- Elevating pancreatic cystic lesion stratification: Current and future pancreatic cancer biomarker(s).Biochimica et biophysica acta. Reviews on cancer · 2020Review
- Review
- Single nucleotide polymorphisms within MUC4 are associated with colorectal cancer survival.PloS one · 2019Article
- USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization.Cell death and differentiation · 2018Article
- Complete sequence-based pathway analysis by differential on-chip DNA and RNA extraction from a single cell.Scientific reports · 2017Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
MUC4 is a transmembrane mucin lining the normal colonic epithelium. The aberrant/de novo over-expression of MUC4 is well documented in malignancies of the pancreas, ovary and breast. However, studies have reported the loss of MUC4 expression in the majority of colorectal cancers (CRCs). A MUC4 promoter analysis showed the presence of three putative TCF/LEF sites, implying a possible regulation by the Wnt/β-catenin pathway, which has been shown to drive CRC progression. Thus, the objective of our study was to determine whether MUC4 is regulated by β-catenin in CRC. We first knocked down (KD) β-catenin in three CRC cell lines; LS180, HCT-8 and HCT116, which resulted in increased MUC4 transcript and MUC4 protein. Additionally, the overexpression of stabilized mutant β-catenin in LS180 and HCT-8 resulted in a decrease in MUC4 expression. Immunohistochemistry (IHC) of mouse colon tissue harboring tubular adenomas and high grade dysplasia showed dramatically reduced Muc4 in lesions relative to adjacent normal tissue, with increased cytosolic/nuclear β-catenin. Luciferase assays with the complete MUC4 promoter construct p3778 showed increased MUC4 promoter luciferase activity in the absence of β-catenin (KD). Mutation of all three putative TCF/LEF sites showed that MUC4 promoter luciferase activity was increased relative to the un-mutated promoter. Interestingly, it was observed that MUC4 expressing CRC cell lines also expressed high levels of Hath1, a transcription factor repressed by both active Wnt/β-catenin and Notch signaling. The KD of β-catenin and/or treatment with a Notch γ-secretase inhibitor, Dibenzazepine (DBZ) resulted in increased Hath1 and MUC4 in LS180, HCT-8 and HCT116. Furthermore, overexpression of Hath1 in HCT-8 and LS180 caused increased MUC4 transcript and MUC4 protein. Taken together, our results indicate that the Wnt/β-catenin pathway suppresses the Notch pathway effector Hath1, resulting in reduced MUC4 in CRC.
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