Differential expression of MUC genes in endometrial and cervical tissues and tumors

Hebbar, Vidya; Damera, Gautam; Sachdev, Goverdhan P.

doi:10.1186/1471-2407-5-124

Cited by 38 publications

(21 citation statements)

References 46 publications

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“…MUC1-Cter contains a CQCRRK motif that is necessary for nuclear localization of MUC1 and regulation of gene expression [11]. Despite extensive study of MUC1 in the context of breast and pancreatic cancers, there is limited understanding of MUC1 in endometrial cancer beyond expression studies [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

MUC1 stimulates EGFR expression and function in endometrial cancer

et al. 2016

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The current standard of care for endometrial cancer patients involves hysterectomy with adjuvant radiation and chemotherapy, with no effective treatment for advanced and metastatic disease. MUC1 is a large, heavily glycosylated transmembrane protein that lubricates and protects cell surfaces and increases cellular signaling through the epidermal growth factor receptor (EGFR). We show for the first time that MUC1 stimulates EGFR expression and function in endometrial cancer. siRNA knockdown and CRISPR/Cas knockout of MUC1 reduced EGFR gene expression, mRNA, protein levels and signaling. MUC1 bound strongly to two regions of the EGFR promoter: −627/−511 and −172/−64. MUC1 knockout also reduced EGFR-dependent proliferation in two dimensional culture, as well as growth and survival in three dimensional spheroid cultures. MUC1 knockout cells were more sensitive to the EGFR inhibitor, lapatinib. Finally, MUC1 and EGFR co-expression was associated with increased cellular proliferation in human endometrial tumors. These data demonstrate the importance of MUC1-driven EGFR expression and signaling and suggest dual-targeted therapies may provide improved response for endometrial tumors.

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Section: Introductionmentioning

confidence: 99%

MUC1 stimulates EGFR expression and function in endometrial cancer

et al. 2016

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“…MUC8 mRNA levels are upregulated in middle ear effusions, chronic sinusitis, and endometrial adenocarcinomas Takeuchi et al, 2003;Hebbar et al, 2005]. In our previous study, we found that MUC8 mRNA levels were up-regulated in human nasal polyps epithelium whereas MUC5AC gene was not Yoon et al, 2002].…”

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confidence: 95%

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Moon

Kim

Choi

et al. 2010

J of Cellular Biochemistry

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Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein-2 alpha (AP2 alpha) in human nasal polyp epithelium. We hypothesized that AP2 alpha overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12-myristate 13-acetate (PMA) treatment of the airway epithelial cell line NCI-H292 increases MUC8 gene and AP2 alpha expression. In this study, we sought to determine which signal pathway is involved in PMA-induced MUC8 gene expression. The results show that the protein kinase C and mitogen-activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO-31-8220 or PKC siRNA significantly suppress AP2 alpha as well as MUC8 gene expression in PMA-treated cells. To verify the role of AP2 alpha, we specifically knocked down AP2 alpha expression with siRNA. A significant AP2 alpha knock-down inhibited PMA-induced MUC8 gene expression. While dominant negative AP2 alpha decreased PMA-induced MUC8 gene expression, overexpressing wildtype AP2 alpha increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2 alpha in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2 alpha activation in human airway epithelial cells.

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“…T he epithelial mucin MUC1 is a large transmembrane glycoprotein that is expressed on the apical surface of healthy ductal epithelia and also on a broad range of adenocarcinomas (1)(2)(3)(4)(5). The ability of Abs and T cells to distinguish between normal and tumor-specific glycoforms of MUC1 makes this molecule an attractive immunological target for the treatment of many cancers of epithelial origin (6).…”

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confidence: 99%

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

Turner

Cohen

Finn

2007

The Journal of Immunology

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Glycoprotein tumor Ag MUC1 is overexpressed on the majority of epithelial adenocarcinomas. CTLs that recognize MUC1 and can kill tumor cells that express this molecule have been found in cancer patients, yet they are present in low frequency and unable to eradicate MUC1+ tumors. Patients also make anti-MUC1 Abs but predominantly of the IgM isotype reflecting the lack of effective MUC1-specific Th responses. Mice transgenic for the human MUC1 gene (MUC1-Tg) are similarly hyporesponsive to MUC1. We used a vaccine consisting of dendritic cells loaded with a long synthetic MUC1 peptide to investigate the fate and function of MUC1-specific CD4+ Th elicited in wild-type (WT) or MUC1-Tg mice or adoptively transferred from vaccinated WT mice. We show that hyporesponsiveness of MUC1-Tg mice to this vaccine is a result of insufficient expansion of Th cells, while at the same time their regulatory T cells are efficiently expanded to the same extent as in WT mice and exert a profound suppression on MUC1-specific B and T cell responses in vivo. Adoptive transfer of WT Th cells relieved this suppression and enhanced T and B cell responses to subsequent MUC1 immunization. Our data suggest that the balance between Th and regulatory T cells is a critical parameter that could be modulated to improve the response to cancer vaccines.

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Differential expression of MUC genes in endometrial and cervical tissues and tumors

Cited by 38 publications

References 46 publications

MUC1 stimulates EGFR expression and function in endometrial cancer

MUC1 stimulates EGFR expression and function in endometrial cancer

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Lack of Effective MUC1 Tumor Antigen-Specific Immunity in MUC1-Transgenic Mice Results from a Th/T Regulatory Cell Imbalance That Can Be Corrected by Adoptive Transfer of Wild-Type Th Cells

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