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Nuclear factor I-C regulates E-cadherin via control of KLF4 in breast cancer.

Lee HK, Lee DS, Park JC - BMC Cancer (2015)

Bottom Line: We identified the downstream factors of NFI-C, such as KLF4 and E-cadherin, which play roles in EMT.NFI-C bound directly to the KLF4 promoter and stimulated KLF4 transcriptional activity, thereby regulating E-cadherin expression during tumorigenesis.The results indicate the important role of NFI-C in regulating KLF4 during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehagro, Chongro-gu, Seoul, 110-749, South Korea. h35071221@snu.ac.kr.

ABSTRACT

Background: Progression to metastasis is the leading cause of most cancer-related mortality; however, much remains to be understood about what facilitates the spread of tumor cells. In the present study, we describe a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness.

Methods: We examined nuclear factor I-C (NFI-C) expression in MCF10A human breast epithelial cells, MCF7 non-invasive breast cancer cells, and MDA-MB231 invasive breast cancer cells by real-time PCR and western blotting. To investigate the loss- and gain-function of NFI-C, we determined whether NFI-C regulated KLF4 expression by real-time PCR, western blotting, and promoter assay. To understand the biological functions of NFI-C, we observed cell invasion, migration, adhesion in human tumor cells by transwell assay, wound healing assay, quantitative RT-PCR, cell adhesion assay, western blotting, and immunohistochemistry.

Results: We identified the downstream factors of NFI-C, such as KLF4 and E-cadherin, which play roles in EMT. NFI-C is expressed in normal mammary gland or noninvasive breast cancer cells with epithelial characteristics. NFI-C overexpression induced expression of KLF4 and E-cadherin, but not Slug, in breast cancer cells. NFI-C bound directly to the KLF4 promoter and stimulated KLF4 transcriptional activity, thereby regulating E-cadherin expression during tumorigenesis. Cells overexpressing NFI-C maintained their epithelial differentiation status, which could drive mesenchymal-epithelial transition (MET) via the NFI-C-KLF4-E-cadherin axis in breast cancer cells. Consequently, NFI-C suppressed EMT, migration, and invasion in breast cancer cells.

Conclusions: Our study reveals a novel signaling pathway that is important during breast cancer tumorigenesis: the NFI-C-KLF4-E-cadherin pathway. The results indicate the important role of NFI-C in regulating KLF4 during tumorigenesis.

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Model for the function of NFI-C and KLF4 during tumorigenesis.
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Fig6: Model for the function of NFI-C and KLF4 during tumorigenesis.

Mentions: As summarized in FigureĀ 6, NFI-C was strongly expressed in normal mammary gland cells. NFI-C increased the expression of KLF4 and E-cadherin, and led to a more pronounced epithelial cell phenotype. In contrast, NFI-C knock-down induced migration and invasion. These results demonstrate that NFI-C is essential for the maintenance of epithelial differentiation and is required to reduce EMT and metastasis by regulation of KLF4 and E-cadherin expression. This work is the first to investigate the NFI-C-KLF4-E-cadherin signaling pathway in breast cancer cells, as well as their functional implications during tumorigenesis. This information will lead to a comprehensive understanding of the role of NFI-C in cancer.Figure 6


Nuclear factor I-C regulates E-cadherin via control of KLF4 in breast cancer.

Lee HK, Lee DS, Park JC - BMC Cancer (2015)

Model for the function of NFI-C and KLF4 during tumorigenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359555&req=5

Fig6: Model for the function of NFI-C and KLF4 during tumorigenesis.
Mentions: As summarized in FigureĀ 6, NFI-C was strongly expressed in normal mammary gland cells. NFI-C increased the expression of KLF4 and E-cadherin, and led to a more pronounced epithelial cell phenotype. In contrast, NFI-C knock-down induced migration and invasion. These results demonstrate that NFI-C is essential for the maintenance of epithelial differentiation and is required to reduce EMT and metastasis by regulation of KLF4 and E-cadherin expression. This work is the first to investigate the NFI-C-KLF4-E-cadherin signaling pathway in breast cancer cells, as well as their functional implications during tumorigenesis. This information will lead to a comprehensive understanding of the role of NFI-C in cancer.Figure 6

Bottom Line: We identified the downstream factors of NFI-C, such as KLF4 and E-cadherin, which play roles in EMT.NFI-C bound directly to the KLF4 promoter and stimulated KLF4 transcriptional activity, thereby regulating E-cadherin expression during tumorigenesis.The results indicate the important role of NFI-C in regulating KLF4 during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Histology-Developmental Biology & Dental Research Institute, School of Dentistry, Seoul National University, 101 Daehagro, Chongro-gu, Seoul, 110-749, South Korea. h35071221@snu.ac.kr.

ABSTRACT

Background: Progression to metastasis is the leading cause of most cancer-related mortality; however, much remains to be understood about what facilitates the spread of tumor cells. In the present study, we describe a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness.

Methods: We examined nuclear factor I-C (NFI-C) expression in MCF10A human breast epithelial cells, MCF7 non-invasive breast cancer cells, and MDA-MB231 invasive breast cancer cells by real-time PCR and western blotting. To investigate the loss- and gain-function of NFI-C, we determined whether NFI-C regulated KLF4 expression by real-time PCR, western blotting, and promoter assay. To understand the biological functions of NFI-C, we observed cell invasion, migration, adhesion in human tumor cells by transwell assay, wound healing assay, quantitative RT-PCR, cell adhesion assay, western blotting, and immunohistochemistry.

Results: We identified the downstream factors of NFI-C, such as KLF4 and E-cadherin, which play roles in EMT. NFI-C is expressed in normal mammary gland or noninvasive breast cancer cells with epithelial characteristics. NFI-C overexpression induced expression of KLF4 and E-cadherin, but not Slug, in breast cancer cells. NFI-C bound directly to the KLF4 promoter and stimulated KLF4 transcriptional activity, thereby regulating E-cadherin expression during tumorigenesis. Cells overexpressing NFI-C maintained their epithelial differentiation status, which could drive mesenchymal-epithelial transition (MET) via the NFI-C-KLF4-E-cadherin axis in breast cancer cells. Consequently, NFI-C suppressed EMT, migration, and invasion in breast cancer cells.

Conclusions: Our study reveals a novel signaling pathway that is important during breast cancer tumorigenesis: the NFI-C-KLF4-E-cadherin pathway. The results indicate the important role of NFI-C in regulating KLF4 during tumorigenesis.

Show MeSH
Related in: MedlinePlus