Suppression of the Epithelial-Mesenchymal Transition by Grainyhead-like-2

Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, USA.
Cancer Research (Impact Factor: 9.28). 03/2012; 72(9):2440-53. DOI: 10.1158/0008-5472.CAN-11-4038
Source: PubMed

ABSTRACT Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.

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    • "Reduced expression of GRHL2 in breast tumors has been associated with an EMT phenotype, increased cell survival, and migratory and invasive behaviour, which is reminiscent of a tumor suppressor gene [11] [12]. Conversely, high GRHL2 expression has been related to a poor prognosis for breast cancer metastasis [10] [11] [15] [17], although we are currently exploring the hypothesis that high expression of GRHL2 indicates a loss of function of this protein. Figure 5. GRHL2 expression at the mRNA level in cervical samples without lesions. "
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    ABSTRACT: The transcription factor grainyhead-like 2 (GRHL2) is evolutionarily conserved in many different species, and is involved in morphogenesis, epithelial differentiation, and the control of the epithelial-mesenchymal transition. It has also recently been implicated in carcinogenesis, but its role in this remains controversial. Expression of GRHL2 has not previously been reported in cervical cancer, so the present study aimed to characterize GRHL2 expression in cervical cancer-derived cell lines (CCCLs) and cervical tissues with different grades of lesions. Microarray analysis found that the expression of 58 genes was down-regulated in CCCLs compared to HaCaT cells (non-tumorigenic human epithelial cell line). The expression of eight of these genes was validated by quantitative real-time PCR (qPCR), and GRHL2 was found to be the most down-regulated. Western blot assays corroborated that GRHL2 protein levels were strongly down-regulated in CCCLs. Cervical cells from women without cervical lesions were shown to express GRHL2, while immunohistochemistry found that positivity to GRHL2 decreased in cervical cancer tissues. In conclusion, a loss or strong reduction in GRHL2 expression appears to be a characteristic of cervical cancer, suggesting that GRHL2 down-regulation is a necessary step during cervical carcinogenesis. However, further studies are needed to delineate the role of GRHL2 in cervical cancer and during malignant progression.
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    • "We suspected that SALL4 regulates transcription factors involving in EMT, because SALL4 knockdown induces epithelial transition. In order to identify the factor(s), we used quantitative RT-PCR to screen the transcription factors, SNAI1, SNAI2, TWIST1, TWIST2, FOXC1, FOXC2, TGFB1, TCF3, GSC, GRHL2, ZEB1 and ZEB2 [18] [19] [20]. In the result, we found reduction in the ZEB1 mRNA level in shSALL4-expressing cells (Fig. 2A), while the others were not significantly changed (Fig. 2B and Fig. S4). "
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    ABSTRACT: A variety of chemical compounds are currently being discussed as novel drug delivery strategies. One promising strategy is to selectively open the paracellular pathway of epithelia for the passage of macromolecules. A prerequisite for this effect is a rapid and reversible action of these compounds, to allow a marked translocation of a drug, but also to avoid unwanted adverse effects, such as the translocation of noxious agents. Bioactive molecules that elevate paracellular permeability include Ca(2+) chelators, bacterial toxins, and other compounds, some of which perturb the structural basis of epithelial barrier function--the tight junction. Within the tight junction, organ- and tissue-specific barrier properties are determined mainly by claudins. The majority of members of the claudin protein family seal the paracellular pathway. This paper focuses on recent approaches concerning absorption-enhancing effects, with regard to selectivity and mechanism.
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