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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    ABSTRACT: GRHL2 was implicated in regulating cancer development. Our previous study demonstrated that knockdown GRHL2 in colorectal cancer (CRC) cells inhibited cell proliferation by targeting ZEB1. It is unclear whether GRHL2 expression may have diagnostic or prognostic value in colorectal carcinoma. Additionally, how GRHL2 is associated with the clinical features of colorectal carcinoma is not known. In current study, immunohistochemistry stains were performed to examine GRHL2 in 171 colorectal cancers and paired normal colon mucosa. The prognostic value of GRHL2 was investigated in a retrospective cohort study with a five-year follow-up. The effects of GRHL2 on cell growth in vitro and in vivo were explored by GRHL2 over-expressing in HT29 and SW620 CRC cells. Further, the regulation of cell cycle and proliferation proteins by GRHL2 were assessed by flow cytometry and western blot. We found that GRHL2 was over-expressed in CRC tissues, and played an important role in CRC tumorigenesis. GRHL2 expression positively correlated with tumor size and TNM stage. Kaplan-Meier analysis showed that GRHL2 was an independent prognostic factor for both overall survival and recurrence-free survival. Ectopic over-expression of GRHL2 in CRC cell line HT29 and SW620 induced an increase of cellular proliferation in vitro and promoting tumor growth in vivo. The acquisition of GRHL2 regulated cell cycle and modulates the expression of proliferation proteins p21, p27, cyclin A and cyclin D1. Together, our findings reveal GRHL2 can be used as a novel predictive biomarker and represent a potential therapeutic target against CRC.
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    ABSTRACT: The Neural Crest, a transient epithelium in vertebrate embryos, is the source of putative stem cells known to give rise to neuronal, glial and endocrine components of the peripheral (sensory, autonomic and enteric) nervous system (PNS) and pigment cells in the skin. The Neural Crest is also widely believed to be the source of mesectodermal derivatives (skeletogenic, odontogenic, connective tissue and smooth muscle mesenchyme) in the vertebrate head [see (Bronner and LeDouarin, 2012, Le Douarin, 2012 and Le Douarin and Kalcheim, 1999); see also (Hörstadius, 1950 and Weston, 1970)]. This conventional understanding of the broad developmental potential of the Neural Crest has been challenged over the past few years (Breau et al., 2008, Lee et al., 2013a, Lee et al., 2013b and Weston et al., 2004), based on recognition that the definition of the embryonic epithelia that comprise the Neural Crest may be imprecise. Indeed, the definition of the embryonic tissues understood to constitute the Neural Crest has changed considerably since it was first described by Wilhelm His 150 years ago (His, 1868). Today, the operational definition of the Neural Crest is inconsistent and functionally ambiguous. We believe that more precise definitions of the embryonic tissues involved in Neural Crest development would be useful to understand (1) the range of cellular phenotypes that actually segregate from it, (2) when this lineage diversification occurs, and (3) how diversification is regulated.
    Developmental Biology 01/2015; 136. DOI:10.1016/j.ydbio.2014.12.035 · 3.64 Impact Factor
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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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