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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN Imprimir: 0893-9675
ISSN On-line: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2018027608
pages 201-217

Regulation of Epithelial Cell Proliferation, Differentiation, and Plasticity by Grainyhead-Like 2 During Oral Carcinogenesis

Mo K. Kang
The Shapiro Family Laboratory of Viral Oncology and Aging Research; Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry
Wei Chen
The Shapiro Family Laboratory of Viral Oncology and Aging Research; Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry
No-Hee Park
The Shapiro Family Laboratory of Viral Oncology and Aging Research; Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry; David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA

RESUMO

Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis.


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