Polymorphism in GRHL2 gene may contribute to noise-induced hearing loss susceptibility: a meta-analysis / Polimorfismo no gene GRHL2 pode contribuir para a suscetibilidade à perda auditivainduzida por ruído: uma metanálise

Abstract Instruction: Noise-induced hearing loss is a leading occupational disease caused by gene-environment interaction. The Grainy Like 2, GRHL2, is a candidate gene. In this regard, many studies have evaluated the association between GRHL2 and noise-induced hearing loss, although the results are ambiguous and conflicting. Objective: The purpose of this study was to identify a precise estimation of the association between rs3735715 polymorphism in GRHL2 gene and susceptibility of noise-induced hearing loss. Methods: A comprehensive search was performed to collect data up to July 8, 2018. Finally, 4 eligible articles were included in this meta-analysis comprising 2410 subjects. The pooled odds ratios with 95% confidence intervals were used to evaluate the strength of the association. Results: Significant association was found in the overall population in the dominant model (GA/AA vs. GG, odds ratio = 0.707, 95% confidence interval = 0.594-0.841) and allele model (G allele vs. A allele, odds ratio = 1.189, 95% confidence interval = 1.062-1.333). When stratified by source of the subjects, we also found association between rs3735715 and noise-induced hearing loss risk in the dominant model (GA/AA vs. GG, odds ratio = 0.634, 95% confidence interval = 0.514-0.783) and allele model (G allele vs. A allele, odds ratio = 1.206, 95% confidence interval = 1.054-1.379). Conclusion: Rs3735715 polymorphism in GRHL2 gene may influence the susceptibility of noise-induced hearing loss. Additional large, well-designed and functional studies are needed to confirm this association in different populations.

Resumo Introdução: Perda auditiva induzida por ruído é uma das principais doenças ocupacionais causadas pela interação gene-ambiente. O Grainy Like 2, ou GRHL2 é um gene que tem sido considerado como candidato. Nesse sentido, muitos estudos avaliaram a associação entre o GRHL2 e perda auditiva induzida por ruído, embora os resultados sejam ambíguos e conflitantes. Objetivo: Identificar uma estimativa precisa da associação entre o polimorfismo rs3735715 no gene GRHL2 e a suscetibilidade à perda auditiva induzida por ruído. Método: Uma pesquisa abrangente foi feita para coletar dados até 8 de julho de 2018. No fim, quatro artigos elegíveis foram incluídos nesta metanálise, abrangeram 2.410 indivíduos. As odds ratios agrupadas com intervalos de confiança de 95% foram usadas para avaliar a força da associação. Resultados: Uma associação significante foi encontrada na população geral no modelo de dominância (GA/AA vs. GG, odds ratio = 0,707, intervalo de confiança 95% = 0,594-0,841) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,189, intervalo de confiança 95% = 1,062 a 1,333). Quando estratificados pelo local de trabalho dos indivíduos, também encontramos associação entre rs3735715 e risco de perda auditiva induzida por ruído no modelo de dominância (GA/AA vs. GG, odds ratio = 0,634, intervalo de confiança 95% = 0,514 ± 0,783) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,206, intervalo de confiança 95% = 1,054- 1,379). Conclusão: O polimorfismo Rs3735715 no gene GRHL2 pode influenciar a suscetibilidade à perda auditiva induzida por ruído. Estudos adicionais, amplos, bem desenhados e funcionais são necessários para confirmar essa associação em diferentes populações.

Expression of transcription factor grainyhead-like-2 in breast cancer tissues and its relationship with clinicopathological features and prognosis of patients / 中国肿瘤生物治疗杂志

@#Objective: To detect the expression of GRHL2 (grainyhead-like-2) in breast cancer tissues and to explore its correlation with clinicopathological characteristics and prognosis of breast cancer (BC) patients，aiming to find new therapeutic target for breast cancer. Method: A total of 88 pairs of BC tissues and corresponding para-cancerous tissues from patients with primary BC that treated and pathologically confirmed at the Second Department of General Surgery, Xinxiang Central Hospital from January 2010 to January 2017 were collected for this study. The expression of GRHL2 in BC tissues and para-cancerous tissues was examined with IHC, and the association between GRHL2 and clinicopathological characteristics of BC patients was analyzed. Moreover, the correlation between GRHL2 and prognosis of BC patients was investigated by analyzing TCGA clinic data for BC. Result: The expression of GRHL2 was significantly higher in BC tissues (75.00%) compared with para-cancerous tissues (36.36%) (P<0.01); Based on the results of GRHL2 expression in 114 cases of normal breast tissues and 1 097 cases of primary breast cancer tissues in TCGA database, the expression of GRHL2 in primary BC tissues was significantly higher than that in normal breast tissues (P<0.01). GRHL2 expression was associated with BC TNM stage,histological grade, HER2 status and lymphnode metastasis status (all P<0.05); TCGA database showed that the RFS of 1 979 BC patients with high GRHL2 expression was significantly shorter than that of the 1 972 cases of BC patients with low GRHL2 expression (HR=1.24, 95%CI:1.11-1.38, P<0.01); GRHL2 expression exerted no significant effect on RFS of TNBC patients or ER+ BC patients (TNBC: HR=1.30，95%CI: 0.89-1.88，P=0.170; ER+: HR=1.17, 95%CI:0.76-1.78， P=0.470); however, the RFS of HER2+ BC patients with high GRHL2 expression was significantly shorter than that of HER2+ BC patients with low GRHL2 expression (HR=1.72, 95%CI:1.11-2.68, P=0.015） . Conclusion：Expression level of GRHL2 was up-regulated in BC tissues, and was associated with BC TNM stage, histological grade, HER2 status and the lymphnode metastasis status. GRHL2 plays an important role in the generation and development of BC, indicating poor prognosis.

Regulatory effect of grainyhead-like 2 gene on proliferation of epithelial ovarian cancer cells by nuclear factor erythroid-2-related factor 2 transcription / 解剖学报

Objective: To study the effect of nuclear factor erythroid-2-related factor 2(Nrf2) and the downstream gene grainyhead-like 2(GRHL2) on epithelial ovarian cancer cell lines and the interaction of Nrf2 and GRHL2. Methods: We conducted ChlP-PCR assay to test the binding of Nrf2 with six candidate genes including GRHL2. Furthermore, we proved whether Nrf2 could bind with the GRHL2 promoter and transcriptionally activate the GRHL2 gene or not. Moreover, if the overexpression and knockdown of Nrf2 could increase and decrease the GRHL2 protein respectively. Results: We discovered that fallopian tube epithelial cells taken from epithelial ovarian cancer patients and ovarian cancer cell lines highly expressed the Nrf2 and GRHL2 at mRNA level. The overexpression and knockdown of Nrf2 could increase and decrease the cells activity, respectively. However, the knockdown of GRHL2 could inhibit the influence of Nrf2 overexpression. Conclusion: Nrf2 promotes the activity of epithelial ovarian cancer cells via modulating the GRHL2 gene transcriptionally.

Research progress of the relationship between granule head-like 2 gene and tumor in Drosophila melanogaster / 实用肿瘤学杂志

Grainhead-like 2 (GRHL2) is one of the homologous genes of Drosophila granule head-like gene in mammals,which is a kind of Drosophila granule head transcription factor.In normal organisms,GRHL2 is involved in the regulation of epithelial cell differentiation and development.In tumors,GRHL2 is complex.GRHL2 not only inhibits tumorigenesis,but it also promotes tumor formation,especially epithelial origin of malignant tumors mostly involving epithelial-mesenchymal transition (EMT) process.Further study of the relationship between GRHL2 and tumor will provide a new idea for the clinical diagnosis and treatment of cancer patients.The relationship between GRHL2 and tumor is reviewed in this paper.

Grainyhead-like-2 (GRHL2) and carcinogenesis: An advance / 第二军医大学学报

Grainyhead-like-2 (GRHL2), a mammalian homolog of Drosophila grainyhead (GRH), is involved in a variety of biological processes, including mammalian embryonic development, epidermal barrier maturation, epithelial wound healing, and central nervous system development. Notably, GRHL2 is also essential for tumor origination and development in various kinds of cancer tissues, such as hepatocellular carcinoma, breast cancer and oral squamous cell carcinoma. In these cancer cells, GRHL2 expression is markedly enhanced, and the gain of GRHL2 can significantly facilitate cancer cell proliferation and inhibit apoptosis. On contrast, in epithelial-mesenchymal transition (EMT) related breast cancer, the down-regulated GRHL2 can promote the EMT process. The underlying mechanisms of GRHL2 in tumorigenesis remain complex and diverse, including the death receptor-mediated apoptosis, aberrant activation of the human telomerase reverse transcriptase (hTERT), EMT, and enhanced anoikis-sensitivity as well. We believe that further research on GRHL2 may cast new lights on cancer therapy.