Prognostic implications of ezrin expression in human hepatocellular carcinoma

Kang, Yun Kyung; Hong, Seong Woo; Lee, Hyucksang; Kim, Woo Ho

doi:10.1002/mc.20653

Cited by 38 publications

(42 citation statements)

References 26 publications

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“…EzR is a cytoplasmic peripheral membrane protein that functions as a substrate of protein tyrosine kinases, regulates cellular survival, adhesion, migration, and invasion. Importantly, EzR is also one of the key factors involved in tumor progression and metastasis in HCC (36)(37)(38)(39). Our finding supports the notion that KAL1 may function through tumor suppressor mechanisms and led us to speculate that KAL1 may interact with EzR and mediate tumorigenesis of HCC.…”

Section: Discussionsupporting

confidence: 83%

Translational implication of Kallmann syndrome-1 gene expression in hepatocellular carcinoma

Tanaka

Kanda

Sugimoto

et al. 2015

International Journal of Oncology

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Abstract. Accumulation of epigenetic alterations causes inactivation of tumor suppressors and contributes to the initiation and progression of hepatocellular carcinoma (HCC).Identification of methylated genes is necessary to improve our understanding of the pathogenesis of HCC and develop novel biomarkers and therapeutic targets. The Kallmann syndrome-1 (KAL1) gene encodes an extracellular matrixrelated protein with diverse oncological functions. However, the function of KAL1 in HCC has not been examined. We investigated the methylation status of the KAL1 promoter region in HCC cell lines, and evaluated KAL1 mRNA levels and those of genes encoding potential interacting cell adhesion factors. KAL1 mRNA expression level was heterogeneous in nine HCC cell lines, and reactivation of KAL1 mRNA expression was observed in cells with promoter hypermethylation of KAL1 gene after demethylation. In addition, KAL1 mRNA levels inversely correlated with those of ezrin in all nine HCC cell lines. KAL1 expression levels in 144 pairs of surgically-resected tissues were determined and correlated to clinicopathological parameters. KAL1 mRNA level was independent of the background liver status, whereas HCC tissues showed significantly lower KAL1 mRNA levels than corresponding noncancerous liver tissues. Downregulation of KAL1 mRNA in HCC was significantly associated with malignant phenotype characteristics, including elevated tumor markers, larger tumor size, vascular invasion, and hypermethylation of KAL1. Patients with downregulation of KAL1 were more likely to have a shorter overall survival than other patients, and multivariate analysis identified downregulation of KAL1 as an independent prognostic factor (hazard ratio 2.04, 95% confidence interval 1.11-3.90, P=0.022). Our results indicated that KAL1 may act as a putative tumor suppressor in HCC and is inactivated by promoter hypermethylation. KAL1 may serve as a biomarker of malignant phenotype of HCC.

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Section: Discussionsupporting

confidence: 83%

Translational implication of Kallmann syndrome-1 gene expression in hepatocellular carcinoma

Tanaka

Kanda

Sugimoto

et al. 2015

International Journal of Oncology

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“…There is a relationship between high expression of ezrin and metastatic potential of some carcinomas, including medulloblastoma [10], hepatocellular carcinoma [11], lung cancer [12], breast carcinoma [13], pancreatic adenocarcinoma [14], gastric cancer cell [15], and colorectal cancer [16]. We have also demonstrated that ezrin is overexpressed in a malignantly transformed esophageal epithelial cell line compared to an immortalized cell line [17].…”

mentioning

confidence: 63%

Potential transcriptional regulatory regions exist upstream of the human ezrin gene promoter in esophageal carcinoma cells

Gao¹,

Dai²,

Yin³

et al. 2011

ABBS

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We previously demonstrated that the region 287/1134 of the human ezrin gene (VIL2) exhibited promoter activity in human esophageal carcinoma EC109 cells, and a further upstream region 21324/2890 positively regulated transcription. In this study, to identify the transcriptional regulatory regions upstream of the VIL2 promoter, we cloned VIL2 21541/2706 segment containing the 21324/2890, and investigated its transcriptional regulatory properties via luciferase assays in transiently transfected cells. In EC109 cells, it was found that VIL2 21541/2706 possessed promoter and enhancer activities. We also localized transcriptional regulatory regions by fusing 5 0 -or 3 0 -deletion segments of VIL2 21541/2706 to a luciferase reporter. We found that there were three positive and one negative transcriptional regulatory regions within VIL2 21541/2706 in EC109 cells. When these regions were separately located upstream of the luciferase gene without promoter, or located upstream of the VIL2 promoter or SV40 promoter directing the luciferase gene, only VIL2 21297/21186 exhibited considerable promoter and enhancer activities, which were lower than those of 21541/2706. In addition, transient expression of Sp1 increased ezrin expression and the transcriptional activation of VIL2 21297/21186. Other three regions, although exhibiting significantly positive or negative transcriptional regulation in deletion experiments, showed a weaker or absent regulation. These data suggested that more than one region upstream of the VIL2 promoter participated in VIL2 transcription, and the VIL2 21297/21186, probably as a key transcriptional regulatory region, regulated VIL2 transcription in company with other potential regulatory regions.

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“…Ezrin protein overexpression also correlates positively with hepatoma cell proliferation, invasion, and migration. Conversely, downregulation of Ezrin protein expression inhibits the invasion ability of cells with high metastatic potential [18,19]. Moreover, when the breast cancer cell line AC2M2 was transplanted from wild-type mice overexpressing Ezrin to the breast adipose tissue of the same genotype, pulmonary metastases were observed [20].…”

Section: Discussionmentioning

confidence: 95%

Expression and significance of Six1 and Ezrin in cervical cancer tissue

2011

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This study aimed to investigate the expression of Six1 gene and its downstream target gene Ezrin in cervical cancer, and to correlate their expression to the clinical pathology of cervical cancer. RT-PCR and Western blot were used to detect the expression of Six1 and Ezrin in cervical cancer tissue, cervical intraepithelial neoplasia tissue, and normal cervical tissue. The correlation of Six1 and Ezrin expression with the occurrence, development, and clinical pathology of cervical cancer was then analyzed. The expression of Six1 and Ezrin mRNA and protein in cervical cancer and cervical intraepithelial neoplasia was significantly higher than in normal cervical tissue (p < 0.05). Their expression was also significantly higher in the cancerous tissues of patients with advanced cervical cancer than in those of patients with early-stage cervical cancer (p < 0.05). Moreover, they were expressed at significantly higher levels in lymph node metastasis-positive patients than in lymph node metastasis-negative patients (p < 0.05). Finally, we observed that lesser differentiated tumors had elevated expression of Six1 and Ezrin mRNA and protein (p < 0.05). However, the mRNA and protein expression of Six1 and Ezrin were independent of patient age and tumor size (p > 0.05). Further investigation is warranted to describe the relation of whether Six1 and Ezrin protein contributes to the mechanism of occurrence, development, differentiation, and invasiveness of the tumor. These markers could be used as indicators of prognosis in early-stage cervical cancer as Six1 and Ezrin had a synergistic effect on the incidence of cervical cancer.

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Prognostic implications of ezrin expression in human hepatocellular carcinoma

Cited by 38 publications

References 26 publications

Translational implication of Kallmann syndrome-1 gene expression in hepatocellular carcinoma

Translational implication of Kallmann syndrome-1 gene expression in hepatocellular carcinoma

Potential transcriptional regulatory regions exist upstream of the human ezrin gene promoter in esophageal carcinoma cells

Expression and significance of Six1 and Ezrin in cervical cancer tissue

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