GATA 结合蛋白 6 的异常表达与胆管癌的不良预后相关，并促进其转移。

Aberrant expression of GATA binding protein 6 correlates with poor prognosis and promotes metastasis in cholangiocarcinoma.

机构信息

Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.

出版信息

Eur J Cancer. 2013 May;49(7):1771-80. doi: 10.1016/j.ejca.2012.12.015. Epub 2013 Jan 11.

DOI:10.1016/j.ejca.2012.12.015

PMID:23313142

Abstract

AIM

GATA6, a zinc-finger transcription factor, functions as a tumour promoter or suppresser according to different tumour origins. We investigated the clinical significance of GATA6 and its role in invasion and metastasis in cholangiocarcinoma (CCA).

METHODS

Expression of GATA6 in 87 cancerous, 24 paracancerous, 32 lymph-node metastatic and 8 liver metastatic samples from 87 CCA patients undergoing surgical resection was detected by immunohistochemistry. Impact of GATA6 on invasion, metastasis and 67kDa laminin receptor expression (67LR) was evaluated in CCA cells by shRNA lentivirus or expressed-plasmid transfection.

RESULTS

Aberrant expression of GATA6 in CCAs was significantly associated with lymph-node metastasis. GATA6 expression was higher in lymph-node and liver metastatic tissues compared with primary cancerous tissues. Kaplan-Meier analysis showed GATA6 expression correlated with poor overall survival and early recurrence in CCAs. Cox analysis suggested GATA6 was an independent prognostic marker for overall survival and recurrence-free survival. CCA cell invasion and migration were decreased by GATA6 knockdown and enhanced by GATA6 overexpression in vitro. Knockdown of GATA6 reduced CCA cell metastasis by xenotransplantation into nude mice. 67LR, which is overexpressed in CCAs and promotes invasion and metastasis through several pathways, positively correlated with GATA6 expression in 87 CCAs. Both mRNA and protein levels of 67LR were regulated by GATA6 in CCA cells. Moreover, ChIP analysis showed GATA6 bound to 67LR gene promoter in CCA cells.

CONCLUSION

Aberrant expression of GATA6 correlates with poor prognosis and promotes invasion and metastasis in CCA.

摘要

目的

锌指转录因子 GATA6 根据不同的肿瘤起源，可作为肿瘤促进剂或抑制剂发挥作用。我们研究了 GATA6 在胆管癌（CCA）中的临床意义及其在侵袭和转移中的作用。

方法

采用免疫组织化学法检测 87 例接受手术切除的 CCA 患者的 87 例癌组织、24 例癌旁组织、32 例淋巴结转移组织和 8 例肝转移组织中 GATA6 的表达。通过 shRNA 慢病毒或表达质粒转染，评估 GATA6 对 CCA 细胞侵袭、转移和 67kDa 层粘连蛋白受体表达（67LR）的影响。

结果

CCA 中 GATA6 的异常表达与淋巴结转移显著相关。与原发性癌组织相比，淋巴结和肝转移组织中 GATA6 的表达更高。Kaplan-Meier 分析显示 GATA6 表达与 CCA 的总生存率和早期复发相关。Cox 分析表明 GATA6 是总生存率和无复发生存率的独立预后标志物。体外 GATA6 敲低可降低 CCA 细胞的侵袭和迁移能力，而过表达 GATA6 则增强其侵袭和迁移能力。GATA6 敲低可通过异种移植减少 CCA 细胞在裸鼠中的转移。67LR 在 CCA 中过度表达，通过多种途径促进侵袭和转移，与 87 例 CCA 中的 GATA6 表达呈正相关。GATA6 在 CCA 细胞中调节 67LR 的 mRNA 和蛋白水平。此外，ChIP 分析显示 GATA6 在 CCA 细胞中与 67LR 基因启动子结合。