GRP78 activates the Wnt/HOXB9 pathway to promote invasion and metastasis of hepatocellular carcinoma by chaperoning LRP6
GRP78 activates the Wnt/HOXB9 pathway to promote invasion and metastasis of hepatocellular carcinoma by chaperoning LRP6
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GRP78通过陪伴LRP6激活Wnt/HOXB9通路促进肝细胞癌侵袭和转移
DOI：
10.1016/j.yexcr.2019.07.006
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发表时间：
2019-10-01
影响因子：
3.7
通讯作者：
Wang, Kai
中科院分区：
文献类型：
--
作者：
Xiong, Haixia;Xiao, Han;Wang, Kai
近年来的研究表明，葡萄糖调节蛋白78（glucose-regulated protein 78，GRP 78）和同源框B 9（homeobox B 9，HOXB 9）在肝细胞癌（HCC）中的表达水平均上调，且与HCC的侵袭转移密切相关。然而，GRP 78和HOXB 9之间是否存在调节关系尚不清楚。在这项研究中，我们研究了GRP 78和HOXB 9在肝癌组织和癌旁组织中的表达。相关性分析显示GRP 78和HOXB 9的表达呈正相关。GRP 78和HOXB 9的高表达与肿瘤的临床病理特征密切相关。肝癌细胞中GRP 78的敲低降低了HOXB 9的mRNA和蛋白表达，但HOXB 9的表达增加逆转了GRP 78敲低诱导的侵袭和转移的降低。进一步的实验表明，GRP 78通过Wnt信号通路通过陪伴低密度脂蛋白受体相关蛋白6（LRP 6）来调节HOXB 9。重要的是，我们发现GPR 78促进LRP 6的成熟，而GRP 78的敲低导致LRP 6错误折叠和内质网相关降解（ERAD）。因此，成熟LRP 6的水平降低，并且Wnt/HOXB 9信号传导被抑制。我们的数据表明，GRP 78-LRP 6-HOXB 9轴调节肝癌的侵袭和转移，并可能代表一个潜在的治疗肝癌的治疗靶点。
Recent studies have shown that the expression levels of glucose-regulated protein 78 (GRP78) and homeobox B9 (HOXB9) are both upregulated in hepatocellular carcinoma (HCC) and are closely related to HCC invasion and metastasis. However, whether there is a regulatory relationship between GRP78 and HOXB9 is unclear. In this study, we examined the expression of GRP78 and HOXB9 in HCC tissues and adjacent nontumor tissues. Correlation analysis indicated that GRP78 and HOXB9 expression were positively correlated. High levels of GRP78 and HOXB9 expression are closely related to worse clinicopathological features. Knockdown of GRP78 in HCC cells decreased the mRNA and protein expression of HOXB9, but increase HOXB9 expression reversed the decrease in invasion and metastasis induced by knocking down GRP78. Further experiments showed that GRP78 regulates HOXB9 through the Wnt signaling pathway by chaperoning low-density lipoprotein receptor-related protein 6 (LRP6). Importantly, we found that GPR78 promoted maturation of LRP6, while knockdown of GRP78 led to LRP6 misfolding and endoplasmic reticulum-associated degradation (ERAD). Consequently, the levels of mature LRP6 were reduced, and Wnt/HOXB9 signaling was inhibited. Our data suggest that the GRP78-LRP6-HOXB9 axis regulates the invasion and metastasis of HCC and may represent a potential therapeutic target for the treatment of HCC.