Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J Gastroenterol Hepatol. 2020 Dec;35(12):2229-2240. doi: 10.1111/jgh.15115. Epub 2020 Jun 23.
Hepatocellular carcinoma (HCC) is a malignant disease worldwide. It is implicated in high cancer-related mortality rates in humans. β-Arrestin1 (ARRB1) has been demonstrated to be related to the development of several cancers, while the relationship between ARRB1 and metastasis in HCC is unknown.
A tissue microarray of 68 tissues from HCC patients with or without metastasis was collected. Wild-type and ARRB1 knockout mice were used to examine the role of ARRB1 in metastasis in vivo. The level of ARRB1 in HCC tissues, mouse liver tissues, and cell lines was determined by quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry. Migration, invasion, and motility capacities of HCC cells were determined by transwell assay and wound healing assay. Vein injection of nude mice model was used to reveal the metastatic abilities of HCC cell lines. For the mechanism study, we investigated the effects of ARRB1 on the phosphorylation of ERK1/2 and the expression of epithelial-mesenchymal transition (EMT) markers in HCC.
We reveal that ARRB1 accelerates metastasis in HCC and that ARRB1 deficiency inhibits hepatocarcinogenesis and reverses EMT in mice. ARRB1 regulates HCC cell migration and invasion and suppresses HCC metastasis in vivo. Furthermore, we show that ARRB1 promotes EMT through the phosphorylation of ERK1/2.
Our data suggest that ARRB1 promotes HCC invasion and metastasis through p-ERK1/2-mediated EMT and that suppression of ARRB1 or p-ERK1/2 may offer potential therapeutic targets for HCC therapy.
肝细胞癌（HCC）是一种全球性的恶性疾病。它与人类癌症相关的高死亡率有关。β-arrestin1（ARRB1）已被证明与几种癌症的发展有关，而 ARRB1 与 HCC 转移之间的关系尚不清楚。
收集了 68 例伴有或不伴有转移的 HCC 患者的组织微阵列。使用野生型和 ARRB1 敲除小鼠在体内研究 ARRB1 在转移中的作用。通过定量逆转录聚合酶链反应、Western blot 和免疫组织化学检测 HCC 组织、小鼠肝组织和细胞系中 ARRB1 的水平。通过 Transwell 测定和划痕愈合测定检测 HCC 细胞的迁移、侵袭和运动能力。使用裸鼠静脉注射模型揭示 HCC 细胞系的转移能力。为了进行机制研究，我们研究了 ARRB1 对 HCC 中 ERK1/2 磷酸化和上皮-间充质转化（EMT）标志物表达的影响。
我们揭示 ARRB1 加速 HCC 的转移，ARRB1 缺失抑制肝癌发生并在小鼠中逆转 EMT。ARRB1 调节 HCC 细胞的迁移和侵袭，并抑制体内 HCC 的转移。此外，我们表明 ARRB1 通过磷酸化 ERK1/2 促进 EMT。
我们的数据表明，ARRB1 通过 p-ERK1/2 介导的 EMT 促进 HCC 的侵袭和转移，抑制 ARRB1 或 p-ERK1/2 可能为 HCC 治疗提供潜在的治疗靶点。
