Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
J Cell Mol Med. 2020 Sep;24(18):10714-10729. doi: 10.1111/jcmm.15693. Epub 2020 Aug 3.
Sulfiredoxin 1 (SRXN1) is a pivotal regulator of the antioxidant response in eukaryotic cells. However, the role of SRXN1 in hepatocellular carcinoma (HCC) is far from clear. The present study aims to elucidate whether SRXN1 participates in tumorigenesis and metastasis of HCC and to determine the molecular mechanisms. We found that SRXN1 expression was up-regulated in HCC tissue samples and correlated with poor prognosis in HCC patients. We also observed that SRXN1 knockdown by transient siRNA transfection inhibited HCC cell proliferation, migration and invasion. Overexpression of SRXN1 increased HCC cell migration and invasion. B-cell translocation gene 2 (BTG2) was identified as a downstream target of SRXN1. Mechanistic studies revealed that SRXN1-depleted reactive oxygen species (ROS) modulated migration and invasion of HCC cells. In addition, the ROS/p65/BTG2 signalling hub was found to regulate the epithelial-mesenchymal transition (EMT), which mediates the pro-metastasis role of SRXN1 in HCC cells. In vivo experiments showed SRXN1 promotes HCC tumour growth and metastasis in mouse subcutaneous xenograft and metastasis models. Collectively, our results revealed a novel pro-tumorigenic and pro-metastatic function of SRXN1 in HCC. These findings demonstrate a rationale to exploit SRXN1 as a therapeutic target effectively preventing metastasis of HCC.
硫氧还蛋白 1（SRXN1）是真核细胞抗氧化反应的关键调节因子。然而，SRXN1 在肝细胞癌（HCC）中的作用还远不清楚。本研究旨在阐明 SRXN1 是否参与 HCC 的发生和转移，并确定其分子机制。我们发现 SRXN1 在 HCC 组织样本中表达上调，并与 HCC 患者的不良预后相关。我们还观察到，通过瞬时 siRNA 转染敲低 SRXN1 抑制 HCC 细胞增殖、迁移和侵袭。过表达 SRXN1 增加了 HCC 细胞的迁移和侵袭。B 细胞易位基因 2（BTG2）被鉴定为 SRXN1 的下游靶标。机制研究表明，SRXN1 耗竭的活性氧（ROS）调节 HCC 细胞的迁移和侵袭。此外，还发现 ROS/p65/BTG2 信号枢纽调节上皮-间充质转化（EMT），介导了 SRXN1 在 HCC 细胞中促进转移的作用。体内实验表明，SRXN1 在小鼠皮下异种移植和转移模型中促进 HCC 肿瘤的生长和转移。总之，我们的研究结果揭示了 SRXN1 在 HCC 中具有促进肿瘤发生和转移的新功能。这些发现为利用 SRXN1 作为一种有效的治疗靶点来预防 HCC 的转移提供了依据。
