SRXN1 stimulates hepatocellular carcinoma tumorigenesis and metastasis through modulating ROS/p65/BTG2 signalling

Abstract

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.

Identification and validation of a five-gene prognostic signature for hepatocellular carcinoma

“…Sulfiredoxin 1 (SRXN1) acts as a key factor regulating the antioxidant response in eukaryotic cells, can resist oxidative stress injury in cells and has antioxidant protective effects on many diseases [ 32 ]. The findings of Lv [ 33 ] demonstrated that SRXN1 modulated ROS/p65/BTG2 signaling, thereby stimulating HCC tumorigenesis and metastasis. Lactate dehydrogenase A (LDHA) serves as an important metabolic enzyme that is a member of the family of 2-hydroxy acid oxidoreductases and remarkably affects the anaerobic metabolism of cells [ 34 ].…”

Hyperoxidation of Peroxiredoxins and Effects on Physiology of Drosophila

“…On the other hand, by reducing ROS and affecting apoptosis, Srx may favor the survival of cancerous cells and thereby contribute to carcinogenesis [ 48 ]. For instance, Srx underexpression can sensitize cancer cells to ER stress-induced cell death [ 49 ], increase apoptosis of tumor cells and thus decrease tumor cell proliferation, while the opposite effects have been observed in Srx overexpressors, which correlated with more aggressive cancers and poor prognosis [ 8 , 48 , 50 , 51 , 52 , 53 ].…”

Identification of ferroptosis-related genes for overall survival prediction in hepatocellular carcinoma

“…However, it was confirmed that overexpressed PRDX1 was closely related with poor prognosis of HCC patients 29 . Sulfiredoxin-1 (SRXN1) was revealed a pro-tumorigenic in HCC by regulating ROS signaling 30 . In addition, SRXN1 is involved in oxidoreductase activity 31 , its overexpression may play a crucial role in the tumorigenesis and progression of HCC 32 .…”