Clinical Implications of Upregulated RSAD2 Gene Expression in Hepatocellular Carcinoma

<b>Background:</b><i>JAK/STAT</i> interferon signaling interacts with the <i>PI3K/AKT/mTOR</i> pathway to drive hepatocellular carcinoma (HCC) progression and metastasis. <i>RSAD2</i>, an interferon-inducible gene, is upregulated by the <i>PI3K/AKT/mTOR</i> pathway and serves as a key factor for metabolic reprogramming to promote stem-like properties of cancer stem cells and tumor proliferation. In patients with resected HCC, <i>RSAD2</i> upregulation showed an association with microvascular invasion, which is a proven risk factor for developing HCC metastasis. This clinical observation was compatible with preclinical findings. On the other hand, <i>RSAD2</i> upregulation has been reported to confer poor prognosis in breast and gastric cancers. However, further clinical study of <i>RSAD2</i> in HCC is lacking. As a result, we investigated the clinical implications of <i>RSAD2</i> gene expression in HCC patients, in terms of its associations with survival, the presence of extra-hepatic metastasis, and other clinical manifestations. <b>Methods:</b> We studied 309 treatment-naïve HCC patients, as well as data from the TCGA and GTEx databases. <b>Results:</b><i>RSAD2</i> gene expression was differentially upregulated in HCC tumors when compared to normal liver tissues (<i>p</i> < 0.01). Elevated <i>RSAD2</i> mRNA levels in the blood and the presence of extra-hepatic metastasis were independent prognostic factors for poor overall survival (OS) (<i>p</i> < 0.01). The median OS of patients with high <i>RSAD2</i> expression vs. low expression were 5.4 vs. 14.2 months, respectively (<i>p</i> < 0.01). A high <i>RSAD2</i> mRNA level was significantly correlated with the presence of extra-hepatic metastasis, nutritional disturbance, and functional impairment after controlling for confounding clinical factors (<i>p</i> < 0.05). <b>Conclusions:</b> High <i>RSAD2</i> gene expression is associated with poorer OS, the presence of extra-hepatic metastasis, and quality-of-life disturbances in HCC patients.