<scp>FAM</scp>134B induces tumorigenesis and epithelial‐to‐mesenchymal transition via Akt signaling in hepatocellular carcinoma

<jats:p><jats:italic>Fam134b</jats:italic> (JK‐1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B during tumorigenesis of hepatocellular carcinoma (<jats:styled-content style="fixed-case">HCC</jats:styled-content>) and in epithelial‐to‐mesenchymal transition (<jats:styled-content style="fixed-case">EMT</jats:styled-content>) were previously unclear. In this study, we investigated the function of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B in <jats:styled-content style="fixed-case">HCC</jats:styled-content> and the related tumorigenesis mechanisms, as well as how <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B induces <jats:styled-content style="fixed-case">EMT</jats:styled-content>. We detected the expression of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B in a normal hepatic cell line, <jats:styled-content style="fixed-case">HCC</jats:styled-content> cell lines, fresh specimens, and a <jats:styled-content style="fixed-case">HCC</jats:styled-content> tissue microarray. A retrospective study of 122 paired <jats:styled-content style="fixed-case">HCC</jats:styled-content> tissue microarrays was used to analyze the correlation between <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B and clinical features. Gain‐ and loss‐of‐function experiments, rescue experiments, Akt pathway activator/inhibitors, nude mice xenograft models, and nude mice lung metastasis models were used to determine the underlying mechanisms of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B in inducing tumorigenesis and <jats:styled-content style="fixed-case">EMT </jats:styled-content><jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. The expression level of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B was highly elevated in <jats:styled-content style="fixed-case">HCC</jats:styled-content>, as compared with that in normal liver tissues and normal hepatic cells. Overexpression of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B was significantly associated with tumor size (<jats:italic>P</jats:italic> = 0.025), pathological vascular invasion (<jats:italic>P</jats:italic> = 0.026), differentiation grade (<jats:italic>P</jats:italic> = 0.023), cancer recurrence (<jats:italic>P</jats:italic> = 0.044), and portal vein tumor thrombus (<jats:italic>P</jats:italic> = 0.036) in <jats:styled-content style="fixed-case">HCC</jats:styled-content>. Patients with high expression of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B had shorter overall survival and disease‐free survival than patients with non‐high expression of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B. Furthermore, knockdown of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B with sh<jats:styled-content style="fixed-case">RNA</jats:styled-content>s inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of <jats:styled-content style="fixed-case">FAM</jats:styled-content>134B. Our study demonstrated that <jats:italic>Fam134b</jats:italic> is an oncogene that plays a crucial role in <jats:styled-content style="fixed-case">HCC</jats:styled-content> via the Akt signaling pathway with subsequent glycogen synthase kinase‐3β phosphorylation, accumulation of β‐catenin, and stabilization of Snail, which promotes tumorigenesis, <jats:styled-content style="fixed-case">EMT</jats:styled-content>, and tumor metastasis in <jats:styled-content style="fixed-case">HCC</jats:styled-content>.</jats:p>