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Abstract
Fam134b (JK‐1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of FAM134B during tumorigenesis of hepatocellular carcinoma (HCC) and in epithelial‐to‐mesenchymal transition (EMT) were previously unclear. In this study, we investigated the function of FAM134B in HCC and the related tumorigenesis mechanisms, as well as how FAM134B induces EMT. We detected the expression of FAM134B in a normal hepatic cell line, HCC cell lines, fresh specimens, and a HCC tissue microarray. A retrospective study of 122 paired HCC tissue microarrays was used to analyze the correlation between FAM134B 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 FAM134B in inducing tumorigenesis and EMT in vitro and in vivo. The expression level of FAM134B was highly elevated in HCC, as compared with that in normal liver tissues and normal hepatic cells. Overexpression of FAM134B was significantly associated with tumor size (P = 0.025), pathological vascular invasion (P = 0.026), differentiation grade (P = 0.023), cancer recurrence (P = 0.044), and portal vein tumor thrombus (P = 0.036) in HCC. Patients with high expression of FAM134B had shorter overall survival and disease‐free survival than patients with non‐high expression of FAM134B. Furthermore, knockdown of FAM134B with shRNAs inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of FAM134B. Our study demonstrated that Fam134b is an oncogene that plays a crucial role in HCC via the Akt signaling pathway with subsequent glycogen synthase kinase‐3β phosphorylation, accumulation of β‐catenin, and stabilization of Snail, which promotes tumorigenesis, EMT, and tumor metastasis in HCC.
Highlights
According to the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women worldwide (Forner et al, 2018)
Ecadherin expressed abundantly in most epithelial cells, but it is decreased at cell junctions during Epithelial-to-mesenchymal transition (EMT) (Jawhari et al, 1997), which is related to the metastasis of epithelial tumor cells by mediating of intercellular adhesion and acquiring mesenchymal phenotype, facilitating cellular migration and invasion (Seidel et al, 2004)
Overexpression of FAM134B was detected in 56/122 (45.9%) of HCC tumor tissues as compared with the adjacent non-tumor tissues, and there were 45.1% (55/ 122) HCC tumor tissues showed no significant difference in the expression of FAM134B, but there were only 9% (11/122) HCC tumor tissues were low expressed FAM134B. (Fig. 1G)
Summary
According to the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women worldwide (Forner et al, 2018). Discovery of the mechanisms underlying tumor progression is crucial to develop new strategies for the treatment of HCC. Epithelial-to-mesenchymal transition (EMT) plays an important role in embryonic development as well as the motility and metastasis of tumor cells (De and Berx, 2013). EMT interrupts intercellular adhesion and reorganization of the actin cytoskeletal, which enhances the migration and invasion abilities of cancer cells (Chausovsky et al, 2000; Gumbiner, 2005). Ecadherin expressed abundantly in most epithelial cells, but it is decreased at cell junctions during EMT (Jawhari et al, 1997), which is related to the metastasis of epithelial tumor cells by mediating of intercellular adhesion and acquiring mesenchymal phenotype, facilitating cellular migration and invasion (Seidel et al, 2004). Snail induces EMT by inhibiting the transcription of E-cadherin (Batlle et al, 2000; Cano et al, 2000)
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