Abstract
BackgroundATPase associated with a variety of cellular activities (AAA ATPase) family members are closely linked to tumor formation and progression. However, their roles in hepatocellular carcinoma (HCC) largely remain unclear.MethodsBioinformatic analyses of public databases were used to excavate the potential AAA ATPases that may contribute to HCC, and thyroid hormone receptor interactor 13 (TRIP13) was selected to following researches because of its most prominently differential expression. Western blot, qRT-PCR and immunohistochemistry were used to detect the expression of TRIP13 in HCC tissues, and then the relationship between TRIP13 expression and clinicopathological parameters were evaluated. Finally, its functions and potential mechanisms were investigated through a series gain- and loss-of-function strategies both in vitro and in vivo.ResultsTRIP13 was significantly overexpressed in HCC tissues and high level of TRIP13 was closely correlated with a worse clinical outcome. Functionally, elevated TRIP13 facilitated cell proliferation, migration, invasion, and promoted cellular epithelial–mesenchymal transition (EMT) in vitro, while promote tumor growth and lung metastasis in vivo. Mechanistically, TRIP13 interacted with ACTN4 and positively regulated its expression, thus activating the AKT/mTOR pathway to drive tumor progression. Moreover, miR-192-5p served as an upstream regulator of TRIP13 by directly binding to TRIP13 mRNA 3′ UTR, which may partially explain the high expression of TRIP13 in HCC.ConclusionOur findings identified TRIP13 as a promising candidate oncogene in HCC, and TRIP13 induced cell migration, invasion and metastasis of HCC through the AKT/mTOR signaling via interacting with ACTN4.
Highlights
ATPase associated with a variety of cellular activities (AAA ATPase) family members are closely linked to tumor formation and progression
Identification of thyroid hormone receptor interactor 13 (TRIP13) as a potential target in hepatocellular carcinoma (HCC) To screen AAA ATPase family members involved in HCC development, RNA sequencing and clinical data from the TCGA-LIHC dataset, including 369 HCC samples and 50 normal samples, were firstly analyzed
Overall survival analysis was performed based on each differentiallyexpressed AAA ATPase gene and the results showed that TRIP13, the gene with the most significant expression differences, had the highest prognostic significance (Additional file 1: Figure S1)
Summary
ATPase associated with a variety of cellular activities (AAA ATPase) family members are closely linked to tumor formation and progression. Their roles in hepatocellular carcinoma (HCC) largely remain unclear. AAA ATPase p97, which plays a critical role in the regulation of protein homeostasis pathways, has been identified as a therapeutic target in ovarian cancer and multiple myeloma, and its inhibitor can effectively induce cancer cell death in vitro and inhibit tumor growth in vivo [5,6,7]. To date, little research has focused on the roles of AAA ATPase proteins in HCC pathogenesis
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