Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4

Abstract

Background: ATPase 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. Methods: Bioinformatic 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. Results: TRIP13 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. Conclusion: Our 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.

TRIP13 promotes metastasis of colorectal cancer regardless of p53 and microsatellite instability status

“…In hepatocellular carcinoma (HCC) cells, TRIP13 knockdown increases levels of the epithelial marker, E‐cadherin, and decreases the mesenchymal markers, vimentin, and snail. Thus, in HCC cells, TRIP13 promotes metastasis via inducing the EMT [53]. Further, in bladder cancer cells, TRIP13 knockdown increases E‐cadherin and decreases N‐cadherin and Snail [54].…”

“…The present study showed that TRIP13‐depleted CRC cells had less activity for β‐catenin as well as lower levels of LEF1 and TCF1. In HCCs, it was shown that TRIP13 regulates the WNT/β‐catenin pathway [53]. For CRCs, cyclin D1, a Wnt target gene, is transcriptionally activated by β‐catenin [68].…”

Emerging Role of MiR-192-5p in Human Diseases

“…Mechanistically, the miR-192 promoter is hyper-methylated, which leads to the transcriptional repression of miR-192-5p in HCC cell lines and primary CSC + HCC ( Gu et al, 2019 ). Besides, Zhu and coworkers reported that miR-192-5p is an upstream regulator of thyroid hormone receptor interactor 13 (TRIP13), a promising oncogene in HCC, by directly targeting the 3′-UTR of TRIP13 mRNA, thereby inhibiting the progression of HCC ( Zhu et al, 2019 ). Interestingly, the expression of miR-192-5p is also regulated by other molecules in HCC, including circRNA, although increasing evidence has demonstrated that numerous molecules are influenced by miR-192-5p ( Qiu et al, 2019 ).…”

α-Actinin-4 Promotes the Progression of Prostate Cancer Through the Akt/GSK-3β/β-Catenin Signaling Pathway

“…shACTN4 suppresses the Akt/GSK-3β/β-catenin signaling, and ACTN4 interacts with β-catenin in breast cancer stem cells ( Wang et al, 2017 ). In addition, the ACTN4 and TRIP13 complex promotes EMT and tumor metastasis through the Akt signaling in hepatocellular carcinoma cells ( Zhu et al, 2019 ). We have previously reported that ACTN4 induces the phosphorylation of Akt and GSK-3β in cervical cancer ( An et al, 2016 ).…”