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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.

SUBMITTER: Zhu MX

PROVIDER: S-EPMC6749659 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Zhu Meng-Xuan MX Wei Chuan-Yuan CY Zhang Peng-Fei PF Gao Dong-Mei DM Chen Jie J Zhao Yan Y Dong Shuang-Shuang SS Liu Bin-Bin BB

Journal of experimental & clinical cancer research : CR 20190918 1

<h4>Background</h4>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.<h4>Methods</h4>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 differen ...[more]

PMID: 31533816

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Project description:Resistance to radiotherapy (IR), with consequent disease recurrence, continues to limit the efficacy of contemporary anticancer treatment for patients with hepatocellular carcinoma (HCC), especially in late stage. Despite accruing evidence implicating the PI3K/AKT signaling pathway in cancer-promoting hypoxia, cancerous cell proliferation and radiotherapy-resistance, it remains unclear which molecular constituent of the pathway facilitates adaptation of aggressive HCC cells to tumoral stress signals and drives their evasion of repeated IR-toxicity. This present study investigated the role of PDK1 signaling in IR-resistance, enhanced DNA damage repair and post-IR relapse, characteristic of aggressive HCC cells, while exploring potential PDK1-targetability to improve radiosensitivity. The study employed bioinformatics analyses of gene expression profile and functional protein-protein interaction, generation of IR-resistant clones, flow cytometry-based ALDH activity and side-population (SP) characterization, siRNA-mediated loss-of-PDK1function, western-blotting, immunohistochemistry and functional assays including cell viability, migration, invasion, clonogenicity and tumorsphere formation assays. We showed that the aberrantly expressed PDK1 characterizes poorly differentiated HCC CVCL_7955, Mahlavu, SK-HEP1 and Hep3B cells, compared to the well-differentiated Huh7 or normal adult liver epithelial THLE-2 cells, and independently activates the PI3K/AKT/mTOR signaling. Molecular ablation of PDK1 function enhanced susceptibility of HCC cells to IR and was associated with deactivated PI3K/AKT/mTOR signaling. Additionally, PDK1-driven IR-resistance positively correlated with activated PI3K signaling, enhanced HCC cell motility and invasiveness, augmented EMT, upregulated stemness markers ALDH1A1, PROM1, SOX2, KLF4 and POU5F1, increased tumorsphere-formation efficiency and suppressed biomarkers of DNA damage-RAD50, MSH3, MLH3 and ERCC2. Furthermore, the acquired IR-resistant phenotype of Huh7 cells was strongly associated with significantly increased ALDH activity, SP-enrichment, and direct ALDH1-PDK1 interaction. Moreover, BX795-mediated pharmacological inhibition of PDK1 synergistically enhances the radiosensitivity of erstwhile resistant cells, increased Bax/Bcl-2 apoptotic ratio, while suppressing oncogenicity and clonogenicity. We provide preclinical evidence implicating PDK1 as an active driver of IR-resistance by activation of the PI3K/AKT/mTOR signaling, up-modulation of cancer stemness signaling and suppression of DNA damage, thus, projecting PDK1-targeting as a putative enhancer of radiosensitivity and a potential new therapeutic approach for patients with IR-resistant HCC.

Project description:BackgroundThere is growing evidence that tripartite motif-containing protein 44 (TRIM44) plays crucial role in tumor development. However, the underlying mechanism of this deubiquitinating enzyme remains unclear.MethodsLarge clinical samples were used to detect TRIM44 expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of TRIM44 induced tumor progression. Co-immunoprecipitation (Co-IP) assays and mass spectrometric analyses were applied to verify the interacting proteins of TRIM44.ResultsWe found that TRIM44 was commonly amplified in melanoma tissues compared with paratumoral tissues. TRIM44 expression also positively correlated with more aggressive clinicopathological features, such as Breslow depth (p = 0.025), distant metastasis (p = 0.012), and TNM stage (p = 0.002). Importantly, we found that TRIM44 was an independent indicator of prognosis for melanoma patients. Functionally, overexpression of TRIM44 facilitated cell invasion, migration, apoptosis resistance and proliferation in vitro, and promoted lung metastasis and tumorigenic ability in vivo. Importantly, high level of TRIM44 induced melanoma cell epithelial-mesenchymal transition (EMT), which is one of the most important mechanisms for the promotion of tumor metastasis. Mechanistically, high levels of TRIM44 increased the levels of p-AKT (T308) and p-mTOR (S2448), and a specific AKT inhibitor inhibited TRIM44-induced tumor progression. Co-IP assays and mass spectrometric analyses indicated that TRIM44 overexpression induces cell EMT through activating AKT/mTOR pathway via directly binding and stabilizing TOLL-like receptor 4 (TLR4), and TLR4 interference impeded TRIM44 induced tumor progression. Moreover, we demonstrated that TRIM44 is the target of miR-26b-5p, which is significantly downregulated in melanoma tissues and may be responsible for the overexpression of TRIM44.ConclusionsTRIM44, regulated by miR-26b-5p, promotes melanoma progression by stabilizing TLR4, which then activates the AKT/mTOR pathway. TRIM44 shows promise as a prognostic predictor and a therapeutic target for melanoma patients.

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Project description:Purpose To determine if heat stress and hepatic laser thermal ablation induce hepatocellular carcinoma (HCC) growth and to identify growth factors induced by heat stress. Materials and Methods Non-heat-stressed HCC cells were cocultured with HCC cells or hepatocytes that were heat stressed at 37°C (physiologic), 45°C (moderate), or 50°C (severe) for 10 minutes and proliferation monitored with bioluminescence imaging for up to 6 days after heat stress (three experiments). Rats bearing orthotopic N1S1 HCC were randomly assigned to undergo immediate sham or laser thermal (3 W for 60 or 90 seconds; hereafter, 3W×60s and 3W×90s, respectively) ablation of the median (local) or left (distant) hepatic lobe, and tumor growth was monitored with magnetic resonance imaging for up to 18 days after ablation (six or more rats per group). Experiments were repeated with rats randomly assigned to receive either the adjuvant phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor (NVP-BEZ235) or the vehicle control. Heat-stressed HCC cells and hepatocytes were analyzed by using microarray or quantitative real-time polymerase chain reaction analysis for growth factor expression (three or more experiments). Groups were compared by using one- or two-way analysis of variance, and post hoc pairwise comparison was performed with the Dunnett test. Results There were more non-heat-stressed HCC cells when cells were cocultured with cells subjected to moderate but not physiologic or severe heat stress (P < .001 for both). Local intrahepatic N1S1 tumors were larger at day 18 in the 3W×60s (mean, 3102 mm3 ± 463 [standard error]; P = .004) and 3W×90s (mean, 3538 mm3 ± 667; P < .001) groups than in the sham group (mean, 1363 mm3 ± 361) but not in distant intrahepatic tumors (P = .31). Adjuvant BEZ235 resulted in smaller N1S1 tumors in the BEZ235 and laser thermal ablation group than in the vehicle control and laser thermal ablation group (mean, 1731 mm3 ± 1457 vs 3844 mm3 ± 2400, P < .001). Moderate heat stress induced expression of growth factors in HCC cells and hepatocytes, including heparin-binding growth factor, fibroblast growth factor 21, and nerve growth factor (range, 2.9-66.9-fold; P < .05). Conclusion Moderate heat stress and laser thermal ablation induce hepatocellular carcinoma growth, which is prevented with adjuvant PI3K/mTOR/protein kinase B inhibition.

Dataset Information

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

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

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