TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells

Liu, Xing; Liao, Weijia; Yuan, Qing; Ou, Ying; Huang, Jian

doi:10.18632/oncotarget.5295

Cited by 84 publications

(91 citation statements)

References 29 publications

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“…1,2 The pathogenesis of HCC is very complicated with lots of genes and proteins to participate in. [3][4][5] The advanced clinical stage system is the only accepted method for predicting the prognosis of clinical HCC patients with progressive disease, with surgery being the only major therapeutic option. Diagnosis of HCC is usually dependant on image techniques, blood indicators, and histopathology.…”

Section: Introductionmentioning

confidence: 99%

“…nanoparticle/ miR-con, nanoparticle/miR-221 mimic [miR-221 mimic], nanoparticle/miR-scramble [scramble], nanoparticle/miR-221 inhibitor [miR-221 inhibitor], n=6 per group), when the tumor volume increased to 100 mm3 . Prior to administration of each complexe, animals were anesthetized and injected with nanoparticle/miRNA complexes (1 nmol of miRNA per injection) through the tail vein twice per 5 days for 25 days.…”

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confidence: 99%

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miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker

Li¹,

Wang²,

Zhu³

et al. 2018

IJN

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BackgroundMicroRNA-221(miR-221) is frequently dysregulated in cancer. The purpose of this study was to explore whether miR-221 can be used as a potential diagnostic marker or therapeutic target for hepatocellular carcinoma (HCC).MethodsIn this study, we investigated whether miR-221 expression was associated with clini-copathological characteristics and prognosis in HCC patients, and we developed a nanoparticle-based miRNA delivery system and detected its therapeutic efficacy in vitro and in vivo.ResultsWe found that miR-221 was upregulated in HCC tissues, cell lines and blood of HCC patients. Upregulated miR-221 was associated with clinical TNM stage and tumor capsular infiltration, and showed poor prognosis, suggesting that its suppression could serve as an effective approach for hepatocellular carcinoma therapy. Treatment of HCC cells with nanoparticle/miR-221 inhibitor complexes suppressed their growth, colony formation ability, migration and invasion. In vivo, the growth of the tumors treated by the nanoparticle/miR-221 inhibitor complexes were significantly less than those treated by the nanoparticle/miRNA scramble complexes. In addition, circulating miR-221 may act as a potential tumor biomarker for early diagnosis of HCC, and combined serum miR-221 and AFP detection gave a better performance than individual detection in early diagnosis of HCC.ConclusionThese findings suggest that a nanoparticle-based miRNA delivery system could potentially serve as a safe and effective treatment and miR-221 could also be a potential diagnostic marker for HCC.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker

Li¹,

Wang²,

Zhu³

et al. 2018

IJN

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“…Using both NGS and bioinformatics approaches to characterize the gene profile of lung cancer, we identified TTK had the oncogenic potential in lung cancer, compared to non-cancerous cells. TTK is regulated in multiple types of cancers, including breast, liver, lung and pancreatic cancer [6,18,19]. Despite its basic biological function and clinical significance, the underlying mechanisms of TTK-mediated cancer progression remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

Tsai

Chang

et al. 2020

IJMS

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Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (Thr/Tyr kinase), a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer.

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“…A lack of Mps1 perturbs centrosome duplication (Fisk et al, 2003) (Continued) BJP M Choi et al Santaguida et al, 2010;Dou et al, 2015), a failure to correct erroneous microtubule attachment (Jelluma et al, 2008), cytokinesis failure (Fisk et al, 2003) and apoptosis (Jemaa et al, 2016), shortens mitosis (Dou et al, 2015;Jemaa et al, 2016), and prevents the recruitment of SAC-related proteins, including Mad1, Mad2, Bub1, BubR1 and RodZw10-Zwilch (Martin-Lluesma et al, 2002;Santaguida et al, 2010;Jemaa et al, 2016). In addition, depletion of (Hewitt et al, 2010) Chromosome misalignment (Dou et al, 2015) Failure in recruitment of Mad1, Mad2, Bub1 and CENP-E (Hewitt et al, 2010) Short mitotic duration (Hewitt et al, 2010;Gurden et al, 2015) Apoptosis (Jemaa et al, 2016) BAY 1161909 0.34 nM (Wengner et al, 2016) Breast, lung and ovarian cancer (Wengner et al, 2016) Phase I ClinicalTrials.gov ID: NCT02138812 BAY 1217389 0.63 nM (Wengner et al, 2016) Phase I ClinicalTrials.gov ID: NCT02366949 CFI-402257 1.7 nM (Liu et al, 2016) MPI-0479605 1.8 nM (Tardif et al, 2011) Chromosome missegregation Colon cancer (Tardif et al, 2011) Hyperploidy Apoptosis Up-regulation of p53, p21 and γ-H2AX (Tardif et al, 2011) continues Effect of Mps1 inhibitor on hepatocellular carcinoma cells BJP Mps1 inhibits proliferation of HCC cells (Liang et al, 2014;Liu et al, 2015;Miao et al, 2016). Overall, because the dysregulation of Mps1 leads to an accumulation of chromosomal instabilities and, finally, cell death, it may be a target for cancer therapeutics.…”

Section: Discussionmentioning

confidence: 99%

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Choi

Min

Pyo

et al. 2017

British J Pharmacology

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contributed equally to the work. BACKGROUND AND PURPOSEChromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. EXPERIMENTAL APPROACHThe effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. KEY RESULTSTreatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. CONCLUSION AND IMPLICATIONSTC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer.Abbreviations HCC, hepatocellular carcinoma; MCC, mitotic checkpoint complex; Mps1 (TTK), monopolar spindle 1; SAC, spindle assembly checkpoint

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TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells

Cited by 84 publications

References 29 publications

miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker

miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker

Upregulation of Thr/Tyr kinase Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer

TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

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