Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Wei, Tong‐You Wade; Wu, Pei; Wu, Tingqing; Hou, Hsin‐An; Chou, Wen‐Chien; Teng, Chieh‐Lin Jerry; Lin, Chih-Ru; Chen, Jo‐Mei Maureen; Lin, Tzu‐En; Su, Hsiang-Chun; Huang, Chia-Chi Flora; Yu, Chang‐Tze Ricky; Hsu, Shih-Lan; Tien, Hwei‐Fang; Tsai, Ming‐Daw

doi:10.1158/0008-5472.can-16-1004

Cited by 47 publications

(50 citation statements)

References 53 publications

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“…In line with this concept, the role of NF-κB and its downstream molecules in the modulation of lung cancer cell cycle and survival was explored in this study. In agreement with previous reports [15,27], we established that the silencing of TIFA promoted apoptosis and inhibited the cell migration of the lung cancer cell lines. Moreover, it attenuated the phosphorylation of IKK, IκB, and p65, and decreased the levels of Bcl-2, cyclin D1, and CDK4, but increased those of p21, p53, and cleaved caspase-3.…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 93%

“…Cellular Physiology and Biochemistry reported that TIFA was expressed in acute myeloid leukemia (AML), and suppression of TIFA in AML cell lines by siRNA successfully decreased the leukemic cell growth and chemotherapy resistance [15]. By contrast, Shen et al reported that the expression of TIFA in hepatocellular carcinoma (HCC) cells was lower than that in normal liver control cells; furthermore, the reconstitution of TIFA expression promoted the apoptosis of the HCC cells [14].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

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TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma

Men

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: TNF-α receptor-associated factor (TRAF)-interacting protein with a forkhead-associated (FHA) domain (TIFA) may mediate the impact of TRAF on the development of lung cancer. The current study was conducted to investigate the expression of TIFA in lung adenocarcinoma and its potential role in the regulation of cancer cell proliferation and migration, and its influence on patient survival. Methods: Specimens of lung adenocarcinoma tissues and their adjacent normal lung tissues were obtained from 116 patients who underwent surgical resection of lung cancer. The expression of TIFA in the lung tissues was examined by immunohistochemistry, immunoblotting, and real-time RT-PCR in four different lung cancer cell lines and one normal bronchial epithelial cell line (BEAS-2B). TIFA was silenced by RNAi technique, and cell proliferation was then assessed by the CCK8 method. Furthermore, cell migration was determined by wound-healing trans-well and wound-healing migration assays. Additionally, cell-cycle arrest and apoptosis were assessed by flow cytometry analysis. Results: TIFA was positively detected in 63 (54.3%) out of 116 lung adenocarcinoma specimens, which was significantly higher than the respective rate established in normal tissues adjacent to the tumor (30.1%, p < 0.05). The overall survival rate was significantly lower in the patients with positive TIFA expression than that in the patients with negative TIFA expression (p < 0.05). TIFA was also highly expressed in the lung cancer cell lines (H1299, H1975, and HCC827) tested. It is noteworthy that siRNA suppressed the expression of TIFA, which contributed to the attenuation of cell proliferation and migration, but promoted cell-cycle arrest and apoptosis. Furthermore, the silencing of TIFA caused upregulation of p53, p21, and cleaved-caspase-3, but downregulation of Bcl-2, cyclin D1, and CDK4, as well as phosphorylation of IKKß, IκB, and p65. Conclusions: TIFA may serve as a biomarker in the prediction of lung adenocarcinoma. Furthermore, TIFA may modulate lung cancer cell survival and proliferation through regulating the synthesis of apoptosis-associated proteins.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 93%

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma

Men

Zhao

et al. 2018

Cell Physiol Biochem

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“…Because unresolved innate immunity in the endothelium plays a pathophysiological role in vascular impairments, targeting TIFA may provide a new therapeutic strategy for vascular diseases. In light of this, Aurora A kinase has recently been shown to phosphorylate Thr9 of TIFA as well, and targeting TIFA can enhance therapeutic efficacies in the treatment of acute myeloid leukemia (44).…”

Section: Discussionmentioning

confidence: 99%

TIFA as a crucial mediator for NLRP3 inflammasome

Lin

Wei

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Toll-like receptor-mediated NF-κB activation is a major innate immune reaction of vascular endothelial cells (ECs) in response to prooxidative and proinflammatory stimuli. We identified that TNF-α receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA) is a regulator of priming (signal 1) and activating (signal 2) signals of nucleotide oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and hyperlipidemia induce and activate TIFA in vitro and in vivo. For the priming of signal 1, sterol regulatory element-binding protein 2 transactivates TIFA, which in turn induces NF-κB activation and augments the transcription of NLRP3 inflammasome components. For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. Our results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting signals 1 and 2.endothelial cells | inflammasome | innate immunity | NLRP3 | TIFA

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“…Prior studies have shown that AURKB overexpression can lead to multinuclear cells and polyploidy [47] and is highly correlated with genomic instability and poor prognosis in neuroblastoma [48]. Other studies have shown that AURKA can promote the expression of anti-apoptotic proteins in tumor cells, and this gene can be used as a biomarker and target for a variety of tumor treatments [49–51].…”

Section: Disscusionmentioning

confidence: 99%

Identification of differentially expressed genes in hepatocellular carcinoma by integrated bioinformatic analysis

Yan

2019

Preprint

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31Hepatocellular carcinoma is one of the most common tumors in the world 32 and has a high mortality rate. This study elucidates the mechanism of hepatocellular 33 carcinoma-(HCC) related development. The HCC gene expression profile 34 (GSE54238, GSE84004) was downloaded from Gene Expression Omnibus for 35 comprehensive analysis. A total of 359 genes were identified, of which 195 were 36 upregulated and 164 were downregulated. Analysis of the condensed results showed 37 that "extracellular allotrope" is a substantially enriched term. "Cell cycle", "metabolic 38 pathway" and "DNA replication" are three significantly enriched Kyoto Encyclopedia 39 of Genes and Genomespathways. Subsequently, a protein-protein interaction network 40 was constructed. The most important module in the protein-protein interaction 41 network was selected for path enrichment analysis. The results showed that CCNA2, 42 PLK1, CDC20, UBE2C and AURKA were identified as central genes, and the 43 expression of these five hub genes in liver cancer was significantly increased in The 44 Cancer Genome Atlas. Univariate regression analysis was also performed to show that 45 the overall survival and disease-free survival of patients in the high expression group 46 were longer than in the expression group. In addition, genes in important modules are 47 mainly involved in "cell cycle", "DNA replication" and "oocyte meiosis" signaling 48 pathways. Finally, through upstream miRNA analysis, mir-300 and mir-381-3p were 49 found to coregulate CCNA2,AURKA and UBE2C. These results provide a set of 50 targets that can help researchers to further elucidate the underlying mechanism of 51 liver cancer. 3 52 53 Key Words HCC;GEO;TCGA;DEGs;bioinformatic analysis; 54 55 1. Introduction 56 Liver cancer is one of the most common cancers in the world, and mainly 57 includes three different pathological types comprising hepatocellular carcinoma 58 (HCC), intrahepatic bile duct (ICC) and HCC-ICC hybrid types, among which HCC 59accounts for 85% to 90% of all HCCs.The incidence and mortality of HCC increase 60 with age, and the incidence of HCC is about three times higher in men than in 61 women[1]. Although HCC treatment has made great progress in recent years, the 62 5-year survival rate of HCC patients is still <25%[2]. Therefore, more research are 63 needed to understand the molecular mechanisms of HCC development and 64 progression, which is important to develop more effective diagnostics and treatments. 65 66 At present, gene microarray technology has been widely used to collect 67 gene chip expression profiling data and to study gene expression profiles in many 68 human cancers. A large amount of data has been published in public database 69 platforms, and researchers have integrated these databases to find valuable 70 information about cancer pathogenesis. Lau et al. identified approximately 4,000 71 genes in 10 pairs of HCC and non-tumor tissues by microarray technology[3].Zhou et 72 al. analyzed the mRNA expression profiles of a large number of human HCC 73 spe...

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Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Cited by 47 publications

References 53 publications

TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma

TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma

TIFA as a crucial mediator for NLRP3 inflammasome

Identification of differentially expressed genes in hepatocellular carcinoma by integrated bioinformatic analysis

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