TNFAIP8 Overexpression: Clinical Relevance to Esophageal Squamous Cell Carcinoma

Hadisaputri, Yuni Elsa; Miyazaki, Tatsuya; Suzuki, Shigemasa; Yokobori, Takehiko; Kobayashi, Tsutomu; Tanaka, Naritaka; Inose, Takanori; Sohda, Makoto; Kuwano, Hiroyuki

doi:10.1245/s10434-011-2097-1

Cited by 60 publications

(54 citation statements)

References 12 publications

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“…It was originally known as SCC-C2, as it was found in a cell line derived from metastatic head and neck squamous cell cancer and was determined to be a negative regulator of apoptosis in overexpression assays. 17,20,25 Its expression levels correlate with the tumor, node, metastasis (TNM) staging of esophageal squamous cell carcinoma, 26 and a similar pattern has been observed in pancreatic cancer, 27 gastric adenocarcinoma 28 and endometrial cancer. 29 It is also a risk factor for non-Hodgkin's lymphoma, and high levels of TNFAIP8 expression are associated with more aggressive forms of epithelial ovarian cancer with poor survival rates 22,30 as well as with non-small cell lung cancer (NSCLC).…”

Section: Introductionmentioning

confidence: 60%

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Goldsmith

Chen

2017

Cell Mol Immunol

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The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signaling that has been elucidated to date.

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Section: Introductionmentioning

confidence: 60%

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Goldsmith

Chen

2017

Cell Mol Immunol

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“…The last exon is common, whereas usage of other exons differs across variants (Supplementary Figure S1). Several reports have shown that TNFAIP8 is overexpressed in human cancers, [3][4][5]8,[19][20][21][22] yet none of these publications have used methods with adequate specificity to discriminate among TNFAIP8 variants. In order to determine the expression patterns of the variants in human tumors compared with normal tissue, we analyzed cataloged RNA-sequencing (RNA-seq) data from primary human tumor and normal tissue for 11 cancer types in The Cancer Genome Atlas (TCGA) (Figure 1a and Supplementary Figure S2A).…”

Section: Resultsmentioning

confidence: 99%

“…The last exon is common, whereas usage of other exons differs across variants (Supplementary Figure S1). Several reports have shown that TNFAIP8 is overexpressed in human cancers, [3][4][5]8,[19][20][21][22] yet none of these publications have used methods with adequate specificity to discriminate among Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; ChIP-seq, chromatin immunoprecipitation sequencing; DOX, doxorubicin; Gadd45A, growth arrest and DNA damageinducible 45a; H3K4me1, histone H3 mono-methylation on lysine 4; H3K4me3, histone H3 tri-methylation on lysine 4; H3K27ac, histone H3 acetylation on lysine 27; p53RE, p53 response element; PCNA, proliferating cell nuclear antigen; Scri, cells expressing scrambled shRNA; shRNA, short hairpin RNA; TCGA, The Cancer Genome Atlas; TNFAIP8, tumor necrosis factor-α-induced protein 8; TP8i, cells expressing TNFAIP8 shRNA …”

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confidence: 99%

“…1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10 Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells.…”

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confidence: 99%

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The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

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“…With regard to the possible role of TNFAIP8 in tumorigenesis and its progression, TNFAIP8 overexpression has frequently occurred in several types of cancer tissues and has exhibited clinical relevance (Kumar et al , 2004; Dong et al , 2010; Hadisaputri et al , 2012; Liu et al , 2012; Miao et al , 2012; Zhang et al , 2012, 2013; Shi et al , 2013). As of this writing, no studies on TNFAIP8 in primary EOC tissues have been conducted.…”

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confidence: 99%

TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer

et al. 2013

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Background:Tumour necrosis factor-α-induced protein 8 (TNFAIP8) has been recently documented in various malignancies, but its role in epithelial ovarian cancer (EOC) remains unknown.Methods:Tumour necrosis factor-α-induced protein 8 expression was determined by real-time reverse transcription PCR and western blot analysis. Tumour tissues, consisting of serous, mucinous, endometrioid and clear cell histotypes, from 202 EOC patients (International Federation of Gynecologists and Obstetricians I–IV) who underwent primary cytoreduction were collected. Then, we examined the immunohistochemical expression of TNFAIP8 and evaluated its clinical significances.Results:Tumour necrosis factor-α-induced protein 8 overexpression was significantly associated with high histologic grade (P=0.005), large residual tumour size (P=0.014), recurrence (P=0.024) and response to chemotherapy (P<0.001). Multivariate analysis showed that TNFAIP8 overexpression was independently correlated with the presence of lymph node (odds ratio (OR): 4.129; 95% confidence interval (CI): 1.491–11.435; P=0.006) and intraperitoneal metastasis (OR: 2.209; 95% CI: 1.174–4.156; P=0.014). Moreover, results revealed that the status of TNFAIP8 expression was an independently prognostic factor for both cancer-specific survival (hazard ratio (HR): 1.852; 95% CI: 1.322–2.594; P<0.001) and disease-free survival (HR: 1.724; 95% CI: 1.235–2.407; P=0.001) in patients with EOC.Conclusion:The present data provide evidence that TNFAIP8 predicts EOC metastasis and poor survival, highlighting its potential function as a therapeutic target for EOCs.

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TNFAIP8 Overexpression: Clinical Relevance to Esophageal Squamous Cell Carcinoma

Abstract: Our results suggest that TNFAIP8 might be an effective therapeutic target for ESCC in the future.

Cited by 60 publications

References 12 publications

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer

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