Overexpression of <scp><i>TRIM44</i></scp> contributes to malignant outcome in gastric carcinoma

Kashimoto, Kingo; Komatsu, Shuhei; Ichikawa, Daisuke; Arita, Tomohiro; Konishi, Hirotaka; Nagata, Hiroaki; Takeshita, Hitoshi; Nishimura, Yukihide; Hirajima, Shoji; Kawaguchi, Tsutomu; Shiozaki, Atsushi; Fujiwara, Hitoshi; Okamoto, Kazuma; Tsuda, Hitoshi; Otsuji, Eigo

doi:10.1111/j.1349-7006.2012.02407.x

Cited by 73 publications

(84 citation statements)

References 29 publications

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“…This is supported by a recent publication suggesting that gastric cancers with TRIM44 overexpression are more aggressive (13). TRIM44 belongs to a family of 70 proteins involved in diverse pathological conditions, including developmental disorders, neurodegenerative diseases, and viral infections (14).…”

supporting

confidence: 65%

Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy

Ong

Shannon

Ross-Innes

et al. 2014

JNCI: Journal of the National Cancer Institute

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BackgroundMany prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene.MethodsGenomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160).ResultsTRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p-mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models.ConclusionsGenomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors.

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supporting

confidence: 65%

Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy

Ong

Shannon

Ross-Innes

et al. 2014

JNCI: Journal of the National Cancer Institute

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“…We assessed the invasive potential according to the protocol of Corning BioCoat Matrigel Invasion Chamber (Catalogue No. 354480) by calculating the number of cells, which is the ratio of the percentage invasion through the Matrigel-coated filters relative to the migration through the uncoated filters of test cells over that in the control counterparts as described elsewhere (Kashimoto et al , 2012; Nishimura et al , 2013; Komatsu et al , 2015). …”

Section: Methodsmentioning

confidence: 99%

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma

et al. 2016

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Background:PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine–threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC).Methods:We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003.Results:Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71–14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner.Conclusions:These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.

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“…no. 354480; Corning, New York, NY, USA) by calculating the percentage invasion through the Matrigel-coated filters relative to the migration through the uncoated filters of test cells over that in the control counterparts as described elsewhere (20)(21)(22).…”

Section: Loss-of-function By Small Interfering Rna (Sirna) and Cell Gmentioning

confidence: 99%

Overexpression of PBK/TOPK Contributes to Tumor Development and Poor Outcome of Esophageal Squamous Cell Carcinoma

Ohashi

Komatsu

Ichikawa

et al. 2016

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Abstract. Background: PDZ-binding kinase/T-celloriginated protein kinase (PBK/TOPK) is a serine-threonine kinase and overexpressed in various types of cancer. PBK/TOPK is associated with tumor cell development and 58). Knockdown of PBK/TOPK using specific siRNAs inhibited the cell proliferation, invasion/migration of PBK/TOPK-overexpressing ESCC cell lines. Conclusion: These findings suggest that PBK/TOPK plays a crucial role in tumor malignant potential through its overexpression in ESCC.Esophageal cancer is the eighth most common cancer in the world (1) and esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal carcinomas diagnosed in Asian countries. Although surgical techniques and perioperative management have progressed, ESCC remains one of the most aggressive carcinomas of the gastrointestinal tract. Since finding molecular targets for ESCC treatment might help improve the survival of patients with this lethal disease, studies have attempted to identify biological factors involved in the malignant potential of ESCC. However, few genes have been demonstrated to be associated with biological or pathological features of ESCC, suggesting that novel genes associated with the progression of ESCC need to be identified.Because identifying molecular targets for ESCC treatment may contribute to the improvement of survival of patients with this lethal disease, several recent studies have clarified that certain molecules, such as cyclo-oxygenase 2 (COX2), B-cell lymphoma (BCL2), tumor protein P53 (TP53), p16, cyclin D1, FAS, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and E-cadherin (2-6), have important roles in tumorigenesis and the development of ESCC. Moreover, various genetic and epigenetic alterations that contribute to the carcinogenesis of ESCC have been elucidated. In clinical settings, however, only a few molecules have been validated as diagnostic, therapeutic, or prognostic biomarkers for ESCC. These findings prompted us to further search for novel cancerassociated molecules.PDZ binding kinase/T-LAK cell originated protein kinase (PBK/TOPK) encodes a serine/threonine protein kinase and is 6457

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Overexpression of TRIM44 contributes to malignant outcome in gastric carcinoma

Cited by 73 publications

References 29 publications

Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy

Amplification of TRIM44: Pairing a Prognostic Target With Potential Therapeutic Strategy

Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma

Overexpression of PBK/TOPK Contributes to Tumor Development and Poor Outcome of Esophageal Squamous Cell Carcinoma

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