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

Abstract

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.

TRIM44 promotes human esophageal cancer progression via the AKT/mTOR pathway

“…Accumulating evidence indicates that the activation of the AKT/mTOR pathway plays a key role in controlling fundamental cellular processes, including cell growth, proliferation, apoptosis and metabolism in different cancer types . A previous study showed a statistically significant correlation between TRIM44 and the mTOR signaling pathway in EGC . The TRIM44‐overexpression gene signature of EGC was reversed by AKT/mTOR pathway inhibitors .…”

TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma

“…Accumulating studies have shown that TRIM family proteins may positively or negatively regulate carcinogenesis depending on the types of TRIM or the origin of cancer . Specifically, TRIM44 has been reported in a number of studies showing oncogenic effect in various cancers . Ong et al have reported that TRIM44 overexpression resulted from genomic amplification in 16.1% of all epithelial cancers.…”

“…10,11 Specifically, TRIM44 has been reported in a number of studies showing oncogenic effect in various cancers. [17][18][19][20][21][22][23][24][25][26] Ong et al 20 have reported that TRIM44 overexpression resulted from genomic amplification in 16.1% of all epithelial cancers. From a clinicopathological point of view, we previously showed that TRIM44 overexpression was associated with poor prognosis in testicular germ cell tumors.…”

“…The oncogenic effects of TRIM44 have been reported in a number of studies in various types of cancers . We have previously shown that TRIM44 is involved in carcinogenesis of testicular germ cell tumor and breast cancer .…”

“…[14][15][16] The oncogenic effects of TRIM44 have been reported in a number of studies in various types of cancers. [17][18][19][20][21][22][23][24][25][26] We have previously shown that TRIM44 is involved in carcinogenesis of testicular germ cell tumor and breast cancer. 21,22 Other reports have suggested its involvement with various pathways, including mTOR, 23,24 NFκB 25 and MAPK.…”