Multi-Omics Database Analysis of Aminoacyl-tRNA Synthetases in Cancer

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the mRNA translation machinery, yet they possess numerous non-canonical functions developed during the evolution of complex organisms. The aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are continually being implicated in tumorigenesis, but these connections are often limited in scope, focusing on specific aaRSs in distinct cancer subtypes. Here, we analyze publicly available genomic and transcriptomic data on human cytoplasmic and mitochondrial aaRSs across many cancer types. As high-throughput technologies have improved exponentially, large-scale projects have systematically quantified genetic alteration and expression from thousands of cancer patient samples. One such project is the Cancer Genome Atlas (TCGA), which processed over 20,000 primary cancer and matched normal samples from 33 cancer types. The wealth of knowledge provided from this undertaking has streamlined the identification of cancer drivers and suppressors. We examined aaRS expression data produced by the TCGA project and combined this with patient survival data to recognize trends in aaRSs’ impact on cancer both molecularly and prognostically. We further compared these trends to an established tumor suppressor and a proto-oncogene. We observed apparent upregulation of many tRNA synthetase genes with aggressive cancer types, yet, at the individual gene level, some aaRSs resemble a tumor suppressor while others show similarities to an oncogene. This study provides an unbiased, overarching perspective on the relationship of aaRSs with cancers and identifies certain aaRS family members as promising therapeutic targets or potential leads for developing biological therapy for cancer.

The Aminoacyl-tRNA Synthetase and tRNA Expression Levels Are Deregulated in Cancer and Correlate Independently with Patient Survival

“…Regardless of the alteration frequencies at the DNA level, the mRNA expression of most ARSs was upregulated in the examined cancers ( Figure 2 A). This is in general agreement with a recent study that also found that most ARSs were upregulated independently of the DNA alteration frequencies [ 37 ]. More specifically, in eight of the ten cancers, the median ARS mRNA expression was significantly upregulated ( Figure 2 A).…”

“…Statistical significance ( p < 0.05, q < 0.05) was not reached for some cancers, such as LUAD, LUSC, PRAD, STAD and THCA, although, apart from PRAD, they presented at least one ARS with which its overexpression correlated with decreased patient survival ( p < 0.05, but q > 0.05) ( Figure 3 A). Similar conclusions were reached by a recent study that followed different research methodologies and included the mitochondrial ARSs as well as the AIMPs [ 37 ]. Taken together, the above data indicate that it is not the overall overexpression of ARSs that is related to patients’ survival, but rather the overexpression of specific ARSs in specific tumours.…”

High expression of DARS2 indicates poor prognosis in lung adenocarcinoma

“…19 A number of studies have confirmed that AARS are involved in RNA splicing, transcription and translation regulation, cell apoptosis, and tumorigenesis in higher eukaryotes. [20][21][22] The DARS2 gene encodes mitochondrial aspartyl-tRNA synthetase, which is essential to the progression of HCC. 16 However, the role of DARS2 in LUAD has remained largely unknown.…”

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

“…Recently, more and more evidences have shown that a variety of ARSs are responsible for non-canonical functions other than enzymatic catalytic activity, such as translation regulation, transcription regulation, synthesis, signal transduction, angiogenesis, inflammation, apoptosis, and the development of cancer [25][26][27][28][29]. The nonclassical function of LARS was first reported in 2012.…”