YARS as an oncogenic protein that promotes gastric cancer progression through activating PI3K-Akt signaling

Abstract

Purpose Members of the aaRS (aminoacyl-tRNA synthetase) family are proteins controlling the aminoacylation process, in which YARS (tyrosyl-tRNA synthetase) catalyzes the binding of tyrosine to its cognate tRNA and plays an important role in basic biosynthesis. Several studies have demonstrated the association between YARS mutation and certain developmental abnormalities/diseases, yet YARS's linkage with cancer remains uncategorized. In this study, by combining in silico, in vitro, and in vivo studies, we explored the expressions and functions of YARS in gastric cancer (GC). Methods We evaluated YARS's distribution in tumor and paired normal tissues/specimens of GC by referring to large cohort online datasets and patient-derived tissue specimens. YARS-related changes were assessed by phenotypical/molecular experiments and RNA-sequencing analysis in GC cell lines harboring YARS knockdown or overexpression. Results Both the transcript and protein levels of YARS were evidently higher in gastric cancer tissues than in paired normal tissues. YARS knockdown induced repressed proliferation and invasiveness, as well as enhanced apoptosis in GC cell lines, while abnormally upregulating YARS expression promoted gastric cancer growth in vivo. We inferred based on RNAsequencing that YARS modulates multiple cancerous signaling pathways and proved through cellular experiments that YARS promoted GC progression, as well as homologous recombination by activating PI3K-Akt signaling. Conclusions By revealing the existence of a YARS-PI3K-Akt signaling axis in gastric cancer, we discovered that tRNA synthetase YARS is a novel tumorigenic factor, characterized by its upregulation in tumor-derived specimens, as well as its functions in promoting gastric cancer progression.

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

“…The knockdown of YARS results in repressed proliferation and invasion in gastric cancer whilst enhancing apoptosis. The upregulation of YARS yields the reverse effects ( 57 ). RPL6, RPL7, and RPL27a are all components comprising the large ribosomal subunit.…”

Limb‑bud and heart as a novel biomarker for gastric intestinal type adenocarcinoma

“…Consequently, PI3K-AKT inhibitors are widely used in cancer treatment (32). Several previous studies have reported the role of the PI3K-AKT pathway in promoting GC proliferation and invasion (32,33). Therefore, the present study hypothesized that LBH may promote the malignant proliferation of GITA through the PI3K-AKT pathway.…”

“…Through the phosphorylation of the PI3K and AKT proteins, tumor cell proliferation and malignant transformation are promoted whereas tumor cell apoptosis is inhibited (30,31). Consequently, PI3K-AKT inhibitors are widely used in cancer treatment (32). Several previous studies have reported the role of the PI3K-AKT pathway in promoting GC proliferation and invasion (32,33).…”

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…Of these, rs384490 and rs7394702 were found to alter the DNA methylation or transcription factor response elements of CARS by silico analysis, and rs384490 and rs729662 were found to regulate the expression of CARS-related genes by expression quantitative trait loci analysis, indicating that CARS might be involved in the development of gastric cancer ( Tian et al, 2017 ). Moreover, TyrRS knockdown significantly inhibited the proliferation of gastric cancer cell lines AGS, HGC-27 and MGC-803, while TyrRS overexpression promoted the tumor growth in HGC-27 xenograft models ( Zhang et al, 2020 ). Further studies found that TyrRS could facilitate gastric cancer progression and homologous recombination process by regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling ( Zhang et al, 2020 ).…”

“…Moreover, TyrRS knockdown significantly inhibited the proliferation of gastric cancer cell lines AGS, HGC-27 and MGC-803, while TyrRS overexpression promoted the tumor growth in HGC-27 xenograft models ( Zhang et al, 2020 ). Further studies found that TyrRS could facilitate gastric cancer progression and homologous recombination process by regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling ( Zhang et al, 2020 ). Melanoma is a type of aggressive skin cancer with high heterogeneity ( Pierce and Simmons, 2020 ).…”