Abstract
BackgroundMethionyl-tRNA synthetase (MRS) plays a critical role in initiating translation by transferring Met to the initiator tRNA (tRNAiMet) and protection against ROS-mediated damage, suggesting that its overexpression is related to cancer growth and drug resistance. In this study, the clinical implication of MRS expression in non-small cell lung cancer (NSCLC) was evaluated.MethodsImmunoblot and immunohistochemical (IHC) analyses were performed using tissue lysates and formalin-fixed paraffin embedded (FFPE) tissue blocks from wild type C57BL/6, LSL-Kras G12D, and LSL-Kras G12D:p53fl/fl mice. For human studies, 12 paired adjacent normal appearing lung tissue lysates and cancer tissue lysates, in addition to 231 FFPE tissue samples, were used.ResultsMRS was weakly expressed in the spleen and intestinal epithelium and only marginally expressed in the kidney, liver, and lungs of wild type C57BL/6 mice. On the other hand, MRS was strongly expressed in the neoplastic region of lung tissue from LSL-Kras G12D and LSL-Kras G12D:p53fl/fl mice. Immunoblot analysis of the human normal appearing adjacent and lung cancer paired tissue lysates revealed cancer-specific MRS overexpression, which was related to mTORC1 activity. IHC analysis of the 231 FFPE lung cancer tissue samples showed that MRS expression was frequently detected in the cytoplasm of lung cancer cells (179 out of 231, 77.4%), with a small proportion (73 out of 231, 31.6%) also showing nuclear expression. The proportion of cases with positive MRS expression was higher in the advanced pStage subgroup (P = 0.018, χ2-test) and cases with MRS expression also had shorter DFS (161.6 vs 142.3, P = 0.014, log-rank test).ConclusionsTaken together, MRS is frequently overexpressed in NSCLC. Moreover, MRS is related to mTORC1 activity and its overexpression is associated with poor clinical outcomes, indicating that it has potential as a putative therapeutic target.
Highlights
Methionyl-transfer RNAs (tRNAs) synthetase (MRS) plays a critical role in initiating translation by transferring Met to the initiator tRNA and protection against ROS-mediated damage, suggesting that its overexpression is related to cancer growth and drug resistance
Methionyl-tRNA synthetase (MRS) expression in various mouse tissues To explore the potential of MRS as a therapeutic target of lung cancer, we first evaluated MRS expression in the non-neoplastic tissues of the major organs of 8-week-old wild type C57BL/6 mice (Fig. 1 and Additional file 1)
MRS was not detected in alveolar type I and type II pneumocytes, nor was it detected in the vascular structures
Summary
Methionyl-tRNA synthetase (MRS) plays a critical role in initiating translation by transferring Met to the initiator tRNA (tRNAiMet) and protection against ROS-mediated damage, suggesting that its overexpression is related to cancer growth and drug resistance. Lung cancer is a major public health problem worldwide. Low-dose computerized tomography (LDCT) scans are currently used as a screening tool Their use is supported by the National Lung Screening Trial (NLST), a randomized collected study involving more than 53,000 current or former heavy smokers [3]. Lung cancer screening with LDCT has serious problems, such as false-positive rates exceeding 95%. This drawback leads to unnecessary repeated testing and increased costs [4]. Because of this and other limitations, new noninvasive methods for the early detection of lung cancer are needed. Multiple peripheral blood or body fluid matrix biomarkers in lung cancer have been proposed, such as
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