Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer

Eun Young Kim; Ji Ye Jung; Arum Kim; Kwangsoo Kim; Yoon Soo Chang

doi:10.1186/s12885-017-3452-9

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Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer

Authors: Eun Young Kim ; Ji Ye Jung ; Arum Kim ; Kwangsoo Kim ; Yoon Soo Chang

Citation: BMC CANCER, Vol.17(1) : 467, 2017

Journal Title: BMC CANCER

Issue Date: 2017

MeSH: Adult Aged Animals Biomarkers, Tumor* Carcinoma, Non-Small-Cell Lung/genetics* Carcinoma, Non-Small-Cell Lung/mortality* Carcinoma, Non-Small-Cell Lung/pathology Disease Models, Animal Female Gene Expression* Humans Immunohistochemistry Kaplan-Meier Estimate Lung Neoplasms/genetics* Lung Neoplasms/mortality* Lung Neoplasms/pathology Male Methionine-tRNA Ligase/genetics* Mice Mice, Transgenic Middle Aged Neoplasm Grading Neoplasm Staging Prognosis Proportional Hazards Models

Keywords: Aminoacyl-tRNA synthetase (ARS) ; Lung cancer ; Methionyl-tRNA synthetase (MRS) ; NSCLC

Abstract: BACKGROUND: 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. In this study, the clinical implication of MRS expression in non-small cell lung cancer (NSCLC) was evaluated.

METHODS: Immunoblot 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.

RESULTS: MRS 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).

CONCLUSIONS: Taken 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.