Ratio of Autoantibodies of Tumor Suppressor AIMP2 and Its Oncogenic Variant Is Associated with Clinical Outcome in Lung Cancer

Abstract

Aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) works as potent tumor suppressor, while its splicing variant lacking exon 2 (AIMP2-DX2) competes with AIMP2 for binding to target proteins and compromises its anti-tumor activity. Assuming that AIMP2 and its variant AIMP2-DX2 could be released out to human sera in pathological condition, we investigated the diagnostic and prognostic usefulness of autoantibodies against AIMP2 and AIMP2-DX2 by measuring their serum levels in 80 normal and lung cancer samples that were matched in age, gender and smoking status. The area under the curve of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 autoantibody ratio was low (0.416, 0.579, and 0.357, respectively), suggesting limited diagnostic value. A total of 165 lung cancer patients were classified into low and high AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 based on the median expression of each parameter. The high AIMP2-DX2 group was older and had larger tumors (>3 cm) than the low AIMP2-DX2 group. The high AIMP2-DX2/AIMP2 group had higher CYFRA-21 levels and significantly shorter overall survival than the low AIMP2-DX2/AIMP2 group (18.6 vs. 48.9 months, P = 0.021, Log Rank Test). Taken together, autoantibodies against AIMP2-DX2 and AIMP2 are detectable in the human blood and the increased ratio of AIMP2-DX2/AIMP2 is related to poor clinical outcome of lung cancer.

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

“…For example, AIMP2-DX2 overexpression is associated with increased proliferation, migration, and invasion of nasopharyngeal carcinoma cells [127] . Autoantibodies against AIMP2-DX2 in sera of lung cancer patients is associated with poor outcomes [128] . In contrast, down-regulation of AIMP2-DX2 inhibits chemo-resistant ovarian and lung cancer cell growth [ 129 , 130 ].…”

Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer

“…Interestingly, transgenic mice expressing AIMP2-DX2 showed increased sensitivity to lung tumorigenesis compared to the wild type counterpart. Jung et al discovered that lung cancer patients with high AIMP2-DX2/AIMP2 autoantibody ratio had significantly shorter overall survival than those with low ratio, suggesting that AIMP2-DX2 levels were related to the clinical outcome of lung cancer 91 . Moreover, AIMP2-DX2 was highly expressed in chemoresistant ovarian cancer 92 .…”

Roles of Aminoacyl-tRNA Synthetases in Cancer

“…Certain ARSs, such as isoleucyl-tRNA synthetase 2 (IARS2), lysyl-tRNA synthetase (KRS) and asparaginyl-tRNA synthetase (NRS), have been shown to promote cancer development ( Kim et al, 2012 ; Fang et al, 2018 ; Yeom et al, 2020 ), while AIMPs and seryl-tRNA synthetase (SerRS) usually exert anti-tumor effects ( Li Y. et al, 2019 ; Zhou Z. et al, 2020 ). Furthermore, some ARSs are abnormally expressed in various cancer tissues and have diagnostic and prognostic value ( Jung et al, 2017 ; Lee and Kim, 2019 ). For instance, methionyl-tRNA synthetase (MRS) was highly expressed in non-small cell lung cancer (NSCLC) cells that had metastasized to lymph nodes but was weakly expressed in cells adjacent to the lesion ( Lee and Kim, 2019 ).…”