Plasma tRNA-derived small RNAs signature as a predictive and prognostic biomarker in lung adenocarcinoma

Background The prevalence of lung adenocarcinoma (LUAD) has increased, thus novel biomarkers for its early diagnosis is becoming more important than ever. tRNA-derived small RNA (tsRNA) is a new class of non-coding RNA which has important regulatory roles in cancer biology. This study was designed to identify novel predictive and prognostic tsRNA biomarkers. Methods tsRNAs were identified and performed differential expression analysis from 10 plasma samples (6 LUAD and 4 normal, SRP266333) and 96 tissue samples (48 LUAD and 48 normal, SRP133217). Then a tsRNA-mRNA regulatory network was constructed to find hub tsRNAs. Functional enrichment analysis was performed to infer the potential pathways associated with tsRNAs. Afterwards, a Support Vector Machine (SVM) algorithm was used to explore the potential biomarkers for diagnosing LUAD. Lastly, the function of tRF-21-RK9P4P9L0 was explored in A549 and H1299 cell lines. Results A significant difference of read distribution was observed between normal people and LUAD patients whether in plasma or tissue. A tsRNA-mRNA regulatory network consisting of 155 DEtsRNAs (differential expression tsRNAs) and 406 DEmRNAs (differential expression mRNAs) was established. Three tsRNAs (tRF-16-L85J3KE, tRF-21-RK9P4P9L0 and tRF-16-PSQP4PE) were identified as hub genes with degree > 100. We found Co-DEmRNAs (intersection of DEtsRNAs target mRNAs and differentially expressed mRNAs in LUAD) were engaged in a number of cancer pathways. The AUC of the three hub tsRNAs' expression for diagnosing LUAD reached 0.92. Furthermore, the qPCR validation of the three hub tsRNAs in 37 paired normal and LUAD tissues was consistent with the RNA-Seq results. In addition, tRF-21-RK9P4P9L0 was negatively associated with LUAD prognosis. Inhibition of tRF-21-RK9P4P9L0 expression reduced the proliferation, migration and invasion ability of A549 and H1299 cell lines. Conclusion These findings will help us further understand the molecular mechanisms of LUAD and contribute to novel diagnostic biomarkers and therapeutic target discovery.

Automated summary

This study identified and characterized novel tsRNA biomarkers for early diagnosis of lung adenocarcinoma (LUAD) by analyzing differential expression in tissue and plasma samples. A tsRNA-mRNA regulatory network was constructed to reveal the functional pathways associated with tsRNAs. Three hub tsRNAs were identified and their diagnostic potential was validated. Moreover, one hub tsRNA was found to be negatively associated with LUAD prognosis and its inhibition reduced cancer cell proliferation, migration, and invasion.