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The functional roles of ANG, RNASE1, and AGO2 in the biogenesis and stablization regualtion of cellular and extracellular tDRs

ABSTRACT: The cellular response to stress is an important determinant of disease pathogenesis. Uncovering the molecular fingerprints of distinct stress responses may identify novel biomarkers and key signaling pathways for different diseases. Emerging evidence shows that tRNA-derived small RNAs (tDRs) play pivotal roles in stress responses. However, the RNA modifications on tDRs have been obstacles for accurately identifying tDRs with conventional RNA sequencing. Here, we use AlkB-facilitated methylation sequencing (ARM-seq) to uncover a comprehensive landscape of cellular and extracellular tDR expression in various cells during different stress responses. We find that extracellular tDRs have a distinct fragmentation signature from intracellular tDRs and these tDR signatures are better discriminators of different stress responses than miRNAs. The distinct extracellular tDR fragmentation pattern and signatures are also noted in plasma from patients on cardiopulmonary bypass. Most importantly, we demonstrate that ANG and RNASE1 critically contribute to the stress-modulated cellular and extracellular tDR signatures and we identify a sub population of extracellular tDRs that are either transported or stabilized by AGO2. Together, our findings further the knowledge about tDR biogenesis in both cells and extracellular environments in response to different stressors and position extracellular tDRs as reliable candidates for novel biomarkers in human diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196072 | GEO | 2022/06/27

REPOSITORIES: GEO

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Project description:Background: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs (tDRs), a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tDRs and trastuzumab resistance is still unknown. Methods: We detected the levels of tDRs expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed tDRs in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tDRs. Progression-free survival (PFS) was analyzed using Cox-regression. Furthermore, Gene Ontology (GO) and pathway analyses indicated the potential mechanism underlying tDR-mediated trastuzumab resistance. Results: Our sequence results showed that tDRs were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tDR-1960 and tDR-1969 expression were associated with signiﬁcantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Additionally, the GO analysis indicated that tDR-1960 and tDR-1969 were mainly involved in the cellular response to drug, which may partially explain the molecular mechanism underlying trastuzumab resistance in HER-2 positive breast cancer. Conclusion: we comprehensively analyzed tDRs in trastuzumab-sensitive and -resistant breast cancer. Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance. Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs. tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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The functional roles of ANG, RNASE1, and AGO2 in the biogenesis and stablization regualtion of cellular and extracellular tDRs

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