TRF-Val-CAC-016 Modulates the Transduction of CACNA1d-Mediated MAPK Signaling Pathways to Suppress the Proliferation of Gastric Carcinoma

Background: As a new kind of non-coding RNAs (ncRNAs), tRNA derivatives play an important role in gastric carcinoma (GC). Nevertheless, the underlying mechanism tRNA derivatives were involved in was rarely illustrated. Methods: We screened out the tRNA derivative, tRF-Val-CAC-016, based on the tsRNA sequencing and demonstrated the effect tRF-Val-CAC-016 exerted on GC proliferation in vitro and in vivo. We applied Dual-luciferase reporter assay, RIP assay, and bioinformatic analysis to discover the downstream target of tRF-Val-CAC-016. Then CACNA1d was selected, and the oncogenic characteristics were verified. Subsequently, we detected the possible regulation of the canonical MAPK signaling pathway to further explore the downstream mechanism of tRF-Val-CAC-016. Results: As a result, we found that tRF-Val-CAC-016 was low-expressed in GC, and upregulation of tRF-Val-CAC-016 could significantly suppress the proliferation of GC cell lines. Meanwhile, tRF-Val-CAC-016 regulated the canonical MAPK signaling pathway by targeting CACNA1d. Conclusions: tRF-Val-CAC-016 modulates the transduction of CACNA1d-mediated MAPK signaling pathways to suppress the proliferation of gastric carcinoma. This study discussed the function and mechanism of tRF-Val-CAC-016 in GC for the first time. The pioneering work has contributed to our present understanding of tRNA derivative, which might provide an alternative mean for the targeted therapy of GC.

Roles of tRNA metabolism in aging and lifespan

Transfer RNAs (tRNAs) mainly function as adapter molecules that decode messenger RNAs (mRNAs) during protein translation by delivering amino acids to the ribosome. Traditionally, tRNAs are considered as housekeepers without additional functions. Nevertheless, it has become apparent from biological research that tRNAs are involved in various physiological and pathological processes. Aging is a form of gradual decline in physiological function that ultimately leads to increased vulnerability to multiple chronic diseases and death. Interestingly, tRNA metabolism is closely associated with aging and lifespan. In this review, we summarize the emerging roles of tRNA-associated metabolism, such as tRNA transcription, tRNA molecules, tRNA modifications, tRNA aminoacylation, and tRNA derivatives, in aging and lifespan, aiming to provide new ideas for developing therapeutics and ultimately extending lifespan in humans.

tRNA-Derived Fragment tRF-17-79MP9PP Attenuates Cell Invasion and Migration via THBS1/TGF-β1/Smad3 Axis in Breast Cancer

tRNA derivatives have been identified as a new kind of potential biomarker for cancer. Previous studies have identified that there were 30 differentially expressed tRNAs derivatives in breast cancer tissue with the high-throughput sequencing technique. This study aimed to investigate the possible biological function and mechanism of tRNA derivatives in breast cancer cells. One such tRF, a 5’-tRF fragment of tRF-17-79MP9PP (tRF-17) was screened in this study, which is processed from the mature tRNA-Val-AAC and tRNA-Val-CAC. tRF-17 with significantly low expression in breast cancer tissues and serum. The level of tRF-17 differentiated breast cancer from healthy controls with sensitivity of 70.4% and specificity of 68.4%. Overexpression of tRF-17 suppressed cells malignant activity. THBS1 (Thrombospondin-1) as a downstream target of tRF-17, and reduction of THBS1 expression also partially recovered the effects of tRF-17 inhibition on breast cancer cell viability, invasion and migration. Besides, THBS1, TGF-β1, Smad3, p-Smad3 and epithelial-to-mesenchymal transition related genes N-cadherin, MMP3, MMP9 were markedly down-regulated in tRF-17 overexpressing cells. Moreover, tRF-17 attenuated the THBS1-mediated TGF-β1/Smad3 signaling pathway in breast cancer cells. In general, the tRF-17/THBS1/TGF-β1/smad3 axis elucidates the molecular mechanism of breast cancer cells invasion and migration and could lead to a potential therapeutic target for breast cancer.

Prediction of Functional Outcome in Patients with Acute Stroke by Measuring tRNA Derivatives

<b><i>Background and Purpose:</i></b> Transfer RNA (tRNA) is a noncoding RNA that delivers amino acids to ribosomes for protein synthesis. tRNA is also involved in cell stress response programs. Oxidative stress induces direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation. Using an antibody against tRNA-specific modified nucleoside 1-methyladenosine (m1A), we can detect tRNA derivatives such as conformationally changed tRNA, tRNA-derived fragments, and mononucleotide-free m1A. Based on these findings, tRNA derivatives may have potential as an early tissue damage marker. The purpose of this study was to investigate the plasma tRNA derivatives in stroke patients to clarify whether tRNA derivatives in the acute phase can detect early brain damage and then predict the functional outcome. <b><i>Methods:</i></b> Patients (75 patients with ischemic and 66 with hemorrhagic stroke) and 22 healthy volunteers were prospectively enrolled for this study between November 2016 and February 2019. Plasma samples were collected within 24 h and at 1 day, 7 days, and 30 days from the onset. Plasma tRNA derivative concentrations were measured by ELISA kit using the anti-m1A antibody. <b><i>Results:</i></b> The plasma tRNA derivative level on admission was significantly increased in both ischemic (mean ± standard error, 232.2 ± 33.1 ng/mL) and hemorrhagic stroke patients (212 ± 23.4 ng/mL) compared to the healthy volunteers (86.0 ± 7.9 ng/mL) (<i>p</i> = 0.00042 and <i>p</i> = 0.00018, respectively). The infarction size (<i>r</i> = 0.445, <i>p</i> = 0.00018) and hematoma volumes (<i>r</i> = 0.33, <i>p</i> = 0.0072) were also significantly correlated with tRNA derivatives. The concentrations of tRNA derivatives were associated with poor functional outcome (Modified Rankin Scale score 3–6 at 30 days from the onset) in patients with ischemic stroke at 7 days after onset (<i>p</i> = 0.020). <b><i>Conclusions:</i></b> Stress-induced tRNA derivatives can detect brain tissue damage, predicting functional outcome in patients with ischemic stroke.