Contribution of miRNAs, tRNAs and tRFs to Aberrant Signaling and Translation Deregulation in Lung Cancer

Abstract

Transcriptomics profiles of miRNAs, tRNAs or tRFs are used as biomarkers, after separate examination of several cancer cell lines, blood samples or biopsies. However, the possible contribution of all three profiles on oncogenic signaling and translation as a net regulatory effect, is under investigation. The present analysis of miRNAs and tRFs from lung cancer biopsies indicated putative targets, which belong to gene networks involved in cell proliferation, transcription and translation regulation. In addition, we observed differential expression of specific tRNAs along with several tRNA-related genes with possible involvement in carcinogenesis. Transfection of lung adenocarcinoma cells with two identified tRFs and subsequent NGS analysis indicated gene targets that mediate signaling and translation regulation. Broader analysis of all major signaling and translation factors in several biopsy specimens revealed a crosstalk between the PI3K/AKT and MAPK pathways and downstream activation of eIF4E and eEF2. Subsequent polysome profile analysis and 48S pre-initiation reconstitution experiments showed increased global translation rates and indicated that aberrant expression patterns of translation initiation factors could contribute to elevated protein synthesis. Overall, our results outline the modulatory effects that possibly correlate the expression of important regulatory non-coding RNAs with aberrant signaling and translation deregulation in lung cancer.

A Novel Prognostic Model Based on Seven Necroptosis-Related miRNAs for Predicting the Overall Survival of Patients with Lung Adenocarcinoma

“…Our results indicated that targeted genes of these necroptosis-related miRNAs were mainly related to functions of cell proliferation, focal adhesion, cell matrix adhesion, and cell aggregation adhesion, which were reported to be closely associated to tumor cell migration and tumor metastasis. [23][24][25]. Therefore, targeted therapy by inhibiting these cell-cell interactions may represent an important therapeutic strategy to improve the outcome of LUAD treatment.…”

Mitochondrial tRNA-Derived Fragments and Their Contribution to Gene Expression Regulation

“…Finally, specific mt-tRFs and particularly, mt-itRF Glu(UUC) , mt-5'tRF Leu(UUA) carrying the A3243G mutation and another mt-5'tRF Leu(UAA) , apart from being accumulated inside the mitochondria, have been detected also in the cytosol. Similar to their cytoplasmic counterparts, mt-tRFs presumably can act like miRNAs to induce gene silencing and, in some cases, may share common mRNA targets (Meseguer et al, 2019;Skeparnias et al, 2020). Interestingly, the differential expressed mt-tRFs in MELAS cybrid cells are predicted to target several mRNAs involved in the regulation of striated and cardiac muscle contraction but also in the development of these tissues (Meseguer et al, 2019).…”

“…More interestingly, each distinct class has been linked to specific biological function; global translation inhibition has been attributed mainly to 5' tRNA halves (but also to tRF-5 s), translation repression of specific mRNAs mainly to tRF-3 s, inhibition of specific gene transcription to tRF-5 s, inhibition of viral RNA translation to tRF-1 s, inhibition of apoptosis to 5' tRNA halves, and regulation of retrotransposon expression both to tRF-3 s and tRF-5 s (Schimmel, 2018;Su et al, 2020). In general, although tRFs production can be induced by stress, or the lack of specific post-transcriptional tRNA modifications, a certain number of tRFs has been proposed to act like miRNAs and to mediate gene silencing (Kumar et al, 2014;Skeparnias et al, 2020). Finally, although several known ribonucleases seem to contribute in the production of specific tRFs (see below), it is also likely that additional ribonucleolytic activities and/or biogenesis steps may mediate tRFs biogenesis (Su et al, 2020).…”

Διερεύνηση Αλληλεπιδράσεων RNA-πρωτεϊνών Και Του Ρόλου Τους Στη Ρύθμιση Της Πρωτεϊνοσύνθεσης Και Της Διαφοροποίησης Των Κυττάρων

“…Ανάλογα με την προέλευση και το μήκος τους ταξινομούνται σε tRF-5, tRF-3, tRF-1 και i-tRF (Εικόνα 61). Πρόσφατα δεδομένα υποστηρίζουν την συμμετοχή τους στη ρύθμιση της γονιδιακής έκφρασης μέσω στόχευσης μορίων mRNA, με τρόπο παρόμοιο με αυτόν των μορίων miRNA, αναστέλλοντας τη μετάφραση των μορίων mRNA γεγονός που έχει παρατηρηθεί τόσο σε φυσιολογικές όσο και σε παθολογικές καταστάσεις όπως ο καρκίνος(262)(263)(264). Επιπλέον, αξίζει να σημειωθεί πως πολλά μόρια tRF μπορούν και δρουν και με τρόπο παρόμοιο με αυτόν των piRNA μορίων, συμβάλλοντας στην άμυνα του κυττάρου έναντι των μεταθετών στοιχείων.…”