Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

Menegazzi, Marta; Gotte, Giovanni

doi:10.3390/ijms23126556

Cited by 5 publications

(10 citation statements)

References 177 publications

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“…Thereby, RNase-L can act as tumor-suppressor in mammalian cells also via destabilization of the miRNA-regulated transcriptome [ 58 ]. This multiplicity of targets, which is a typical feature of other antitumor RNases [ 59 ], results in pleiotropic effects, ranging from cell growth inhibition to pro-apoptotic activity [ 57 ], and suggests that RNase-L can play a protective effect on tumor progression and participate in the survival advantage in female melanoma patients. Remarkably, RNase-L negatively regulates androgen signaling by a protein-protein interaction mechanism [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

Orlandi

Tomi

Campagnari

et al. 2022

CIMB

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Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines. Direct targeting of miR-146a to the 3’ untranslated region (3′UTR) of RNASEL was examined using a luciferase reporter system. Our results indicate that RNASEL is a direct target of miR-146a in both melanoma cell lines. Trough qPCR and western blot analyses, we explored the effect of miR-146a mimic transfection in the presence of each hormone either on RNASEL mRNA level or on protein expression of RNase-L, the enzyme codified by RNASEL gene. In the presence of testosterone or 17β-estradiol, miR-146a overexpression did not influence RNASEL transcript level in LM-20 cell line, but it slightly induced RNASEL mRNA level in A375 cells. Remarkably, miR-146a overexpression was able to repress the protein level of RNase-L in both LM-20 and A375 cells in the presence of each hormone, as well as to elicit high expression levels of the activated form of the extracellular signal-regulated kinases (ERK)1/2, hence confirming the pro-tumorigenic role of miR-146a overexpression in melanoma. Thereafter, we assessed if the administration of each hormone could affect the endogenous expression of RNASEL and miR-146a genes in LM-20 and A375 cell lines. Testosterone exerted no significant effect on RNASEL gene expression in both cell lines, while 17β-estradiol enhanced RNASEL transcript level at least in LM-20 melanoma cells. Conversely, miR-146a transcript augmented only in the presence of testosterone in either melanoma cell line. Importantly, each hormone acted quite the opposite regarding the RNase-L protein expression, i.e., testosterone significantly decreased RNase-L expression, whereas 17β-estradiol increased it. Overall, the data show that, in melanoma cells treated with 17β-estradiol, RNase-L expression increased likely by transcriptional induction of its gene. Testosterone, instead, decreased RNase-L expression in melanoma cell lines with a post-transcriptional mechanism in which miR-146a could play a role. In conclusion, the pro-tumor activity of androgen hormone in melanoma cells could be exacerbated by both miR-146a increase and RNase-L downregulation. These events may contribute to the worse outcome in male melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

Orlandi

Tomi

Campagnari

et al. 2022

CIMB

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“…Lastly, Onconase (ONC) is a small RNase that has great cellular uptake, resistance against RNase Inhibitors and a propensity for tRF-20-S998LO9D 5' tsRNA Correlates with tumour progression via an unknown mechanism [153] tsRNA-ValTAC-41 3' tRNA half Upregulated in patients with pancreatic adenocarcinoma and in exosomes of liver cancer patients [126,142] tsRNA-26576 Not classified Upregulated in breast cancer, proposed to promote cellular growth, and inhibit apoptosis [154] 5' tiRNA-Pro TGG 5' tRNA half Downregulated in colorectal adenocarcinoma patients and associated with poor patient survival; proposed to regulate several pathways (AMPK, MAPK and mTOR) [155] tsRNA-5001a Not classified Upregulated in lung adenocarcinoma tissue, promotes the proliferation of lung adenocarcinoma cells [156] AS-tDR-007872 5' tRNA half Downregulated in lung cancer patients and regulates apoptosis by downregulating BCL2L11 [157] targeting cancer cells [148]. Since the first clinical trial in 1993, ONC has been administered to cancer patients alone or in combination with other treatments [148]. ONC functions by exerting regulatory roles, mainly regarding cell cycle arrest and induction of apoptosis [148].…”

Section: Tsrna-based Therapeutic Applicationsmentioning

confidence: 99%

An old friend with a new face: tRNA-derived small RNAs with big regulatory potential in cancer biology

Fazio

Gullerová

2023

Br J Cancer

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Transfer RNAs (tRNAs) are small non-coding RNAs (sncRNAs) essential for protein translation. Emerging evidence suggests that tRNAs can also be processed into smaller fragments, tRNA-derived small RNAs (tsRNAs), a novel class of sncRNAs with powerful applications and high biological relevance to cancer. tsRNAs biogenesis is heterogeneous and involves different ribonucleases, such as Angiogenin and Dicer. For many years, tsRNAs were thought to be just degradation products. However, accumulating evidence shows their roles in gene expression: either directly via destabilising the mRNA or the ribosomal machinery, or indirectly via regulating the expression of ribosomal components. Furthermore, tsRNAs participate in various biological processes linked to cancer, including apoptosis, cell cycle, immune response, and retroviral insertion into the human genome. It is emerging that tsRNAs have significant therapeutic potential. Endogenous tsRNAs can be used as cancer biomarkers, while synthetic tsRNAs and antisense oligonucleotides can be employed to regulate gene expression. In this review, we are recapitulating the regulatory roles of tsRNAs, with a focus on cancer biology.

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“…miRNA biogenesis and maturation is a stepwise process that starts in the nucleus and ends in cytoplasm. Most miRNA genes are transcribed by RNA polymerase II (Pol II) into long primary transcripts of miRNA called pri-miRNAs harboring a hairpin structure (2)(3)(4). The pri-miRNA are processed within the nucleus by Drosha, an RNAse III enzyme, into stem-loop intermediates called precursor-miRNA (pre-miRNAs) (2).…”

Section: Introductionmentioning

confidence: 99%

“…Most miRNA genes are transcribed by RNA polymerase II (Pol II) into long primary transcripts of miRNA called pri-miRNAs harboring a hairpin structure (2)(3)(4). The pri-miRNA are processed within the nucleus by Drosha, an RNAse III enzyme, into stem-loop intermediates called precursor-miRNA (pre-miRNAs) (2). These pre-miRNAs are then transported from the nucleus to the cytoplasm where they are further processed by the Dicer enzyme.…”

Section: Introductionmentioning

confidence: 99%

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The diverse roles of miRNAs in HIV pathogenesis: Current understanding and future perspectives

et al. 2023

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Despite noteworthy progress made in the management and treatment of HIV/AIDS-related disease, including the introduction of the now almost ubiquitous HAART, there remains much to understand with respect to HIV infection. Although some roles that miRNAs play in some diseases have become more obvious of late, the roles of miRNAs in the context of HIV pathogenesis have not, as yet, been elucidated, and require further investigations. miRNAs can either be beneficial or harmful to the host, depending upon the genes they target. Some miRNAs target the 3′ UTR of viral mRNAs to accomplish restriction of viral infection. However, upon HIV-1 infection, there are several dysregulated host miRNAs which target their respective host factors to either facilitate or abrogate viral infection. In this review, we discuss the miRNAs which play roles in various aspects of viral pathogenesis. We describe in detail the various mechanisms thereby miRNAs either directly or indirectly regulate HIV-1 infection. Moreover, the predictive roles of miRNAs in various aspects of the HIV viral life cycle are also discussed. Contemporary antiretroviral therapeutic drugs have received much attention recently, due to their success in the treatment of HIV/AIDS; therefore, miRNA involvement in various aspects of antiretroviral therapeutics are also elaborated upon herein. The therapeutic potential of miRNAs are discussed, and we also propose herein that the therapeutic potential of one specific miRNA, miR-34a, warrants further exploration, as this miRNA is known to target three host proteins to promote HIV-1 pathogenesis. Finally, future perspectives and some controversy around the expression of miRNAs by HIV-1 are also discussed.

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Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

Cited by 5 publications

References 177 publications

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

An old friend with a new face: tRNA-derived small RNAs with big regulatory potential in cancer biology

The diverse roles of miRNAs in HIV pathogenesis: Current understanding and future perspectives

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