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

Our plain-English summary of Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections, by M. Menegazzi, G. Gotte (International Journal of Molecular Sciences, 2022).

The study

• Authors: M. Menegazzi, G. Gotte
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(12)
• Type of article: Review
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity. Additionally, ONC administration in patients resulted in clinical effectiveness and in a well-tolerated feature, at least for lung carcinoma and malignant mesothelioma. Moreover, the ONC therapeutic effects are actually potentiated by cotreatment with many conventional antitumor drugs. This review not only aims to describe the ONC activity occurring either in different tumors or in viral infections but also to analyze the molecular mechanisms underlying ONC pleiotropic and cellular-specific effects. In cancer, data suggest that ONC affects malignant phenotypes by generating tRNA fragments and miRNAs able to downregulate oncogenes expression and upregulate tumor-suppressor proteins. In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives.

In plain English

This article was a review, not an original study. The authors summarized published laboratory, animal and clinical research on onconase, an enzyme that cuts RNA, taken from the oocytes (egg cells) of the leopard frog Rana pipiens. The review focused on cancer and viral infections. The article did not study asbestos exposure. Among the earlier trials it described, the largest phase II trial, in patients with unresectable malignant mesothelioma, reported clinical effectiveness in 51% of patients and a median survival of six months. A phase III trial in 154 patients with malignant mesothelioma compared onconase with doxorubicin. Average survival was 11.6 versus 9.6 months, which the review called a mild advantage. The main dose-limiting side effect in early trials was kidney toxicity that was reversible. Laboratory studies covered by the review reported that onconase lowered a protein called NF-kappaB in mesothelioma cells and changed levels of small regulatory RNAs called microRNAs. The authors concluded that onconase may change protein production by generating RNA fragments and might become therapeutically useful. They noted that many questions remain unanswered.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on the ribonuclease onconase (ONC) in cancer and viral infections
• Who was studied: No study population of its own. The review covered tumor cell lines, animal studies and clinical trials. These included trials in patients with malignant mesothelioma, among them a phase III trial of 154 patients, plus studies of viral infections.
• Exposure: Treatment with onconase, a 104-amino-acid amphibian ribonuclease. Asbestos exposure was not studied; asbestos is mentioned only in describing asbestos-induced mesothelioma cells in earlier work.
• Main results:
  • As reported by the review: in the largest phase II trial, in patients with unresectable malignant mesothelioma, 51% showed clinical effectiveness, and overall median survival was six months.
  • As reported by the review: in a phase III trial of 154 malignant mesothelioma patients, those given ONC (480 µg/m2/week) had an average survival of 11.6 months. Those given doxorubicin (60 mg/m2 every three weeks for six cycles) had 9.6 months. The review described this as a mild advantage.
  • As reported by the review: the dose-limiting toxicity of ONC in early trials was reversible nephrotoxicity (kidney toxicity). Other side effects included flushing and myalgia.
  • As reported by the review: in mesothelioma cells, ONC lowered expression of NF-kappaB and of its target genes.
  • As reported by the review: in malignant pleural mesothelioma cells, one earlier study found that ONC changed microRNA expression. The text says the most significant changes were an upregulation of miR-17* and a downregulation of miR-30c.
• The authors' conclusion: The authors concluded that ONC can affect protein expression by generating RNA fragments with interfering properties, particularly in pathological conditions. They also concluded that ONC might become therapeutically efficacious, especially when combined with standard drugs.
• Limitations the authors state:
  • The authors stated that many questions remain unanswered, including which other RNA species ONC acts on and what the RNA fragments it generates do inside cells.
  • The authors stated that the mechanisms behind the stronger effects of ONC combined with other treatments have been poorly investigated.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Mesothelioma.

Related studies

• Onconase mediated NFKβ downregulation in malignant pleural mesothelioma — C.M. Goparaju, J.D. Blasberg, et al. (2011)
• Onconase responsive genes in human mesothelioma cells: implications for an RNA damaging therapeutic agent — D.A. Altomare, S.M. Rybak, et al. (2010)
• Dysregulation of microRNAs and tRNA-derived ncRNAs in mesothelial and mesothelioma cell lines after asbestiform fiber exposure — V. Filetti, A. La Ferlita, et al. (2022)
• The role of iNOS-mediated DNA damage in infection- and asbestos-induced carcinogenesis — Y. Hiraku, S. Kawanishi, et al. (2010)
• Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs — G. Gotte, M. Menegazzi (2019)
• Combination of onconase and dihydroartemisinin synergistically suppresses growth and angiogenesis of non-small-cell lung carcinoma and malignant mesothelioma — R. Shen, J. Li, et al. (2016)

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