📰 Misleading appearances – the ambiguous role of a microRNA in tumorigenesis

© Herve Seitz

MicroRNAs (« miRNAs »), which repress specific genes, could be tumor suppressors. This role seems well established for the miRNA miR-34a by molecular biology – but it is contradicted by data (In information technology (IT), data is an elementary description, often…) live at the Mouse (The term mouse is an ambiguous vernacular name which can designate, for French speakers, before…) and theMale (A man is an adult male individual of the species called Modern Man (Homo…). An article published in Nucleic Acids Research ask what paradox (A paradox is a proposition which contains or appears to contain a logical contradiction, or a…): it shows that miR-34a is actually not a suppressor tumor (The term tumor (from the Latin tumere, to swell) designates, in medicine, an increase in…), the assignment problem was due to analysis biases. The article therefore reconciles molecular biology (Molecular biology (sometimes abbreviated bio mol or BM) is a discipline…) and physiology (Physiology (from the Greek φύσις, phusis, nature, and…)and provides a theoretical framework and method that can be generalized to other functions of miRNAs.

The microRNA (Micro RNAs (miRNA or miRNA) are single-stranded RNAs about 21 to 24 long…) (« miRNA ») repress a large number (The notion of number in linguistics is treated in the article « Number…) of target genes, and as such, they can participate in signaling pathways, in particular by context (The context of an event includes the circumstances and conditions surrounding it; the…) pathological. This is how some miRNAs are considered tumor suppressors. The most studied of them (miR-34a) has been attracting the attention of molecular oncologists since 2007, and numerous studies have effectively concluded that it suppresses cell proliferation, and that the mutation of its embarrassed (A gene is a deoxyribonucleic acid (DNA) sequence that specifies the…) was a engine (A motor (from the Latin mōtor: « the one who moves ») is a device…) probable tumorigenesis.

However, some data live seem to contradict this apparent consensus: in mice, the mutation of the miR-34a gene does not lead to any visible defect in matter (Matter is the substance that makes up any body having a tangible reality. Its…) tumorigenesis; in humans, administration of synthetic miR-34a to patients with solid tumors does not improve their condition.

The scientists therefore decided to question this apparent paradox. Their results show that miR-34a is not a tumor suppressor, in agreement with studies live. The source of this assignment problem is parsing errors in biology (Biology, commonly called « bio », is the science of life….) molecular and genetic (Genetics (from the Greek genno γεννώ = to give birth) is…) human, clearly highlighted here:

– MiR-34a mutations had long been thought to be enriched in cancers, but miR-34a mutations occasionally observed in tumors are independent ofactivity (The term activity can refer to a profession.) of miR-34a itself, since gene-restricted mutations miR-34a are very rare in tumor cells. It is therefore likely that these occasional mutations are due to the proximity genomics (Genomics is a discipline of modern biology. It studies how…) of the miR-34a gene with an authentic tumor suppressor, the deletion of which sometimes affects miR-34a fortuitously.

– The apparent role of miR-34a in the control (The word control can have several meanings. It can be used as a synonym of examination, of…) of the proliferation is due to a artifact (An artifact or artefact is an effect (lat. factum) artificial (lat. ars, artis). The term…) over-expression of miRNA in simplified experimental systems: the methods commonly employed to measure the proliferative activity of miRNA involved over-expressions of several hundred to thousands of times, whereas doses closer to the level of endogenous expression of the miRNAs do not trigger a net proliferative defect.

In addition to their interest in molecular oncology, this work illustrates a frequent defect in the analysis functional (In mathematics, the term functional refers to certain functions….) miRNAs, and provide a clear theoretical framework and an easily generalizable method, to resolve the frequent disagreements observed between molecular analyzes and phenotypic characterizations live.

A – The comparison of the abundance of miR-34a between a primary tumor and the adjacent healthy tissue does not reveal a decrease in its abundance in the tumor (the miRNAs are arranged along the abscissa axis, and the column representing miR- 34a is enlarged on the right; the 20 types of cancer analyzed are arranged along the y-axis).

B – The methods most commonly used to assess the cellular function of miR-34a are based on transfection of high concentrations (several nanomolars or tens of nanomolars) of synthetic miRNA. In HCT-116 cells (where the anti-proliferative activity of miR-34a is reportedly well established), these transfections result in over-expressions of several hundreds or thousands of times, at least point (graphics) to exceed the abundance of the most abundant miRNA (miR-21) by several orders of magnitude.

© Herve Seitz

To know more:
A rationalized definition of general tumor suppressor microRNAs excludes miR-34a.
Mockly S., Houbron E., Seitz H.
Nucleic Acids Research. April 26, 2022 doi:10.1093/nar/gkac277

Laboratory:
Institute of Human Genetics (CNRS/University of Montpellier) – 141 street (The street is a circulation space in the city that serves housing and places…) of Cardonilla. 34396 Montpellier.

Contact:
Herve Seitz – Searcher (A researcher (fem. researcher) refers to a person whose job is to do research…) CNRS (The National Center for Scientific Research, better known by its acronym CNRS, is the largest…) at theInstitute (An institute is a permanent organization created for a certain purpose. It is…) of human genetics – herve.seitz at igh.cnrs.fr