The authors propose a problematic and speculative model wherein miR-24-1 acts as epigenetic mimic of the second somatic hit in MEN1-related parathyroid tumorigenesis. According to this model, overexpression of miR-24-1 silences translation of MEN1 mRNA derived from the wild-type allele, effectively repressing menin expression in the absence of allelic loss. While the narrative is constructedwith confidence, the paper fails to critically evaluate key mechanistic and translational limitations of this claim.
First and foremost, the functional sufficiency of miR-24-1 to drive tumorigenesis remains speculative. Nowhere in the review is there direct experimental evidence presented (e.g., from transgenic mouse models or organoid systems) demonstrating that upregulation of miR-24-1 alone, in the presence of an intact MEN1 allele, is capable of initiating or promoting hyperplasia or adenoma formation. The authors cite expression patterns and in silico predictions but overlook the crucial need to demonstrate causality, not just correlation. This weakens the claim that miR-24-1 truly phenocopies a genetic second hit in a Knudsonian framework.
Secondly, the authors assert that miR-24-1 can repress MEN1 translation despite the presence of wild-type mRNA, yet they do not account for tissue specificity or feedback regulation in vivo. For example, if miR-24-1 exerts this repression broadly, why is parathyroid tissue selectively vulnerable, while other menin-expressing tissues are spared or show different tumor spectra? The review ignores this discrepancy and assumes an overly deterministic role for miR-24-1 in parathyroid-specific tumorigenesis without exploring possible tissue-specific co-factors or differential microRNA processing in endocrine tissues.
Moreover, the proposed positive feed-forward loop, in which menin promotes pri-miR-24-1 processing, which then represses menin itself , is paradoxical. While such regulatory loops do exist, their existence in this context raises more questions than it answers. If menin upregulates the maturation of its own repressor, why would this loop not self-limit or collapse before reaching tumorigenic thresholds? The authors cite this mechanism as evidence of autoregulation but fail to discuss why such a destabilizing feedback loop wouldn’t prevent or buffer against complete menin loss in physiological conditions. The lack of such a discussion significantly undermines the plausibility of the model.
Finally, although the review proposes that this miR-24-1 mechanism may precede or even replace LOH, it does not address why LOH at the MEN1 locus remains highly prevalent even in cases with detectable miR-24-1 upregulation. If miR-24-1 were a fully sufficient surrogate for the second hit, one would expect to see a reduction in LOH frequency among these tumors, but no such inverse relationship is documented. This weakens the central thesis that miR-24-1-driven repression represents an alternative molecular route to MEN1 loss.