Long Non-Coding RNA MAPK8IP1P2 Inhibits Lymphatic Metastasis of Thyroid Cancer by Activating Hippo Signaling via Sponging miR-146b-3p

RNA is not only a messenger operating between DNA and protein. Transcription of essentially the entire eukaryotic genome generates a myriad of non-protein-coding RNA species that show complex overlapping patterns of expression and regulation. Although long noncoding RNAs (lncRNAs) are among the least well-understood of these transcript species, they cannot all be dismissed as merely transcriptional "noise." Here, we review the evolution of lncRNAs and their roles in transcriptional regulation, epigenetic gene regulation, and disease.

Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs. Copyright © 2011 Elsevier Inc. All rights reserved.

SUMMARY Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, is implicated in various diseases such as ischemic organ damage and cancer 1,2 . As a central regulator of ferroptosis, the enzyme glutathione peroxidase 4 (GPX4) protects cells from ferroptosis by neutralizing lipid peroxides, which are byproducts of cellular metabolism; as such, inhibiting GPX4 directly, or indirectly by depriving its substrate glutathione or building blocks of glutathione (such as cysteine), can trigger ferroptosis 3 . Ferroptosis contributes to the antitumour function of multiple tumour suppressors including p53, BAP1, and fumarase 4-7 . Counterintuitively, mesenchymal cancer cells, which are prone to metastasis and often resistant to various treatments, have shown to be highly susceptible to ferroptosis 8,9 . Here, we demonstrate that ferroptosis can be regulated non-cell autonomously by cadherin-mediated intercellular contacts. In epithelial cells, E-cadherin-mediated intercellular interaction suppresses ferroptosis through intracellular Merlin-Hippo signalling. Antagonizing this signalling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through upregulation of multiple ferroptosis modulators, including acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor. This finding provides mechanistic insights into the observations that epithelial mesenchymal transition (EMT)/metastasis-prone cancer cells are highly sensitive to ferroptosis 8 . Importantly, the regulation of ferroptosis by cell-cell contact and Merlin-YAP signalling is not limited to epithelial cells; a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, we found that genetic inactivation of the tumour suppressor Merlin, a frequent tumourigenic event in mesothelioma 10,11 , renders cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Together, this study unveils the role of intercellular interaction and intracellular Merlin-YAP signalling in dictating ferroptotic death; it also suggests that malignant mutations in Merlin-YAP signalling can serve as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies.