Fong, LY;
Taccioli, C;
Palamarchuk, A;
Tagliazucchi, GM;
Jing, R;
Smalley, KJ;
Fan, S;
... Croce, CM; + view all
(2020)
Abrogation of esophageal carcinoma development in miR-31 knockout rats.
Proceedings of the National Academy of Sciences of the United States of America
, 117
(11)
pp. 6075-6085.
10.1073/pnas.1920333117.
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Abstract
MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10−6 ). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB–controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31–associated EGLN3/NF-κB– controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31−/− rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.
| Type: | Article |
|---|---|
| Title: | Abrogation of esophageal carcinoma development in miR-31 knockout rats |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1920333117 |
| Publisher version: | https://doi.org/10.1073/pnas.1920333117 |
| Language: | English |
| Additional information: | This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Keywords: | constitutive miR-31 knockout rat, esophageal cancer rat model, esophageal squamous cell carcinoma, in vivo antimiR-31 delivery, zinc deficiency |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10100701 |
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