Abrogation of esophageal carcinoma development in miR-31 knockout rats
| Autor: | Karl J. Smalley, Ruiyan Jing, Sili Fan, Carlo M. Croce, Guidantonio Malagoli Tagliazucchi, Louise Y.Y. Fong, Oliver Fiehn, Joseph Altemus, Cristian Taccioli, Kay Huebner, Alexey Palamarchuk, John L. Farber |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Genome instability
Male Medical Sciences Knockout rat Esophageal Neoplasms Transgenic law.invention Transcriptome Gene Knockout Techniques 0302 clinical medicine law Neoplasms in vivo antimiR-31 delivery constitutive miR-31 knockout rat zinc deficiency In vivo antimiR-31 delivery 2.1 Biological and endogenous factors Aetiology Cancer Esophageal cancer rat model 0303 health sciences Multidisciplinary Tumor Zinc deficiency NF-kappa B Biological Sciences Constitutive miR-31 knockout rat Esophageal squamous cell carcinoma 3. Good health esophageal squamous cell carcinoma Gene Expression Regulation Neoplastic mir-31 Zinc 030220 oncology & carcinogenesis Rats Transgenic medicine.symptom Biotechnology Signal Transduction Nitrosamines Inflammation Biology Cell Line Hypoxia-Inducible Factor-Proline Dioxygenases 03 medical and health sciences Experimental Rare Diseases Esophagus Cell Line Tumor Genetics medicine Carcinoma Animals Humans neoplasms Gene knockout Nutrition 030304 developmental biology Neoplastic esophageal cancer rat model Human Genome Neoplasms Experimental medicine.disease digestive system diseases Rats MicroRNAs Gene Expression Regulation Dietary Supplements Cancer research Carcinogens Suppressor Digestive Diseases |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 11 Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance ESCC is a deadly disease with few prevention or treatment options. In a dietary Zn deficiency-promoted rat ESCC model with miR-31–controlled inflammation pathway up-regulation, systemic antimiR-31 reduces miR-31 level and inflammation, suppressing ESCC development. We identified Egln3 as a direct miR-31 target and developed a constitutive miR-31 knockout rat model. Interactions of oncogenic miR-31, EGLN3 down-regulation, and inflammation occur in rat and human ESCC tissue. Since miR-31 genetic knockout prevents Zn deficiency-associated ESCC by eliminating or greatly reducing the entire miR-31-EGLN3/STK40-NF-κB–controlled inflammatory process, we conclude that miR-31 and downstream signaling proteins should be tested as prognostic and therapeutic targets and inexpensive Zn supplementation should be implemented for ESCC prevention in deficient populations. 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. |
| Databáze: | OpenAIRE |
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