Abrogation of esophageal carcinoma development in miR-31 knockout rats

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 followingN-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.

Downregulation of miR-135b-5p Suppresses Progression of Esophageal Cancer and Contributes to the Effect of Cisplatin

“…Emerging studies reported that miRNAs play a significant contribution to EC. For example, miR-31 is upregulated in esophageal squamous cell carcinoma (ESCC) tissues and serum samples, which is negatively associated with relapse-free survival of patients ( 14 ). The knockdown of miR-31 suppresses EC development by targeting Egln3 ( 14 ).…”

Zinc dysregulation in cancers and its potential as a therapeutic target

“…It has been reported that zinc deficiency is correlated with increased tumor size, tumor stage, and increased unplanned hospitalizations in head and neck cancer patients 18 . A series of in vivo studies have been conducted by Fong and his colleagues to show that dietary zinc deficiency (ZD) increases the incidence of N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer 19 – 21 . High dietary zinc intake can also decrease the risk of colon cancer in a prospective cohort study 22 .…”

LncRNA FAM83A-AS1 promotes ESCC progression by regulating miR-214/CDC25B axis

“…Approximately 80% of EC is clarified as esophageal cell squamous carcinoma (ESCC) in China 2 . Despite greatly advanced progress that has been achieved in the diagnosis and treatment of ESCC over the past decades, the high occurrence and poor survival of ESCC remains a public health concern 3 , 4 , and the molecular mechanism of ESCC development remains to be largely elucidated. Therefore, it is urgent to find out the precise molecular mechanism underlying ESCC pathogenesis.…”