Dataset Information

Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKII?-associated activation of autophagy.

ABSTRACT: Background:NF-E2-related factor 2 (Nrf2) is involved in the radiation resistance of esophageal squamous cell carcinoma (ESCC), but the underlying molecular mechanism is unclear. The purpose of our study was to explore the role of Nrf2 in the radiation resistance of ESCC and the potential molecular mechanism. Results:Nrf2 expression was introduced into Ec109 and KYSE-30 ESCC cells with lentivirus. CCK-8 and colony formation assays were used to evaluate the effect of Nrf2 on radioresistance in culture. The autophagy level was assessed by western blotting, flow cytometry, and confocal fluorescence microscopy. The effect of Nrf2 on the transcription of Ca2?+/calmodulin-dependent protein kinase II ? (CaMKII?) was studied by chromatin immunoprecipitation. We found that the overexpression of Nrf2 increased the radiation resistance of ESCC cells. Mechanistically, Nrf2 triggered the radiation resistance of ESCC cells by targeting CaMKII? and subsequently activating autophagy. In addition, we found that Nrf2 directly regulated the transcription of CaMKII? by binding to its promoter region. The effect of Nrf2 on radiation resistance was also explored in both a xenograft mouse model and ESCC patient samples. Consistent with the results of the in vitro study, high Nrf2 expression level resulted in in vivo radioresistance in an Ec109-derived xenograft mouse model. Furthermore, we also demonstrated that upregulations of both Nrf2 and CaMKII? was closely related to lower survival rates of ESCC patients. Conclusions:Our study reveals that Nrf2 promotes the radiation resistance of ESCC by targeting CaMKII? and subsequently activating autophagy, which is characterized by the suppression of phosphorylated mTOR and p62, activation of Beclin 1, and transformation of LC3-I to LC3-II.

SUBMITTER: Xia D

PROVIDER: S-EPMC7392680 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy.

Xia Di D Zhang Xiao-Ran XR Ma Yan-Li YL Zhao Zhi-Jun ZJ Zhao Ren R Wang Yan-Yang YY

Cell & bioscience 20200730

<h4>Background</h4>NF-E2-related factor 2 (Nrf2) is involved in the radiation resistance of esophageal squamous cell carcinoma (ESCC), but the underlying molecular mechanism is unclear. The purpose of our study was to explore the role of Nrf2 in the radiation resistance of ESCC and the potential molecular mechanism.<h4>Results</h4>Nrf2 expression was introduced into Ec109 and KYSE-30 ESCC cells with lentivirus. CCK-8 and colony formation assays were used to evaluate the effect of Nrf2 on radiore ...[more]

PMID: 32760495

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Project description:MicroRNAs (miRNAs) are an endogenous conserved class of non-coding 20–22 nt small RNAs that regulate gene expression at post-transcriptional level by mostly binding to 3′-UTR of target mRNAs, leading to mRNA degradation or translation inhibition. Recent reports demonstrate a role for miRNA expression in the disease progression and outcome. By now, many researcher focusing on miRNA expression profiles in Barrett's esophagus and esophageal adenocarcinoma have been reported. Nevertheless, there is still a little information available about specific miRNA expression pattern and their roles in ESCC. To develop novel diagnostic and therapeutic targets for esophageal squamous cancer, we first investigated the expression profile of miRNA in three pairs of ESCC clinical samples. Tissues of ESCC and the matched normal counterparts were obtained from surgical specimens immediately after resection from patients undergoing primary surgical treatment of esophageal carcinoma from the Department of Tumor Surgery of Shantou Central Hospital, China. RNA labeling and hybridization were completed by KangChen Bio-tech Inc. (Shanghai, China) according to the manufacturer's instructions. Briefly, total RNA from three pairs of esophageal carcinoma and matched normal tissues were isolated by Trizol (Invitrogen, USA) and purified by RNeasy mini kit (QIAGEN, German). The concentration and quality of total RNA were measured by NanoDrop ND-1000 at 260 and 280 nm (A260/280) and checked by gel electrophoresis. Each RNA sample from three pairs of ESCC was separately labeled either using the miRCURY Hy3/Hy5 labeling kit and hybridized on the six miRCURYTM locked nucleic acid (LNA) array version 11.0 (Exiqon, Denmark), which contains probes for 1700 mature miRNA. Scans were quantified by using GenePix software (Molecular Devices). The data were exported to Microsoft Excel worksheets, log2 transformed, normalized using global Lowess (Locally Weighted Scatter plot Smoothing) regression algorithm (MIDAS, TIGR Microarray Data Analysis System).

Project description:BackgroundEstrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC). This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC) as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC.ResultsBased on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs) mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418) of ESCC genes of which 43.75% (56/128) are known to be estrogen responsive, while 56.25% (72/128) are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290) are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs) in the promoters of the 202 (56+146) known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs). We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32) of these 32 predicted genes are indeed responsive to estrogen.ConclusionTo the best of our knowledge our study is the first to use a cancer disease model as the framework to identify hormone responsive genes. Although we used ESCC as the disease model and estrogen as the hormone, the methodology can be extended analogously to other diseases as the model and other hormones. We believe that our results provide useful information for those interested in genes responsive to hormones and in the design of hormone-based therapies.

Dataset Information

Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKII?-associated activation of autophagy.

Publications

Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy.

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