miR-432 Induces NRF2 Stabilization by Directly Targeting KEAP1

NF-E2–related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-translational level. In human cancers, aberrantly stabilized NRF2, by the mutation of either NRF2 or KEAP1 or by the potential inhibition of autophagy, plays a vital role in tumor growth and chemoresistance through the activation of target genes. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with translation and/or stability of target transcripts. However, miRNA-mediated regulation of the NRF2–KEAP1 pathway under physiological conditions is poorly understood. Here, miR-432-3p positively regulates NRF2 activity through the downregulation of KEAP1 by a direct-binding mechanism to the coding region of KEAP1. Overexpression of miR-432-3p resulted in a decreased sensitivity of esophageal squamous cell carcinoma (ESCC) cells to chemotherapy drugs including cisplatin (CDDP). Conversely, the inhibition of miR-432-3p expression by the CRISPR/Cas9 system resulted in an increased sensitivity of ESCC cells to CDDP. Furthermore, miR-432-3p was overexpressed in primary ESCC tumors (55 of 84, 65.5%) and a negative correlation between the expression level of KEAP1 and miR-432-3p in primary ESCC tumors was observed. Implications: These findings provide novel insights into the mechanism of NRF2 stabilization in human canc...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Oncogenes and Tumor Suppressors Source Type: research

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BackgroundThis retrospective study compared the efficacy and side effect profile between postoperative adjuvant radiotherapy and chemoradiotherapy in stage II or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients who underwent curative (R0) esophagectomy.MethodsA total of 272 TESCC patients who underwent radical esophagectomy from 2007 to 2016 were included in this retrospective analysis. All cases were pathologically confirmed with stage II or III disease and 148 patients received postoperative chemoradiotherapy (CRT), while the remaining 124 patients received postoperative radiotherapy (RT) alone.Resu...
Source: Thoracic Cancer - Category: Cancer & Oncology Authors: Tags: ORIGINAL ARTICLE Source Type: research
CONCLUSION: Pretreatment texture parameters are associated with survival time, and the combination of post volume performed better in survival models. PMID: 31903981 [PubMed - as supplied by publisher]
Source: Cancer Biomarkers - Category: Cancer & Oncology Tags: Cancer Biomark Source Type: research
Authors: Lee MC, Chen YK, Hsu YJ, Lin BR Abstract Niclosamide is an FDA‑approved anthelmintic drug, and may elicit antineoplastic effects through direct STAT3 inhibition, which has been revealed in numerous human cancer cells. Chemotherapy is the standard treatment for advanced esophageal cancers, but also causes severe systemic side effects. The present study represents the first study evaluating the anticancer efficacy of niclosamide in esophageal cancers. Through western blot assay, it was demonstrated that niclosamide suppressed the STAT3 signaling pathway in esophageal adenocarcinoma cells (BE3) and esophage...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy.
Source: Digestive and Liver Disease - Category: Gastroenterology Authors: Tags: Progress Report Source Type: research
ConclusionsPembrolizumab has recently been FDA-approved for PD-L1 positive, locally advanced or metastatic ESCC. Despite comprehensive molecular characterization, however, available targed therapies for ESCC are still lagging behind. Herein, we discuss current trends towards more targeted therapies in esophageal cancers, taking into consideration unique features of ESCCs and EACs. Patients progressing on standard therapies should be subjected to genomic profiling and considered for clinical trials aimed at testing targeted therapies. Future targeted therapies may include CDK4/6 inhibitors, PARP inhibitors and inhibitors &n...
Source: Cellular Oncology - Category: Cancer & Oncology Source Type: research
This study aimed to explore the underlying mechanism of linc01014 in oesophagus cancer gefitinib resistance. Gefitinib-resistant oesophagus squamous cell carcinoma (ESCC gefitinibR) cell lines were constructed by using different gefitinib treatment in FLO-1, KYAE-1, TE-8 and TE-5 cell lines and confirmed by MTS50 and proliferation assays. Expression of linc01014 was overexpressed/silenced in FLO-1 cells followed by gefitinib treatment, and then, the apoptosis-associated markers Bax and Bcl-2, and PI3KCA in PI3K signalling pathway were determined using Western blotting. MST50 and morphology analyses showed that ESCC gefitin...
Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
Esophageal cancer (EC) is a lethal disease, and ranks 7th in incidence and 6th in mortality worldwide. Patients are treated with surgery and/or chemoradiotherapy for a curative intent, but for those with advanced diseases systemic chemotherapy and targeted therapy are the mainstay treatment with poor prognosis. For the patients with squamous cell carcinoma and those progressed after chemotherapy, treatment option is even fewer, and effective treatment modalities are urgently needed. Preclinical and clinical studies have found the PD-1/PD-L1 inhibitors activate T lymphocytes, inhibit cancer growth, and improve survival in c...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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Source: Journal of Thoracic Disease - Category: Respiratory Medicine Tags: J Thorac Dis Source Type: research
ConclusionsOur results suggest that more data is needed regarding the clinical benefits of CRT+S for treatment of localized esophageal SCC, although CRT should be cautiously preferred.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research
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