التفاصيل البيبلوغرافية
| العنوان: |
miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC. |
| المؤلفون: |
Shibata, Tomohiro, Cao, Duo-Yao, Dar, Tahir B., Ahmed, Faizan, Bhat, Shabir A., Veiras, Luciana C., Bernstein, Ellen A., Khan, Abdul Arif, Chaum, Manita, Shiao, Stephen L., Tourtellotte, Warren G., Giani, Jorge F., Bernstein, Kenneth E., Cui, Xiaojiang, Vail, Eric, Khan, Zakir |
| المصدر: |
Cancers; Nov2022, Vol. 14 Issue 21, p5273, 28p |
| مصطلحات موضوعية: |
IMMUNOHISTOCHEMISTRY, HEAD & neck cancer, DRUG resistance, MICRORNA, APOPTOSIS, GENE expression, TREATMENT effectiveness, DESCRIPTIVE statistics, KAPLAN-Meier estimator, DATA analysis software, BIOLOGICAL assay, SQUAMOUS cell carcinoma |
| مستخلص: |
Simple Summary: Despite improvements in therapeutics, head and neck squamous cell carcinomas (HNSCC) relapse in more than 50% of cases due to the development of chemo-radiotherapy resistance during sequential treatments. Our findings provide a strong rationale which can improve potential therapeutic strategies for overcoming drug resistance in HNSCC. We demonstrated that expression of miR124-3p and miR766-3p is associated with drug resistance in HNSCC, and their blockade greatly enhances the efficacy of standard anti-HNSCC therapeutics including 5-fluorouracil and cisplatin (FP chemotherapy), as well as radiotherapy. We discovered miR124-3p and miR766-3p-mediated mechanisms of resistance involve transcriptional factors CREBRF and NR3C2 in HNSCC. These results warrant testing miR766-3p and miR124-3p as predictors of response to chemo-radiotherapy in clinical settings and as markers for selecting patients for alternative treatment approach. Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and β-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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