miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC

• Published in: Cancers Vol. 14; no. 21; p. 5273
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: MDPI AG 27-10-2022; MDPI
• Subjects: Drug resistance; Drug therapy; Genetic aspects; Head and neck cancer; Health aspects; MicroRNA; Patient outcomes; Squamous cell carcinoma; United States
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14215273

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.