miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

• Published in: Molecular therapy 2018-04, Vol.26 (4), p.1066-1081
• Main Authors: Deng, Xiaojie, Liu, Zhen, Liu, Xiong, Fu, Qiaofen, Deng, Tongyuan, Lu, Juan, Liu, Yiyi, Liang, Zixi, Jiang, Qingping, Cheng, Chao, Fang, Weiyi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 3' Untranslated Regions; Adult; Aged; AKT protein; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor; c-Myc protein; Cell adhesion & migration; Cell cycle; Cell Cycle - genetics; Cell growth; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Chemoresistance; Chemotherapy; Disease Models, Animal; Drug resistance; Drug Resistance, Neoplasm - genetics; Ectopic Gene Expression; Experiments; Extracellular signal-regulated kinase; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Generalized linear models; Humans; Infections; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lung cancer; Male; MAP kinase; Medical prognosis; Mesenchyme; Metastases; Metastasis; Mice; MicroRNAs - genetics; Middle Aged; miR-296-3p; miRNA; MK2; Myc protein; Nasopharyngeal carcinoma; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nicotine; Nicotine - pharmacology; Original; Pathogenesis; Phosphatidylinositol 3-Kinases - metabolism; Protein kinase; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA Interference; Science; Signal Transduction - drug effects; Survival analysis; Therapeutic applications; Throat cancer; Tobacco; Tumor suppressor genes; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.01.023

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC. [Display omitted] Deng et al. found that miR-296-3p was negatively regulated by nicotine in nasopharyngeal carcinoma (NPC) cells. Additionally, miR-296-3p overexpression inhibited the growth, metastasis, and chemoresistance of NPC cells via targeting MK2-mediated cytoplasm translocation of c-Myc. These findings suggested that the restoration of tumor suppressor miR-296-3p might represent a therapeutic strategy in NPC.