RESUMO
Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.
Assuntos
Antígenos de Superfície/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose/genética , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Família Multigênica , Oncogenes , Prognóstico , Interferência de RNA , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Previous studies have suggested that dysregulation of microRNA (miR) -124a is associated with various types of human cancer. However, there are few studies reporting the level of miR124a expression in nonsmall cell lung cancer (NSCLC). The present study investigated the association between miR124a and NSCLC by analyzing the differential expression of miR124a in NSCLC using the GEO database, as well as subsequently performing reverse transcriptionquantitative polymerase chain reaction analysis on 160 NSCLC biopsies, 32 of which were paired with adjacent normal tissues. The results indicated that mir124a expression levels were decreased in NSCLC tumor biopsies compared with adjacent normal tissues. The overall survival (OS) in patients with a high expression of miR124a was prolonged relative to patients with low expression of miR124a. The expression levels of miR124a were associated with clinical characteristics, including lymphnode metastasis, tumor differentiation, tumor node metastasis (TNM) stage and diameter. Frequently, lymphnode metastasis, TNM stage, diameter and lack of chemotherapy have been associated with a worse prognosis in patients. In addition, the present study identified that high expression of miR124awith chemotherapy may increase OS. In conclusion, the current study demonstrated that miR124a was downregulated in NSCLC, and miR124a was a potential prognostic tumor biomarker response to chemotherapy.