Abstract
Increasing evidence shows that dysregulation of microRNAs (miRNAs) is involved in malignant transformation. We investigated the clinical significance of miR-650 and its involvement in chemoresistance to docetaxel. Our results showed that the relative expression level of miR-650 was significantly higher in LAD tissues than in corresponding nontumor tissues and high level of miR-650 expression was found to be significantly associated with high incidence of lymph node metastasis, advanced clinical stage and poor prognosis of LAD patients. Univariate and multivariate analyses indicated that high miR-650 expression was an independent prognostic factor for survival. Also, we found that the level of miR-650 in LAD tissues was correlated with the response of patients to docetaxel-based chemotherapy. Silencing of miR-650 could increase the in vitro sensitivity of docetaxel-resistant LAD cells to docetaxel, while upregulation of miR-650 decreased the sensitivity of parental LAD cells to docetaxel both in vitro and in vivo. Additionally, silencing of miR-650 could enhance the caspase-3-dependent apoptosis, which might be correlated with the decreased ratio of Bcl-2/Bax. Further researches suggested that inhibitor of growth 4 (ING4) was a direct target of miR-650. Downregulated or upregulated ING4 expression could partially rescue the effects of miR-650 inhibitor or mimics in docetaxel-resistant or parental LAD cells. Furthermore, we found that ING4 was upregulated in docetaxel-responding LAD tissues, and its expression was inversely correlated with miR-650. Thus, miR-650 is a novel prognostic marker in LAD and its expression is a potential indicator of chemosensitivity to docetaxel-based chemotherapy regimen.
Highlights
Lung cancer is one of the commonest malignant malignancies all over the world [1]
By statistical analysis (Table 1), it was shown that the level of miR-650 expression was significantly correlated with lymph node metastasis and clinical stage of LAD patients (P=0.023 and 0.019, respectively), suggesting that high miR-650 expression group showed a higher incidence of lymph node metastasis (70.7%) and more advanced clinical stage (75.6%) than the low miR-60 expression group (51.2% and 40.0%, respectively)
We have showed that upregulation of inhibitor of growth 4 (ING4) could significantly increase the apoptosis of docetaxel-resistant LAD cells, suggesting that downregulation of miR-650 could lead to the same apoptosisinducing effect as upregulation of ING4
Summary
Lung cancer is one of the commonest malignant malignancies all over the world [1]. The estimated incidence of new cases of lung cancer in the world is nearly 1,000,000 every year. In China, about 300,000 new lung cancer patients and more than 250,000 deaths from the disease are predicted each year. Adenocarcinoma of the lung (LAD) is the most common type of lung cancer and accounts for 30 to 35 percent of primary lung tumors [2]. Lung carcinogenesis is a complex, stepwise process that involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, to in situ carcinoma, and to invasive and metastatic cancers [3]. Elucidation of the molecular mechanisms involved in the pathogenesis of LAD will be helpful for the development of better prognostic markers and novel therapeutic targets to improve clinical treatment of LAD patients
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