Project description:Background Neuroendcrine carcinoma (NEC) of lung consists of small-cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Although long-term outcomes of SCLC patients are usually poor, a few patients achieve long-term survivals. Prognostic factors in SCLC have not been fully elucidated. microRNAs (miRNAs) are known to negatively regulate gene expression and to be relevant to tumorigenesis, tumor classification and prognosis. Methods 63 samples (46 neuroendocrine carcinoma including 35 SCLC and 11 LCNEC, 4 adenocarcinoma, 5 squamous cell carcinoma and 8 normal lung) were obtained through surgical resection. miRNA expression in each sample was comprehensively investigated using miRNA microarray. Results Unsupervised hierarchial clustering classified the all NEC into two subgroups, group 1 and 2. Group 1 was felt into an independent branch that consisted of only NEC, whereas group 2 was included in a branch that contained both NEC and non-NEC. Compared with SCLC of group 1 (SCLC 1), SCLC of group 2 (SCLC 2) was a distinct subgroup with surprisingly good prognosis (0% v 79% survived for 5 years; p=0.007). Serum proGRP level was significantly lower in SCLC 2 than in SCLC 1 despite of similar tumor stages between the two groups. Among 12 cases treated by presurgical chemotherapy, PR:NC ratio was 6:3 in SCLC 1 and 2:1 in SCLC 2, suggesting no apparent difference of chemosensitivity. Histologically, distinction between both groups was difficult. Cox regression analysis demonstrated that three miRNA signature was correlated with survival of SCLC patients. These prognostic miRNAs were differentially expressed between SCLC 1 and 2, which were validated by quantitative real time RT-PCR. Bioinformatics analysis predicted that these miRNAs targeted not only genes involving with tumorigenesis but also genes associated with neuroendocrine function. Conclusion miRNA expression profiling identified a distinct subgroup of SCLC with favorable prognosis. This subgroup might have less neuroendocrine character than usual SCLC.

Project description:Background Neuroendcrine carcinoma (NEC) of lung consists of small-cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Although long-term outcomes of SCLC patients are usually poor, a few patients achieve long-term survivals. Prognostic factors in SCLC have not been fully elucidated. microRNAs (miRNAs) are known to negatively regulate gene expression and to be relevant to tumorigenesis, tumor classification and prognosis. Methods 63 samples (46 neuroendocrine carcinoma including 35 SCLC and 11 LCNEC, 4 adenocarcinoma, 5 squamous cell carcinoma and 8 normal lung) were obtained through surgical resection. miRNA expression in each sample was comprehensively investigated using miRNA microarray. Results Unsupervised hierarchial clustering classified the all NEC into two subgroups, group 1 and 2. Group 1 was felt into an independent branch that consisted of only NEC, whereas group 2 was included in a branch that contained both NEC and non-NEC. Compared with SCLC of group 1 (SCLC 1), SCLC of group 2 (SCLC 2) was a distinct subgroup with surprisingly good prognosis (0% v 79% survived for 5 years; p=0.007). Serum proGRP level was significantly lower in SCLC 2 than in SCLC 1 despite of similar tumor stages between the two groups. Among 12 cases treated by presurgical chemotherapy, PR:NC ratio was 6:3 in SCLC 1 and 2:1 in SCLC 2, suggesting no apparent difference of chemosensitivity. Histologically, distinction between both groups was difficult. Cox regression analysis demonstrated that three miRNA signature was correlated with survival of SCLC patients. These prognostic miRNAs were differentially expressed between SCLC 1 and 2, which were validated by quantitative real time RT-PCR. Bioinformatics analysis predicted that these miRNAs targeted not only genes involving with tumorigenesis but also genes associated with neuroendocrine function. Conclusion miRNA expression profiling identified a distinct subgroup of SCLC with favorable prognosis. This subgroup might have less neuroendocrine character than usual SCLC. All samples were tissue samples obtained by surgical resection. 35 samples of small-cell lung cancer were investigated. 11 samples of larege cell neuroendocrine cancer, 4 samples of adenocarcinoma, 5 samples of squamous cell carcinoma and 8 samples of normal lung were also included as reference.

Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. However, science has not yet been able to substantially improve the prognosis of lung cancer patients. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor development and metastasis. Expression of six miRNAs previously shown to play roles in tumor development (miR-146b-5p, miR-128b, miR-21, miR-221, miR-34a, and Let-7a) in other tumor types was examined using real-time RT-PCR in 78 specimens of NSCLC. The results revealed that patients with low expression of miR-146b-5p had significant shorter median and mean survival time than those with high miR-146b-5p expression (33.00 and 30.44 months versus 42.0 and 36.90 months, respectively; log-rank test P=0.048), thus low miR-146b-5p expression level was associated with poor prognosis in NSCLC patients. Univariate Cox hazard regression analysis demonstrated that miR-146b-5p expression levels tended to be a significant prognostic indicator of NSCLC (adjusted hazard ratio=0.482, 95% CI: 1.409- 29.593, P=0.016). Multivariate Cox proportional hazard regression analysis showed that miR-146b-5p expression levels were an independent prognostic factor for NSCLC patients (hazard ratio=0.259, 95% CI: 0.083-0.809, P=0.020). Furthermore, the effects of miR-146b-5p and miR-146b-3p on NSCLC cell growth and invasion in vitro were investigated. Our findings demonstrate that ectopic expression of miR-146b-5p suppressed cell proliferation, clonogenicity, migration/ invasion and also induced G1 arrest in vitro, but did not induce cell apoptosis; whereas enforced expression of miR-146b-3p did not have a significant effect on cell growth and metastasis. Further experiments indicated that miR-146b-5p could reduce mRNA levels of MMP16 and TRAF6 in vitro and was negatively related to the expression of TRAF6 in human NSCLC tissues. In a mouse model, Ago-miR-146b-5p could significantly inhibit the growth of lung cancer xenografts in nude mice. In conclusion, our findings demonstrate that miR-146b-5p functions as a suppressor miRNA and prognosis predictor in NSCLC.

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A small-cell lung cancer subtype with good prognosis found by a three miRNA signature

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