Lung cancer is the most malignant human cancer worldwide, also with the highest incidence rate. However, small-cell lung cancer (SCLC) accounts for 14 % of all lung cancer cases. Approximately 10 % of patients with SCLC have brain metastasis at the time of diagnosis, which is the leading cause of death of patients with SCLC worldwide. The median overall survival is only 4.9 months, and a long-tern cure exists for patients with SCLC brain metastasis due to limited common therapeutic options. Recent studies have enhanced our understanding of the molecular mechanisms leading to meningeal metastasis, and multimodality treatments have brought new hopes for a better cure for the disease. This review aimed to offer an insight into the cellular processes of different metastatic stages of SCLC revealed by the established animal models, and into the major diagnostic methods of SCLC. Additionally, it provided in-depth information on the recent advances in SCLC treatments, and highlighted several new models and biomarkers with promises to improve the prognosis of SCLC.

MicroRNAs (miRNA) are a class of small, noncoding RNA molecules that regulate the expression of target genes. miRNA dysregulation is involved in carcinogenesis and tumor progression. In this study, we identified microRNA-1253 (miR-1253) as being significantly down-regulated in non-small-cell lung carcinoma (NSCLC) tissues and associated with advanced clinical stage, lymph node metastasis, and poor survival. The enhanced expression of miR-1253 significantly inhibited the proliferation, migration, and invasion of NSCLC cells in vitro. Bioinformatics analyses showed that miR-1253 directly targeted WNT5A (long isoform), which was confirmed using the dual-luciferase reporter assay. The inhibitory effects of miR-1253 on the growth and metastasis of NSCLC cells were attenuated and phenocopied by WNT5A (long) overexpression and knockdown, respectively. Consistent with the in vitro results, subcutaneous tumor and metastatic NSCLC mouse models showed that miR-1253 functions as a potent suppressor of NSCLC in vivo. Taken together, our findings indicated that miR-1253 inhibited the proliferation and metastasis of NSCLC cells by targeting WNT5A (long isoform) and provided new evidence of miR-1253 as a potential therapeutic target in NSCLC.

Esophageal cancer is a high incident cancer worldwide with poor survival and limited therapeutic options. Alterations of microRNAs are common in cancers, and many of these micro RNAs are potential therapeutic and diagnostic targets to treat these cancers. miR-10b-3p located in chromosome region 2q31.1, and its expression is frequently increased in esophageal squamous cell carcinoma (ESCC). However, the biological functions, clinical significance and therapeutic implications of miR-10b-3p in ESCC remain unclear. The expression levels of miR-10b-3p in ESCC specimens were analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Ectopic overexpression of miR-10b-3p in ESCC cells, mouse xenograft model, and metastasis model were used to evaluate the effects of miR-10b-3p on proliferation, and migration of cancer cells. Luciferase reporter assay and Western blot were performed to validate the potential targets of miR-10b-3p after the preliminary screening by computer-aided microarray analysis. We found that miR-10b-3p expression levels were significantly upregulated in the tumor tissues and serum samples of patients with ESCC. The expression levels of miR-10b-3p in both tumor tissues and serum samples were inversely associated with lymph node metastasis and clinical stages. We identified the expression level of miR-10b-3p in ESCC cancer samples as an independent prognostic marker of the overall survival rates of ESCC patients. We found more frequent hypomethylation of the CpG sites located upstream of the miR-10b-3p gene in the ESCC tissues compared with in the adjacent normal tissues, and the DNA methylation status of miR-10b-3p promoter region inversely correlated with the expression levels of miR-10b-3p. Ectopic overexpression of miR-10b-3p promoted cell proliferation, colony formation, migration and invasion in ESCC. While knockdown of miR-10b-3p had the opposite effects, particularly in promoting apoptosis. Mouse xenograft model confirmed that miR-10b-3p functions as a potent oncogenic miRNA in ESCC, which also promoting ESCC metastasis. Mechanistically, we found miR-10b-3p regulated FOXO3 expression by directly binding to the 3′-untranslated region. And systemic delivery of miR-10b-3p antagomir reduced tumor growth and inhibit FOXO3 protein expression in nude mice. Collectively, our findings suggested upregulated expression of miR-10b-3p caused by promoter hypomethylation contributed to the progression of ESCC; Thus, miR-10b-3p is a potentially effective biomarker for ESCC that could have further therapeutic implications.

MiR-769-5p suppressed cell proliferation, migration and invasion by targeting TGFBR1 in non-small cell lung carcinoma miR-769-5p suppressed cell proliferation, migration and invasion by targeting TGFBR1 in non-small cell lung carcinoma

Accumulating evidence indicates that miRNAs can be promising diagnostic and/or prognostic markers for various cancers. In this study, we identified a novel miRNA, miR-3607-3p, and its targets in non-small cell lung cancer (NSCLC). The expression of miR-3607-3p was measured and its correlation with patient prognosis was determined. Ectopic expression in NSCLC cells, xenografts, and metastasis models was used to evaluate the effects of miR-3607-3p on proliferation and migration of NSCLC. Luciferase assay and western blotting were performed to validate the potential targets of miR-3607-3p after preliminary screening by microarray analysis and computer-aided algorithms. We demonstrated that miR-3607-3p was downregulated in NSCLC tissues and that miR-3607-3p might act as an independent predictor for overall survival in NSCLC. Moreover, serum miR-3607-3p may be a novel and stable marker for NSCLC. We found that overexpression of miR-3607-3p inhibited cell proliferation, colony formation, migration and invasion, and hampered the cell cycle of NSCLC cell lines in vitro. Our results suggested that miR-3607-3p directly targets TGFBR1 and CCNE2. In accordance with in vitro studies, we confirmed that miR-3607-3p functions as a potent suppressor miRNA of NSCLC. We showed that miR-3607-3p agomir could reduce tumor growth and inhibit TGFBR1 and CCNE2 protein expression. Taken together, our findings indicate that miR-3607-3p can inhibit NSCLC cell growth and metastasis by targeting TGFBR1 and CCNE2 protein expression, and provide new evidence of miR-3607-3p as a potential non-invasive biomarker and therapeutic target for NSCLC. We first showed downregulation of miR-3607-3p in NSCLC tissues and demonstrated that miR-3607-3p may act as an independent predictor of overall survival. Serum miR-3607-3p may be a novel marker of patients with NSCLC. We further found that miR-3607-3p possesses the potency to suppress NSCLC growth and metastasis and induce cell cycle arrest by regulating TGFBR1 and CCNE2. Importantly, agomiR-3607-3p could reduce tumor growth and lung and brain metastasis and inhibit TGFBR1 and CCNE2 protein expression. Our findings suggest that miR-3607-3p is a tumor suppressor in NSCLC and holds promise as a prognostic biomarker and potential therapeutic target for NSCLC.

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. MicroRNAs (miRNAs) have been indicated as crucial actors in cancer biology. Accumulating evidence suggests that miRNAs can be used as diagnostic and prognostic markers for NSCLC. The purpose of this study was to characterize and identify the novel biomarker miR-4317 and its targets in NSCLC. The expression of miR-4317 was analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of miR-4317 on proliferation was evaluated through 3–4,5-dimethylthiazol-2-yl-5-3–carboxymethoxyphenyl-2-4-sulfophenyl-2H-tetrazolium (MTS) and colony formation assays, and cell migration and invasion were evaluated through transwell assays. The expression of target proteins and downstream molecules was analyzed by qRT-PCR and western blot. Dual-luciferase reporter assay was used to assess the target genes of miR4317 in NSCLC cells. Our results demonstrated that miR-4317 was downregulated in NSCLC tissues and serum, particularly in lymph node metastasis and advanced clinical stage tissues. Kaplan-Meier survival analysis showed that NSCLC patients with high expression of miR-4317 exhibited better overall survival (OS). Enhanced expression of miR-4317 significantly inhibited proliferation, colony formation, migration and invasion, and hampered cycles of NSCLC cell lines in vitro. Our results suggested that miR-4317 functions by directly targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2). In concordance with in vitro studies, mouse xenograft, lung, and brain metastatic studies validated that miR-4317 functions as a potent suppressor miRNA of NSCLC in vivo. Systemically delivered agomiR-4317 reduced tumor growth and inhibited FGF9 and CCND2 protein expression. Reintroduction of FGF9 and CCND2 attenuated miR-4317-mediated suppression of migration and invasion in NSCLC. Our results indicate that miR-4317 can reduce NSCLC cell growth and metastasis by targeting FGF9 and CCND2. These findings provide new evidence of miR-4317 as a potential non-invasive biomarker and therapeutic target for NSCLC.