BackgroundReprogrammed energy metabolism as an emerging hallmark of cancer has recently drawn special attention since it facilitate cell growth and proliferation. Recently, long noncoding RNAs (lncRNAs) have been served as key regulators implicated in tumor development and progression by promoting proliferation, invasion and metastasis. However, the associations of lncRNAs with cellular energy metabolism in lung cancer (LC) need to be clarified.MethodsHere, we conducted bioinformatics analysis and found insulin-like growth factor binding protein 4–1 (IGFBP4–1) as a new candidate lncRNA located in the upstream region of IGFBP4 gene. The expression levels of lnc-IGFBP4–1, mRNA levels of IGFBP4 in 159 paired lung cancer samples and adjacent, histological normal tissues by qRT-PCR. Over-expression and RNA interference (RNAi) approaches were adopted to investigate the biological functions of lnc-IGFBP4–1. The intracellular ATP level was measured using the Cell Titer-Glo Luminescent Cell Viability Assay kit, and changes in metabolic enzymes were examined in cancer cells and normal pulmonary epithelial cells with qRT-PCR.ResultsOur results showed that lnc-IGFBP4–1 was significantly up-regulated in LC tissues compared with corresponding non-tumor tissues (P < 0.01), and its expression level was significantly correlated with TNM stage (P < 0.01) and lymph node metastasis (P < 0.05). Further investigation showed that overexpression of lnc-IGFBP4–1 significantly promoted LC cell proliferation in vitro and in vivo, while downregulation of endogenous lnc-IGFBP4–1 could inhibited cell proliferation and induce apoptosis. Moreover, we found lnc-IGFBP4–1 could influences ATP production levels and expression of enzymes including HK2, PDK1 and LDHA, in addition, decline in both ATP production and these enzymes in response to 2-DG and 2-DG-combined Rho123, respectively, was observed in lnc-IGFBP4–1-overespressing LC cells, indicative of an enhanced aerobic glycolysis rate. Finally, lnc-IGFBP4–1 was observed to negatively correlate with gene IGFBP4, and lower expression level of IGFPB4 was found after lnc-IGFBP4–1-overexpression was transfected into PC9 cells, higher expression level of IGFPB4 was also found after lnc-IGFBP4–1-downregulation was transfected into GLC-82 cells, which indicates that IGFBP4 may exert its targeting function regulated by lnc-IGFBP4–1.ConclusionsTaken together, these findings provide the first evidence that lnc-IGFBP4–1 is significantly up-regulated in LC tissues and plays a positive role in cell proliferation and metastasis through possible mechanism of reprogramming tumor cell energy metabolism, which suggests that lnc-IGFBP4–1 may be a promising biomarker in LC development and progression and as a potential therapeutic target for LC intervention.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0722-8) contains supplementary material, which is available to authorized users.

The genetic variations in NBS1 gene have been reported to be associated with cancer risk. The polymorphisms in 3'-untranslated region (3'-UTR) of NBS1 might affect gene's function and thus contribute to cancer susceptibility. We hypothesized that these polymorphisms of NBS1 are associated with the lung cancer risk. In two independent case-control studies conducted in Southern and Eastern Chinese, we genotyped three tagSNPs (rs14448, rs13312986 and rs2735383) in Southern Chinese and then validated the discovered association in Eastern Chinese. No significant association was observed for rs13312986 and rs14448; we only found that the rs2735383CC genotype had a significantly increased risk of lung cancer under a recessive genetic model in the total 1559 cases versus 1679 controls (odds ratio = 1.40, 95% confidence interval = 1.18-1.66, P = 0.0001) when compared with GG or GC genotypes; the rs2735383CC genotype carriers had lower messenger RNA and protein expression levels in tumor tissues than those of other genotypes as quantitative polymerase chain reaction and western blot shown. Luciferase assay revealed that the rs2735383C allele had a lower transcription activity than G allele, and the hsa-miR-629 but not hsa-miR-499-5P had effect on modulation of NBS1 gene in vitro. We further observed that the X-ray radiation induced more chromatid breaks in lymphocyte cells from the carriers of rs2735383CC homozygote than those from the subjects with other genotypes (P = 0.0008). Our data suggested that the rs2735383G>C variation contributes to an increased risk of lung cancer by diminishing gene's expression through binding of microRNA-629 to the polymorphic site in the 3'-UTR of NBS1 gene.

Extrachromosomal circular DNA (eccDNA) refers to a type of circular DNA that originate from but are likely independent of chromosomes. Due to technological advancements, eccDNAs have recently emerged as multifunctional molecules with numerous characteristics. The unique topological structure and genetic characteristics of eccDNAs shed new light on the monitoring, early diagnosis, treatment, and prediction of cancer. EccDNAs are commonly observed in both normal and cancer cells and function via different mechanisms in the stress response to exogenous and endogenous stimuli, aging, and carcinogenesis and in drug resistance during cancer treatment. The structural diversity of eccDNAs contributes to the function and numerical diversity of eccDNAs and thereby endows eccDNAs with powerful roles in evolution and in cancer initiation and progression by driving genetic plasticity and heterogeneity from extrachromosomal sites, which has been an ignored function in evolution in recent decades. EccDNAs show great potential in cancer, and we summarize the features, biogenesis, evaluated functions, functional mechanisms, related methods, and clinical utility of eccDNAs with a focus on their role in evolution and cancer.

Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its expression and thus cancer risk. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G and -1044A>T) with the Taqman assay, and we found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a decreased risk of lung cancer [odds ratio (OR) = 0.74; 95% confidence interval (CI) = 0.61-0.90 for TG, and OR = 0.62; 95% CI = 0.41-0.94 for GG] in an allele dose-response manner (adjusted P(trend) = 0.0005). Further stratification analysis showed that the protective role of the -1304G variant allele was more evident in low or normal body mass index (BMI) but restrained in the overweighters and that the -1304G variant genotypes interacted with BMI in reducing cancer risk (adjusted P(interaction) = 0.003). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 protein expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of lung cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to lung cancer.

Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53.