Project description:Small-cell lung cancer (SCLC) represents about 13–15% of all lung cancers and with a five-year survival rate of less than 7%, it remains one of the most lethal forms of malignant diseases. It has a very aggressive course and is characterized by extensive chromosomal rearrangements, high mutation burden, and almost universal inactivation of the tumor suppressor genes TP53 and RB1. Therefore, the vast majority of SCLC patients are diagnosed with extensive-stage disease when surgery is not feasible and the treatment options are mostly limited to cytotoxic chemotherapy (CHT) and radiation. Importantly, targeted therapies for these patients have so far failed, and the success of immunotherapy in non-SCLC (NSCLC) has not been reflected in SCLC. Although SCLC has been formerly considered as a homogeneous disease with a single morphological type, recent advances in SCLC research have led to the development of subtype-specific classifications primarily based on neuroendocrine (NE) features and unique molecular profiles. Here, we investigate the general cell line characteristics on protein level, the relationship between the RNA-based classification and the protein expression profile, and the distinct biological processes specific for each subtype.
Project description:We report the gene expression profiles by NGFR knockdown in H460 and H1299 cell lines and reveal that NGFR ablation activates p53 target gene expression. We examined gene expression in two different non-small-cell lung cancer cell lines, one with wild-type p53 and the other without p53.
Project description:BackgroundCircular RNAs (circRNAs) are associated with propofol-mediated inhibitory effect on non-small cell lung cancer (NSCLC) progression. Circular hsa_circ_0003028 (circ_0003028) exerts a tumor-promoting role in NSCLC. However, it is unclear whether propofol can mediate NSCLC progression via regulating circ_0003028 expression.MethodsA total of 36 NSCLC patients were recruited in the study. Cell viability, proliferation, apoptosis, migration, and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays. Relative expression of circ_0003028 in NSCLC samples and cells was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Analysis of the latent binding of circ_0003028 to miR-1305 was done by bioinformatic analysis and confirmed by luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenografting in mice was done to verify the relationship between propofol and circ_0003028.ResultsSignificant upregulation of circ_0003028 was detected in NSCLC samples and cells. Functionally, propofol treatment reduced circ_0003028 expression in NSCLC cells, and circ_0003028 overexpression impaired propofol-mediated inhibitory effect on NSCLC cell proliferation, migration, and invasion. Interestingly, circ_0003028 could compete with miR-1305 as a competing endogenous RNA and upregulate CORO1C expression in NSCLC cells.ConclusionPropofol-mediated inhibiting effect on NSCLC growth partly depended on the circ_0003028/miR-1305/CORO1C axis.
Project description:We present data of global proteomes for non-small cell lung cancer for squamous cell and adenocarcinoma, and for normal adjacent tissue.
Project description:The doxorubicin-selected multidrug resistant small cell lung cancer cell line, H69AR, is cross-resistant to the Vinca alkaloids and epipodophyllotoxins, but does not overexpress P-glycoprotein, a 170 kDa plasma membrane efflux pump usually associated with this type of resistance. Monoclonal antibodies were raised against the H69AR cell line and one of these, MAb 3.186, recognises a peptide epitope on a 36 kDa phosphorylated protein that is membrane associated, but not presented on the external surface of H69AR cells (Mirski & Cole, 1991). In the present study, in vitro translation and molecular cloning techniques were used to determine the relative levels of mRNA corresponding to the 3.186 antigen. In addition, a cDNA clone containing an insert of approximately 1.4 kb was obtained by screening an H69AR cDNA library with 125I-MAb 3.186. Fragments of this cloned DNA hybridised to a single mRNA species of approximately 1.6 kb that was 5 to 6-fold elevated in H69AR cells. Partial DNA sequencing and restriction endonuclease mapping revealed identity of the cloned DNA with p36, a member of the annexin/lipocortin family of Ca2+ and phospholipid binding proteins.
Project description:Small-cell lung cancer (SCLC) represents about 15% of all lung cancers and is marked by an exceptionally high proliferative rate, strong predilection for early metastasis and poor prognosis. SCLC is strongly associated with exposure to tobacco carcinogens. Most patients have metastatic disease at diagnosis, with only one-third having earlier-stage disease that is amenable to potentially curative multimodality therapy. Genomic profiling of SCLC reveals extensive chromosomal rearrangements and a high mutation burden, almost always including functional inactivation of the tumour suppressor genes TP53 and RB1. Analyses of both human SCLC and murine models have defined subtypes of disease based on the relative expression of dominant transcriptional regulators and have also revealed substantial intratumoural heterogeneity. Aspects of this heterogeneity have been implicated in tumour evolution, metastasis and acquired therapeutic resistance. Although clinical progress in SCLC treatment has been notoriously slow, a better understanding of the biology of disease has uncovered novel vulnerabilities that might be amenable to targeted therapeutic approaches. The recent introduction of immune checkpoint blockade into the treatment of patients with SCLC is offering new hope, with a small subset of patients deriving prolonged benefit. Strategies to direct targeted therapies to those patients who are most likely to respond and to extend the durable benefit of effective antitumour immunity to a greater fraction of patients are urgently needed and are now being actively explored.
Project description:PurposeSrc family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.Patients and methodsPatients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.ResultsThirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.ConclusionDasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
Project description:Hexokinases II (HK2) is a hub in the regulation of cancer cell glycolysis. Here we reported deguelin, a natural compound which has been studied in various tumor types, has a profound anti-tumor effect on human non-small cell lung cancer (NSCLC) via directly down-regulating of glycolysis. In NSCLC cell lines and primary NSCLC tissue, we found HK2 is overexpressed. Deguelin treatment markedly inhibited anchorage-dependent and independent growth of NSCLC cell lines. We revealed that deguelin exposure impaired glucose metabolism by inhibiting Akt-mediated Hexokinase II expression, overexpression of constitutively activated Akt1 substantially rescued deguelin-induced glycolysis suppression. Moreover, deguelin suppressed HK2 presence on mitochondrial outer membrane and induced apoptosis. The in vivo data indicated that deguelin prominently restrained tumor development in a xenograft mouse model. Thus, deguelin appears to be a promising new therapeutic agent for lung cancer and may be considered for further studies in other animal models and in clinical trials.