Oncogenesis Of Lung Cancer Research Articles

Screening of Phosphoinositide-3 Kinase Inhibitors from Argemone mexicana Leaves

Background: Phosphoinositide 3 kinase belongs to the enzyme family which is responsible for the development of cellular trafficking and uncontrolled cellular division which in turn to cancer metastasis. Activation of the PI3k-Akt-mTOR pathway tends to promote oncogenesis in Lung Cancer and its mutation leads to resistance in EGFR tyrosine kinase inhibitors. Objective: Inhibition of the initial PI3k receptor through natural bioactive phytocompounds from Argemone mexicana that may prevent the side effects caused by the synthetic medication and improve the patient's life quality as natural medicine. Method: According to the previous research we did the Bioactive phytochemical screening from the methanol extract (AME) and powder (AMP) of A. mexicana leaf by analysing the GC-MS (Agilent), UPLC-QTOF-ESI-MS (Waters India Pvt Limited). Analyzed phytochemicals from the studies were subjected to molecular docking analysis using SeeSAR 9.2 software against PI3K (PDP ID: 4FA6) receptor. Result: GC-MS revealed 40 compounds including Cryptopine (17.5), beta-sitosterol (9.57), and Protopine (8.6) were found as major compounds. LC-MS analysis showed the presence of major compounds with 13 elements compared to the literature survey in both positive and negative ESI ranges. 29 compounds from the GC-MS and LC-MS were selected for analyzing the interaction between the cancer receptor-ligand complex according to the binding strategy. Conclusion: Phytoconstituents such as Galactitol, Succinic acid and N-feruloyltryamine from A. mexicana showed good binding affinity range and maximised hydrogen bonding that may assure possessing anticancer effect by controlling the PI3K pathway. This study would lead a major role in the preliminary screening of Drug Targets against the PI3K receptor.

Epigenetic regulation of stem cells in lung cancer oncogenesis and therapy resistance.

Epigenetics plays an important role in regulating stem cell signaling, as well as in the oncogenesis of lung cancer and therapeutic resistance. Determining how to employ these regulatory mechanisms to treat cancer is an intriguing medical challenge. Lung cancer is caused by signals that cause aberrant differentiation of stem cells or progenitor cells. The different pathological subtypes of lung cancer are determined by the cells of origin. Additionally, emerging studies have demonstrated that the occurrence of cancer treatment resistance is connected to the hijacking of normal stem cell capability by lung cancer stem cells, especially in the processes of drug transport, DNA damage repair, and niche protection. In this review, we summarize the principles of the epigenetic regulation of stem cell signaling in relation to the emergence of lung cancer and resistance to therapy. Furthermore, several investigations have shown that the tumor immune microenvironment in lung cancer affects these regulatory pathways. And ongoing experiments on epigenetics-related therapeutic strategies provide new insight for the treatment of lung cancer in the future.

Fusion gene recurrence in non-small cell lung cancers and its association with cigarette smoke exposure.

Lung cancer remains the leading cause of cancer-related deaths in the US despite novel treatment protocols, with about 235,000 new cases and 131,000 deaths expected from this cancer in 2021 alone. Lung adenocarcinoma and squamous cell carcinoma, which are both subtypes of non-small cell lung cancer, account for most lung cancer cases, and comparing the molecular signatures in these two cancers can identify novel mechanisms that contribute to non-small cell lung cancer oncogenesis. We, in this study, performed a comprehensive gene fusion profiling of these cancers, which is understudied in lung cancers. Using an alignment-free fusion detection tool, 'ChimeRScope', we screened for gene fusions in lung adenocarcinoma and squamous cell carcinoma datasets from The Cancer Gene Atlas database. Fusion profiles in these two cancer subtypes were essentially different with minimal overlap. Our analysis revealed a positive association of smoking to fusion frequency in lung adenocarcinoma but not in squamous cell carcinoma and identified several fusion genes that could be explored as markers associated with cigarette smoke exposure. We also identified differentially regulated pathways linked to E2F, G2M checkpoint, and MTORC1 signaling upregulated and P53 pathway downregulated in samples containing high fusions in lung adenocarcinoma. Our results indicate that downregulation of the P53 pathway leads to higher gene fusion formation in lung adenocarcinoma. This manuscript provides a strong rationale for investigating the molecular mechanisms of cigarette smoke-induced gene fusion formation associated with lung cancer. Novel recurrent fusions associated with cigarette smoke were identified in our study, which could further be investigated for patient stratification, personalized therapy, and therapeutic monitoring.

Association between long non-coding RNA HOTAIR polymorphism and lung cancer risk: A systematic review and meta-analysis.

Single nucleotide polymorphism (SNP) of long noncoding RNA (lnc)RNA has been reported to be an important factor in cancer development. Recently, lncRNA homeobox transcript antisense intergenic RNA (HOTAIR) was indicated to induce tumorigenesis of several cancer types, but the association between the SNP of lncRNA HOTAIR and lung cancer susceptibility has remained undetermined. The present meta-analysis aimed to investigate the effect of HOTAIR polymorphism on susceptibility to lung cancer. The PubMed, Ovid Medline, Embase and Cochrane Library databases were thoroughly searched. Studies containing data on the incidence of lung cancer in patients with different HOTAIR SNPs were included. The Hardy-Weinberg equilibrium was analyzed to determine genotype distribution and allele frequencies. The odds ratio (OR) was pooled to evaluate the association of different SNPs with the susceptibility to lung cancer. A total of six studies comprising 1,715 patients with lung cancer and 2,745 healthy controls were finally included. A total of 4 SNPs (rs12826786, rs1899663, rs920778 and rs4759314) were reported. Analyses for all of these SNPs individually indicated that the lncRNA HOTAIR rs1899663 C>A polymorphism was a risk factor for lung cancer (dominant mode, AA+CA vs. CC: OR=0.816, 95% CI=0.707-0.942, P=0.005). The present study was the first meta-analysis investigating the association between lncRNA HOTAIR and lung cancer susceptibility. The results indicated that the lncRNA HOTAIR rs1899663 C>A polymorphism is a risk factor for lung cancer. LncRNA HOTAIR may be of value in lung cancer screening, particularly for populations with high-risk factors, as well as prognosis prediction. Future investigations are required to further clarify the intrinsic mechanism of the role of HOTAIR in the oncogenesis of lung cancer.

Natural killer cell exhaustion in lung cancer

ObjectivesLung cancer is one of the most frequently diagnosed cancers worldwide. However, the potential causes of lung cancer oncogenesis are still unclear. This study aims to explore the phenomenon and mechanism of NK cell exhaustion in lung cancer and lay the foundation for developing a targeting strategy to ameliorate immune cell exhaustion in cancer. Materials and methodsNK cells were isolated from the blood samples of lung cancer patients and healthy volunteers. After culture in vitro, the colony forming ability, cytotoxicity, apoptosis and receptor expression of NK cells in the peripheral blood from the lung cancer patients and the volunteers were analyzed by flow cytometry and the corresponding methods. The correlation between the NK cell profile and lung cancer occurrence was analyzed as well. ResultsThe colony formation and cytotoxicity of the NK cells from the lung cancer group were significantly decreased compared to whose of the NK cells from volunteers. The expression of NKG2A was upregulated and CD226 was downregulated significantly in the lung cancer group compared with the control group. Furthermore, through correlation analysis, the colony forming level, cytotoxicity and CD226 expression level were significantly negatively correlated with lung cancer, and the expression level of NKG2A was significantly positively correlated with lung cancer. Moreover, the impaired colony formation of NK cells was significantly correlated with NK cell functional exhaustion in lung cancer. ConclusionsThe downregulated CD226 expression and the upregulated NKG2A expression may serve as potential markers of NK cells exhaustion in lung cancer.

Transcriptome analysis reveals key signature genes involved in the oncogenesis of lung cancer.

Previous studies have suggested potential signature genes for lung cancer, however, due to factors such as sequencing platform, control, data selection and filtration conditions, the results of lung cancer-related gene expression analysis are quite different. Here, we performed a meta-analysis on existing lung cancer gene expression results to identify Meta-signature genes without noise. In this study, functional enrichment, protein-protein interaction network, the DAVID, String, TfactS, and transcription factor binding were performed based on the gene expression profiles of lung adenocarcinoma and non-small cell lung cancer deposited in the GEO database. As a result, a total of 574 differentially expressed genes (DEGs) affecting the pathogenesis of lung cancer were identified (207 up-regulated expression and 367 down-regulated expression in lung cancer tissues). A total of 5,093 interactions existed among the 507 (88.3%) proteins, and 10 Meta-signatures were identified: AURKA, CCNB1, KIF11, CCNA2, TOP2A, CENPF, KIF2C, TPX2, HMMR, and MAD2L1. The potential biological functions of Meta-signature DEGs were revealed. In summary, this study identified key genes involved in the process of lung cancer. Our results would help the developing of novel biomarkers for lung cancer.

MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice?

Background Lung cancer (LC) development is a process that depends on genetic mutations. The DNA methylation, an important epigenetic modification, is associated with the expression of non-coding RNAs, such as microRNAs. MicroRNAs are particularly essential for cell physiology, since they play a critical role in tumor suppressor gene activity. Furthermore, epigenetic disruptions are the primary event in cell modification, being related to tumorigenesis. In this context, microRNAs can be a useful tool in the LC suppression, consequently improving prognosis and predicting treatment.Conclusion This manuscript reviews the main microRNAs involved in LC and its potential clinical applications to improve outcomes, such as survival and better quality of life.

Long non-coding RNA LCAL62 / LINC00261 is associated with lung adenocarcinoma prognosis

BackgroundMore than half of non-small cell lung cancer (NSCLC) patients present with metastatic disease at initial diagnosis with an estimated five-year survival rate of ~5%. Despite advances in understanding primary lung cancer oncogenesis metastatic disease remains poorly characterized. Recent studies demonstrate important roles of long non-coding RNAs (lncRNAs) in tumor physiology and as prognostic markers. Therefore, we present the first transcriptome analysis to identify lncRNAs altered in metastatic lung adenocarcinoma leading to the discovery and characterization of the lncRNA LCAL62 as a prognostic biomarker. Patients and methodsRNA-Seq, microarray, nanoString expression, and clinical data from 1,116 LUAD patients across six independent cohorts and 83 LUAD cell lines were used to discover and evaluate the survival association of metastasis associated lncRNAs. Coexpression and gene set enrichment analyses were used to establish gene regulatory networks and implicate metastasis associated lncRNAs in specific biological processes. ResultsOur integrative analysis discovered LCAL62 as the most down-regulated lncRNA in metastasis. Further low LCAL62 expression promoted aggressive phenotypes and regulated genes associated with metastasis (such as metastasis repressor FOXA2). Low LCAL62 expression corresponded to poor overall patient survival across five independent lung adenocarcinoma cohorts (n = 881) including our own nanoString validation cohort. ConclusionWe discovered that LCAL62 was down-regulated in lung cancer progression to promote invasive phenotypes, and lower expression was significantly associated with poor patient outcome and aggressive lung adenocarcinoma.

Analysis of the Expression of Cell Division Cycle-Associated Genes and Its Prognostic Significance in Human Lung Carcinoma: A Review of the Literature Databases.

Background Lung cancer (LC) has become the top cause responsible for cancer-related deaths. Cell division cycle-associated (CDCA) genes exert an important role in the life process. Dysregulation in the process of cell division may lead to malignancy. Methods Transcriptional data on CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases. Results CDCA1/2/3/4/5/7/8 expression levels were higher in lung adenocarcinoma tissues, and the CDCA1/2/3/4/5/6/7/8 expression levels were increased in squamous cell LC tissues compared with those in noncarcinoma lung tissues. The expression levels of CDCA1/2/3/4/5/8 showed correlation with tumor classification. The Kaplan–Meier Plotter database was employed to carry out survival analysis, indicating that increased CDCA1/2/3/4/5/6/7/8 expression levels were increased in squamous cell LC tissues compared with those in noncarcinoma lung tissues. The expression levels of P < 0.05). Only LC patients with increased CDCA3/4/5/8 expression were significantly related to lower post-progression survival (PPS) (P < 0.05). Only LC patients with increased CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases. CDCA8, INCENP, AURKB, and BIRC5); CORUM: 127: NDC80 kinetochore complex; M129: the PID PLK1 pathway; and GO: 0007080: mitotic metaphase plate congression, all of which were remarkably modulated since the alterations affected CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases. Conclusions Upregulated CDCA genes' expression levels in LC tissues probably play a crucial part in LC oncogenesis. The upregulated CDCA genes' expression levels are used as the potential prognostic markers to improve patient survival and the LC prognostic accuracy. CDCA genes probably exert their functions in tumorigenesis through the PLK1 pathway.CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases. CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases. CDCA gene family and patient survival data were examined for lung cancer (LC) patients from the GEPIA, Oncomine, cBioPortal, and Kaplan–Meier Plotter databases.

Молекулярные основы рака легких, вызванных радоном

Lung cancer is the most common form of malignant neoplasia and is one of the leading causes of cancer death. According to the World Health Organization (WHO), radon is the second leading cause of lung cancer after smoking. Exposure to radon leads to the death of cells of the bronchial epithelium of the lungs, which is accompanied by the release of a large amount of mitochondrial DNA. Free-circulating mitochondrial DNA (fc mtDNA) can serve as a kind of trigger for the transduction of pro-inflammatory signals in animal cells. The production of fc mtDNA can occur as a result of apoptosis processes. Any ionizing radiation, including alpha radiation, to which radon belongs, promotes the promotion of cell death both as a result of direct mechanical action on the cell due to reactive oxygen species (ROS), and due to the appearance of unrepairable damage to the genetic material. In addition, radon can alter the expression profile of miRNAs, which in turn can activate apoptosis and inflammation. Free-circulating mitochondrial DNA by activating the Nf-kb signaling pathway mediates the synthesis of proinflammatory cytokines, and as a result of this activation, inflammation develops, which is one of the key factors in lung cancer oncogenesis. This short review analyzes the molecular mechanisms of lung cancer associated with the carcinogenic effect of radon based on the analysis of the fc mtDNA level, the profile of the tissue-specific microRNA fraction, the level and spectrum of pro- and anti-inflammatory cytokines

Occupational exposure to volatile organic compounds affects microRNA profiling: Towards the identification of novel biomarkers

In the framework of a project aimed at finding novel predictive biomarkers of VOCs exposure-related diseases, the effect of exposure to ethylbenzene, toluene, and xylene has been analyzed in a group of painters (spray- and roller-painters) working in the shipyard industry. Airborne levels of solvents were higher in spray- than in roller-painters, and comparable to the Occupational Exposure Limits (OELs), particularly for toluene and xylene. The urinary concentration of each volatile organic compound (VOC) and of the corresponding metabolites were also concurrently measured. A set of oxidative stress biomarkers, i.e., the products of DNA and RNA oxidation, RNA methylation, and protein nitration, were measured, and found significantly higher at the end of the work shift. MicroRNA (MiRNA) expression was analyzed in the VOC-exposed workers and in a control group, finding 56 differentially expressed (DE) miRNAs at a statistically significant level (adjusted p ≤ 0.01). The Receiver-Operating Characteristic curves, computed for each identified miRNA, showed high sensitivity and specificity. A pathway analysis in the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that miRNA-1, which was found downregulated in exposed workers, is involved in the lung cancer oncogenesis. A subset of 10 miRNAs (out of the 56 DE) was selected, including those with the highest correlation to the urinary dose biomarkers measured at the end of work-shift. Multivariate ANOVA analysis showed a statistically significant correlation between the urinary dose biomarkers (both the VOCs urinary concentration and the VOCs’ metabolite concentration), and the identified miRNA subset, indicating that the exposure to low VOC doses may be sufficient to activate the miRNA response. Four miRNAs belonging to the subset strongly related to the VOCs and VOCs’ metabolites concentration were individuated, miR-589-5p, miR-941, miR-146b-3p and miR-27a-3p, with well-known implications in oxidative stress and inflammation processes.

MiR-629-3p-induced downregulation of SFTPC promotes cell proliferation and predicts poor survival in lung adenocarcinoma

The long-term prognosis of patients with lung cancer remains poor and thus it is imminent to further elucidate the molecular mechanism for the oncogenesis of lung cancer. In this study, we observed that surfactant protein C (SFTPC) expression was downregulated in human lung adenocarcinoma tissues and cell lines, and low SFTPC expression correlated with poor overall survival of lung adenocarcinoma patients. Moreover, we found that overexpression of SFTPC could inhibit lung cancer cell proliferation in vitro and in vivo, but downregulation of SFTPC showed the opposite results. Besides, it was observed that miR-629-3p expression was upregulated in human lung adenocarcinoma tissues and cell lines. More importantly, we found that miR-629-3p could downregulate SFTPC expression by directly binding to the SFTPC 3'-UTR and inhibit the regulatory effect of SFTPC on lung adenocarcinoma cell proliferation. In conclusion, these data suggested that miR-629-3p-meditated downregulation of SFTPC may promote lung adenocarcinoma progression.

Extracellular RNAs from lung cancer cells activate epithelial cells and induce neutrophil extracellular traps.

Neutrophil infiltration is frequently observed in lung cancer tissues. Extracellular RNAs (exRNAs) may facilitate tumor progression. The present study investigated the cross-talk of tumor exRNAs and neutrophil extracellular traps (NETs) in lung cancer. Lewis lung carcinoma (LLC) cells were cultured with the deprived sera. And the cell culture supernatants (CCS) were analyzed in vitro and in vivo. The results revealed that exRNAs from lung cancer CCS promoted the inflammatory cytokine interleukin-1β and reduced the vascular cell adhesion molecule-1 expression in lung epithelial cells. Lung cancer CCS-treated epithelial cells induced the production of NETs. By contrast, NETs reduced the tight junction protein claudin-5 in epithelial cells. Furthermore, NETs caused the necrosis of epithelial cells, which resulted in the release of exRNAs. In mice, lung cancer cells instilled in the lung recruited neutrophils and initiated NETs. In patients with lung cancer, NETs were also observed. These results suggested that exRNAs in the cell culture supernatant may indirectly induce NETs and contribute to lung cancer oncogenesis.

The expression level of fibulin-2 in the circulating RNA (ctRNA) of epithelial tumor cells of peripheral blood and tumor tissue of patients with metastatic lung cancer.

The Fibulins are a recently discovered family of extracellular matrix proteins. In this study, expression levels of the fibulin-2 (FBLN2) gene and its role in the formation of different metastatic foci were investigated in lung cancer patients. We analyzed 106 lung cancer patients and eight paraffin-embedded tissues, and 27 ethnical-, age- and sex-matched healthy controls for expression levels of the FBLN2 gene. cDNAs obtained from the enriched epithelial cells of peripheral blood lymphocytes and tumor tissues of patients were amplified with specific primers for the target FBLN2 gene and HPRT1 housekeeping gene using quantitative real-time polymerase chain reaction. FBLN2 gene expression levels of the enriched epithelial cells of peripheral blood lymphocytes were found to be decreased approximately twofold in all subsets of patients compared to healthy controls. Our results indicate a significant difference between patient subgroups and controls [F(4.124) = 14.846, p0.05] among patient subgroups: bone metastases versus non-metastatic groups (p = 0.997), bone versus brain metastases (p = 0994), bone metastases versus two primary tumors (p = 0.999), brain metastases versus two primary tumors (p = 0.999), brain metastases versus non-metastatic (p = 0.755), non-metastatic versus two primary tumors (p = 0.996), non-metastatic versus all other metastatic patients (p = 0.731). Moreover, we found a 50-fold upregulation of FBLN2 gene expression in paraffin-embedded tissues compared with the enriched epithelial cells ofperipheral blood lymphocytes of patients. In the study, the enriched epithelial cells of peripheral blood lymphocytes of decreased FBLN2 expression was found to be correlated with metastasis. The fibulin-2 molecules might induce the metastatic potential through interaction with the other molecules in the microenvironment, nevertheless, it is needed further research whether the importance of FBLN2 on lung cancer oncogenesis and as a biomarker for metastatic lung cancer.

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy

IntroductionThere is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. MethodsWe performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma. ResultsWe have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. ConclusionThese results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

&lt;em&gt;PRMT7&lt;/em&gt; contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with &lt;em&gt;HSPA5&lt;/em&gt; and &lt;em&gt;EEF2&lt;/em&gt;

BackgroundNon-small-cell lung cancer (NSCLC) constitutes the leading cause of cancer death in humans. Previous studies revealed the essential role of the protein arginine methyltransferase 7 (PRMT7) in promoting metastasis in breast cancer. However, its function and potential mechanism in NSCLC remain unclear.Materials and methodsThe gene expression of PRMT7 between lung cancer tissues and normal tissues was studied with online database (http://medicalgenome.kribb.re.kr/GENT/). NSCLC cell lines with specific gene overexpression were constructed with lentivirus transduction. Matrigel invasion and colony formation assays were performed to evaluate the invasion and colony formation abilities. Co-immunoprecipitation coupled with mass spectrometry analysis was performed to explore the potential interaction proteins of PRMT7. Bioinformatic analysis was performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases.ResultsOnline analysis of gene expression patterns revealed the relatively high expression of PRMT7 in lung cancer tissues. PRMT7 overexpression was able to promote the invasion and colony formation of A549 and SPC-A1 cells. A total of 19 in-common proteins shared by both NSCLC cell lines were identified to be interacting with PRMT7 and found to participate in a wide variety of pathways and protein–protein interactions according to bioinformatic analysis. Among them, HSPA5 and EEF2 were further investigated for their essential roles in PRMT7-promoted NSCLC cell invasion.ConclusionOur results suggested PRMT7 overexpression was able to promote metastasis in NSCLC possibly through the interaction with HSPA5 and EEF2, which provides the potential mechanism of oncogenesis in lung cancer.

Questioning the role of selected somatic PIK3C2B mutations in squamous non-small cell lung cancer oncogenesis.

PI3K signaling is frequently dysregulated in NSCLC-SQCC. In contrast to well characterized components of the PI3K signaling network contributing to the formation of SQCC, potential oncogenic effects of alterations in PIK3C2B are poorly understood. Here, a large cohort (n = 362) of NSCLC-SQCC was selectively screened for four reported somatic mutations in PIK3C2B via Sanger sequencing. In addition, two mutations leading to an amino acid exchange in the kinase domain (C1181, H1208R) were examined on a functional level. None of the mutations were identified in the cohort while well characterized hotspot PIK3CA mutations were observed at the expected frequency. Ultimately, kinase domain mutations in PI3KC2β were found to have no altering effect on downstream signaling. A set of SQCC tumors sequenced by The Cancer Genome Atlas (TCGA) equally indicates a lack of oncogenic potential of the kinase domain mutations or PIK3C2B in general. Taken together, this study suggests that PIK3C2B might only have a minor role in SQCC oncogenesis.

Molecular design and engineering of phosphopeptide ligands to target lung cancer polo-like kinase

Polo-like kinase (Plk) plays a central role in centrosome cycle and is closely associated with the oncogenesis of lung cancer. The protein consists of a catalytic kinase domain (KD) and a regulatory polo-box domain (PBD); either direct inhibition of the KD’s catalytic activity or indirect disruption of the PBD–substrate interaction can be used to potentially suppress the pathological activation of lung cancer Plk. Here, we reported a successful molecular design and engineering of phosphopeptide ligands to target Plk PBD domain by integrating in silico modeling and in vitro assay. In the procedure, a helical peptide segment hps was derived from dimerization interface of the complex crystal structure of domain dimer using bioinformatics approach, which was then used as sequence template to generate potent phosphopeptide binders of Plk PBD domain in terms of a systematic residue mutation profile. Fluorescence anisotropy assays were conducted to substantiate the findings and conclusions obtaining from the molecular engineering. Consequently, three helical phosphopeptides, including the native hps and its two mutants hps-m 1 and hps-m 2, were successfully designed that can independently rebind to Plk PBD domain with a moderate or high affinity (K d = 127, 26, and 5 μM, respectively). These peptide ligands can be considered as potent self-competitors to disrupt PBD dimerization in lung cancer metastasis. Structural and energetic analysis revealed that hydrophobic forces and van der Waals contacts confer strong stability for domain–peptide complex system, while hydrogen bonds and electrostatic interactions contribute specificity and selectivity to the complex recognition.

A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer.

Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC-mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB-EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention.

LIM and SH3 protein 1 promotes tumor proliferation and metastasis in lung carcinoma.

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. In the present study, we focused on LIM and SH3 protein 1 (LASP-1), a key molecule involved in the development of multiple cancers, and attempted to elucidate its effect on the oncogenesis of lung cancer. We determined the expression level of LASP-1 in lung cancer using reverse transcription-quantitative polymerase chain reaction and western blot analysis, and also studied the potential function of LASP-1 in lung cancer cell growth, apoptosis and migration by small interfering RNA transfection. The results revealed that the levels of LASP-1 mRNA and protein were abnormally high in lung cancer cells. Following RNA interference of LASP-1, the proliferation and migration ability of the human cancer cell line A549 were significantly decreased. In addition, fluorescence-activated cell sorting analysis indicated that the apoptotic process in the A549 cell line was induced by the silencing of LASP-1. Our study is the first to investigate the potential of LASP-1 in lung cancer, and revealed its significant role in regulating the growth and metastasis of lung cancer cells. The present study suggests that LASP-1 has potential as a therapeutic target in the treatment of lung cancer in the clinic.