Prognosis Of Lung Cancer Patients Research Articles

KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a.

BackgroundKDM5C, a histone H3K4-specific demethylase, possess various biological functions in development of cancers. However, its relation to the microRNA (miRNA) regulation in lung cancer remains unknown. This study aims to study the regulatory role of KDM5C on modification of miR-133a in the progression of lung cancer.MethodsDifferentially expressed miRNAs were filtered from 34 paired lung cancer and paracancerous tissues. The correlation between miR-133a expression and the prognosis of lung cancer patients was determined by a bioinformatics website. Furthermore, malignant aggressiveness of lung cancer cells was detected after miR-133a upregulation by CCK-8, flow cytometry, and Transwell assays and in vivo tumorigenesis and metastasis experiments. Subsequently, we analyzed mRNA downregulated in cells overexpressing miR-133a using m microarray analysis and expounded the upstream regulatory mechanism of miR-133a using bioinformatics website prediction and functional validation.ResultsmiR-133a was reduced in lung cancer tissues, and patients with low expression of miR-133a have worse survival rates. miR-133a restoration curtailed growth and metastasis of lung cancer cells in vitro and in vivo. Moreover, miR-133a downregulated PTBP1 expression, whereas overexpression of PTBP1 attenuated the suppressive effect of miR-133a on lung cancer cell aggressiveness. The level of methylation modification of miR-133a was reduced in lung cancer cells. KDM5C inhibited the expression of miR-133a by promoting the demethylation modification of its promoter histone.ConclusionHistone demethylase KDM5C inhibits the expression of miR-133a by elevating the demethylation modification of the promoter histone of miR-133a, thereby promoting the expression of PTBP1, which finally accelerates lung cancer cell growth and metastasis.

Risk factors and survival analysis of arrhythmia following lung cancer surgery: a retrospective study.

BackgroundSurgical treatment of lung cancer is one of the important treatments for early-stage non-small cell lung cancer (NSCLC). However, arrhythmia, especially atrial fibrillation (AF) and supraventricular arrhythmia, are quite common among patients after surgical treatment of lung cancer. The impact of postoperative arrhythmia (PA) on survival is rarely reported. Our aim was to evaluate the risk factors of PA and its impact on overall survival (OS) after lung cancer surgery.MethodsA total of 344 patients diagnosed with NSCLC who underwent lung cancer surgery were enrolled in this study. These patients were divided into two groups based on the occurrence of PA. Univariate and multivariate logistic regression analyses were conducted to identify the risk factors of PA. The Kaplan-Meier method was applied to show the OS differences between the two groups.ResultsThe incidence of PA was 16% (55/344). Among these 55 patients, 20 had AF, 30 had sinus tachycardia, and 5 had premature beats. A total of 332 patients underwent lung cancer radical resection. Operation type (P<0.001), preoperative abnormal ECG (P=0.032), transfusion (P=0.016), postoperative serum potassium concentration (P=0.001) and clinical stage (P<0.05) were risk factors for PA. PA (HR 2.083, 95% CI, 1.334–3.253; P=0.001), age (HR 1.543, 95% CI, 1.063–2.239; P=0.025) and mediastinal lymph node metastasis (HR 2.655, 95% CI, 1.809–3.897; P<0.001) were independent prognostic risk factors for OS by multivariate cox analysis.ConclusionsWe identified PA as an independent prognostic risk factor to predict poor OS in patients who underwent lung cancer surgery and had risk factors for PA. We therefore provides guidance for PA in improving the prognosis of lung cancer patients.

Computational Insights into the Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl Ester for Treatment of Aberrant-EGFR Driven Lung Cancers.

The anticancer activities of Withaferin-A (Wi-A) and Withanone (Wi-N) from Ashwagandha and Caffeic Acid Phenethyl Ester (CAPE) from honeybee propolis have been well documented. Here, we examined the binding potential of these natural compounds to inhibit the constitutive phosphorylation of epidermal growth factor receptors (EGFRs). Exon 20 insertion mutants of EGFR, which show resistance to various FDA approved drugs and are linked to poor prognosis of lung cancer patients, were the primary focus of this study. Apart from exon 20 insertion mutants, the potential of natural compounds to serve as ATP competitive inhibitors of wildtype protein and other common mutants of EGFR, namely L858R and exon19del, were also examined. The potential of natural compounds was compared to the positive controls such as erlotinib, TAS6417 and poziotinib. Similar to known inhibitors, Wi-A and Wi-N could displace and binds at the ATP orthosteric site of exon19del, L858R and exon20, while CAPE was limited to wildtype EGFR and exon 20 insertion mutants only. Moreover, the binding free energy of the natural drugs against EGFRs was also comparable to the positive controls. This computational study suggests that Wi-A and Wi-N have potential against multiple mutated EGFRs, warranting further in vitro and in vivo experiments.

Exploring the Role and Mechanism of pAMPKα-Mediated Dysregulation of Brf1 and RNA Pol III Genes.

TF IIB-related factor 1 (Brf1) is a key transcription factor of RNA polymerase III (Pol III) genes. Our early studies have demonstrated that Brf1 and Pol III genes are epigenetically modulated by histone H3 phosphorylation. Here, we have further investigated the relationship of the abnormal expression of Brf1 with a high level of phosphorylated AMPKα (pAMPKα) and explored the role and molecular mechanism of pAMPKα-mediated dysregulation of Brf1 and Pol III genes in lung cancer. Brf1 is significantly overexpressed in lung cancer cases. The cases with high Brf1 expression display short overall survival times. Elevation of Brf1 expression is accompanied by a high level of pAMPKα. Brf1 and pAMPKα colocalize in nuclei. Further analysis indicates that the carcinogen MNNG induces pAMPKα to upregulate Brf1 expression, resulting in the enhancement of Pol III transcription. In contrast, inhibiting pAMPKα decreases cellular levels of Brf1, resulting in the reduction of Pol III gene transcription to attenuate the rates of cell proliferation and colony formation of lung cancer cells. These outcomes demonstrate that high Brf1 expression reveals a worse prognosis in lung cancer patients. pAMPKα-mediated dysregulation of Brf1 and Pol III genes plays important roles in cell proliferation, colony formation, and tumor development of lung cancer. Brf1 may be a biomarker for establishing the prognosis of lung cancer. It is a new mechanism that pAMPKα mediates dysregulation of Brf1 and Pol III genes to promote lung cancer development.

Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment.

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear.Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients.Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME.Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.

LncRNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 and predicts poor prognosis in lung cancer patients.

Objective:The purpose of this study was to explore the function and gene expression regulation of the newly identified lncRNA DPP10-AS1 in lung cancer, and its potential value as a prognostic biomarker.Methods:qRT-PCR and Western blot were conducted to detect the expression of DDP10-AS1 and DPP10 in lung cancer cell lines and tissues. The effects of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis, and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry, and xenograft animal experiments.Results:The novel antisense lncRNA DPP10-AS1 was found to be highly expressed in cancer tissues (P < 0.0001), and its upregulation predicted poor prognosis in patients with lung cancer (P = 0.0025). Notably, DPP10-AS1 promoted lung cancer cell growth, colony formation, and cell cycle progression, and repressed apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitated lung tumor growth via upregulation of DPP10 protein in a xenograft mouse model. Importantly, DPP10-AS1 positively regulated DPP10 gene expression, and both were coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 was found to associate with DPP10 mRNA but did not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributed to their coordinate upregulation in lung cancer.Conclusions:These findings indicated that the upregulation of the antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10. DPP10-AS1 may serve as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

Preoperative Body Weight and Albumin Predict Survival in Patients With Resectable Lung Neoplasms: Role of COPD

IntroductionThe impact of preoperative nutritional status on survival in lung cancer (LC) patients with underlying chronic obstructive pulmonary disease (COPD) is still unclear. We hypothesized that presurgical nutritional assessment may differentially predict mortality in patients with resectable LC with moderate COPD and relatively well-preserved nutritional status. MethodsNutritional assessment [body mass index (BMI), blood parameters including albumin and protein levels, and body weight loss], and other clinical parameters [cigarette smoking (CS) history, LC staging and histological subtypes, COPD severity, lung function, and adjuvant therapy] were evaluated in 125 patients from the LC Mar Prospective Cohort: 87 LC-COPD patients and 38 LC patients without COPD before thoracotomy. Ten-year overall survival (OS) was analyzed in all patients. ResultsPrior to thoracotomy, in LC-COPD patients compared to LC, BMI and albumin declined relatively, low levels of the parameters BMI, albumin, and total proteins were associated with poorer 10-year survival, especially in the LC-COPD. CS burden also correlated with impaired survival. COPD per se worsened the prognosis in LC patients. ConclusionsIn the present cohort of LC patients with resectable tumors and relatively well-preserved nutritional status, the parameters BMI and blood albumin and protein levels measured prior to thoracotomy predicted OS, especially in those with COPD. These are clinically relevant findings, since values of those nutritional parameters were within the normal ranges in the majority of the analyzed patients. A thorough nutritional preoperative assessment should be included in the study of patients with resectable LC, particularly in those with chronic airway obstruction.

Radiomics for Estimating Recurrence Risk of Patients with Lung Cancer by Using Survival Analysis

Because of the promotion of cancer screening, the number of patients with lung cancer detected at the early stage has increased. However, it was reported that 30-40% of the lung cancer patients at stage I relapsed. If the recurrence risk can be accurately predicted, it is possible to give medical care for improving the prognosis of lung cancer patients. The purpose of this study was to develop a method for the prediction of recurrence risk of patients with lung cancer by using survival analysis of radiomics approach. A public database was used in this study. Fifty patients (25 recurrences and 25 censored cases) classified as stage I or II were selected and their pretreatment computed tomography (CT) images were obtained. First, we selected one slice containing the largest tumor area and manually segmented the tumor regions. We subsequently calculated 367 radiomic features such as tumor size, shape, CT values, and texture. Radiomic features were selected by using least absolute shrinkage and selection (Lasso). Cox regression model and random survival forest (RSF) with the selected radiomic features were used for estimating the recurrence functions of fifty patients. The experimental result showed that average area under the curve (AUC) values of Cox regression model and RSF for the prediction accuracy were 0.81 and 0.93, respectively. Since our scheme can predict recurrence risk of patients with lung cancer by using non-invasive image examinations, it would be useful for the selection of treatment and the follow-up after the treatment.

PTEN/AKT upregulation of TMSB10 contributes to lung cancer cell growth and predicts poor survival of the patients.

PTEN/AKT signaling cascade is frequently activated in various cancers, including lung cancer. The downstream effector of this signaling cascade is poorly understood. β-Thymosin 10 (TMSB10) functions as an oncogene or tumor suppressors in cancers, whereas its significance in lung cancer remains unknown. In this study, we showed that the activation of PTEN/AKT signaling promoted the expression of TMSB10. Based on the TCGA database, TMSB10 was upregulated in lung cancer tissues and its overexpression was correlated with poor prognosis of lung cancer patients. Functional experiments demonstrated that TMSB10 knockdown suppressed, while its overexpression promoted the proliferation, growth, and migration of lung cancer cells. Apoptosis and epithelial-mesenchymal transition were also regulated by TMSB10. We therefore suggest that TMSB10 is a novel oncogene for lung cancer. Targeting TMSB10 may benefit lung cancer patients with activated PTEN/AKT signaling.

Prognostic and clinicopathological value of PD-L2 in lung cancer: A meta-analysis

ObjectiveThe prognostic role of programmed death ligand-2 (PD-L2) expression in lung cancer has been widely studied, however, the results are controversial. Accordingly, we investigated the prognostic and clinicopathological value of PD-L2 in patients with lung cancer in this meta-analysis. MethodsRelevant studies were systematically searched in the PubMed, Web of Science, EMBASE, ClinicalTrials.gov., Scopus, and Cochrane Library until July 10, 2020. The hazard ratio (HR), odds ratio (OR), and their corresponding 95% confidence intervals (CIs) were calculated. ResultsThirteen studies with 3107 participants were included. High PD-L2 expression was associated with poor overall survival (OS) (HR 1.248, 95% CI: 1.071–1.455, p = 0.004) and worse disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) (HR 1.224, 95% CI: 1.058–1.417, p = 0.007) in lung cancer. Furthermore, unfavorable OS was found in lung adenocarcinoma (HR 1.349, 95% CI: 1.051–1.731, p = 0.019), but not in other pathological types (HR 1.192, 95% CI: 0.982–1.447 p = 0.076) with higher PD-L2 expression in our subgroup analysis. Concerning the clinicopathological characteristics, high PD-L2 expression was associated with smoking (OR 0.725, 95% CI: 0.591–0.890, p = 0.002) and PD-L1 (OR 1.607, 95% CI:1.115–2.314, p = 0.011) and vascular invasion (OR 1.500, 95% CI: 1.022–2.203, p = 0.039). ConclusionPD-L2 overexpression might predict a poor prognosis in lung cancer patients after surgery. PD-L2 expression might be a potential biomarker for PD-1/PD-L1-targeted immunotherapy in lung cancer, which should be investigated in future studies.

Knockdown of SALL4 inhibits the proliferation, migration, and invasion of human lung cancer cells in vivo and in vitro.

BackgroundThis study aimed to investigate the SALL4 expression in lung cancer, determine if SALL4 regulates the biological functions of lung cancer cells at the cellular level, and clarify the possible mechanisms involved.MethodsImmunohistochemistry was used to detect the SALL4 expression messenger RNA (mRNA) in 62 cases of lung cancer tissue microarray. The correlation of SALL4 with the clinical pathological parameters and overall life cycle of patients and the impact of disease-free life cycle was analyzed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect the SALL4 expression in lung cancer cell lines and nude mouse models. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, colony-forming assay, and flow cytometry were used to detect the effects of interference with SALL4 expression on lung cancer cell proliferation and transplant tumor models; the effect of interference with SALL4 expression on the growth of transplanted tumors in vivo was also examined.ResultsSALL4 was highly expressed in lung cancer tissues and cell lines and was closely related to the patient’s TNM stage and lymph node metastasis. Compared to patients with a high SALL4 expression, those with a lower SALL4 expression had a longer overall and disease-free survival. The expression of SALL4 is an independent risk factor for the prognosis of lung cancer patients. Interference with SALL4 expression can significantly inhibit cell proliferation and clonal formation. Interfering with the expression of SALL4 can arrest the cells in the G0/G1 phase by inhibiting the expression of the cell cycle–related proteins, cyclin B, cyclin E, and cyclin D1. Furthermore, wound-healing and Transwell assays showed that interference with SALL4 expression could significantly inhibit the migration and invasion of lung cancer cells, while experiments in nude mice showed that interference with SALL4 expression could significantly inhibit the size and weight of transplanted tumors.ConclusionsSALL4 was highly expressed in lung cancer cell lines. Interference with the expression of SALL4 can effectively inhibit the proliferation, migration and invasion of lung cancer cells, promote cell cycle arrest, and play the function of tumor suppressor genes. SALL4 may be a new target for the diagnosis and treatment of lung cancer.

Regulation of extracellular and intracellular prolactin on cell proliferation and survival rate through GHR/JAK2/STAT3 pathway in NSCLC

Styrene increases serum prolactin (PRL) concentration. Hyperprolactinemia is associated with poor prognosis in lung cancer patients, but the mechanism of PRL action is unclear. The aims of this study were to (i) investigate the mechanism of PRL-action receptor in NSCLC cells (ii) measure whether PRL was secreted by NSCLC cells and its stimulatory mechanism in vitro and in vivo. We found that cell proliferation was increased after treatment of a pharmacological dose of PRL in A549 cells, which through up regulation of growth hormone receptor (GHR) and downstream of JAK2/STAT3/VEGF pathway. All NSCLC cells in the present study secreted PRL and expressed GHR, but not PRLR. Inhibition of GHR protein level led to decrease the PRL-induced cell proliferation. PRL was detected in NSCLC cells culture medium. Knockdown of intracellular PRL downregulated JAK2/STAT3 protein activities and GHR and VEGF protein levels. Furthermore, knockdown of intracellular PRL reduced the cell proliferation and the ability of colony-forming. In lung cancer tissues, PRL, GHR and VEGF levels were higher in the tumor tissues than in normal tissues and the protein expressions of these three proteins are positively correlated, respectively. High expression levels of both PRL and GHR cause a poor survival rate in lung cancer patients. Taken together, our results suggested that extracellular and intracellular PRL were involved in cell proliferation through GHR. Combination of in vitro and in vivo results, GHR and PRL are important targets for suppressing NSCLC cell proliferation, which might improve the survival rate in NSCLC patients.

Thoracic Surgery: The Era of Minimally Invasive Lobectomy

The contingent of VATS (video assistend thoracic surgery) lobectomies will continue to increase in the time to come. Thoracic surgery departments that do not integrate this procedure into their routine spectrum will have to justify themselves to referrers and clinic administrations and will have problems with the recruitment of training assistants as well. The advantages of minimally invasive lobectomy are impressive and the long-term oncological results are equivalent to open lobectomy. VATS lobectomies in non-intubated patients will increase significantly in the next few years and further reduce the invasiveness of the operation. The number of clinics that offer RATS (roboter assistend thoracic surgery) lobectomies will also increase as more companies bring robot systems onto the market, making them significantly cheaper. Better screening programs for risk patients for lung cancer, rapid advances in thoracic oncology and further minimization of surgical trauma in lung resections will significantly improve the overall therapy and prognosis for lung cancer patients in the years to come.

Circular RNA circ-PRKCI promotes lung cancer progression by binding to microRNA-1324 to regulate MECP2 expression.

We aimed to investigate the expression and specific molecular mechanism of circ-PRKCI in lung cancer (LCa). The relationship between the expression level of circ-PRKCI and the prognosis of patients was analyzed. The impacts of circ-PRKCI on the invasiveness of LCa cells were examined by Cell Counting Kit-8 (CCK-8) experiments, clone formation experiments, and transwell invasion experiments. Subcellular localization of circ-PRKCI was determined through nuclear separation experiments. Downstream target genes that can bind to circ-PRKCI was predicted through bioinformatics analysis, and was then verified by Dual-Luciferase experiments, quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) experiments, and Western blot experiments. Circ-PRKCI level was remarkably elevated in LCa tumor tissues and cell lines. At the same time, highly expressed circ-PRKCI was correlated with the poor prognosis of LCa patients. In vitro cell experiments revealed that inhibition of circ-PRKCI in LCa cell lines remarkably inhibited cell invasiveness and proliferation. In addition, circ-PRKCI can compete with MECP2 to bind microRNA-1324 and thus affect the progression of LCa. Our study shows for the first time that circ-PRKCI modulates the progression of LCa through microRNA-150-5p/MECP2 axis.

Correlation between preoperative 18F-FDG PET/CT findings and postoperative short-term prognosis in lung cancer patients with idiopathic interstitial pneumonia after lung resection.

The present study aimed to investigate the correlation between preoperative 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/CT findings and short-term survival in lung cancer patients with idiopathic interstitial pneumonia (IIP). We retrospectively reviewed the data of 425 patients who underwent lung resection for non-small cell lung cancer without preoperative radiation therapy between November 2012 and October 2017. The maximum SUV (SUVmax) in the IIP area except the lung cancer site was measured in each patient. Thirty-one of the 425 patients (7.3%) showed findings of IIP in chest CT. Five of the 31 patients (16.1%) developed acute exacerbation (AE) after lung resection (AE+group). Twenty-six of the 31 patients (83.9%) did not develop AE (AE- group). In the AE+group, 18F-FDG SUVmax in the IIP area was significantly higher (1.9±0.6 vs. 2.7±0.7, p=0.02) compared with that in the AE- group. The receiver operating characteristic analysis identified an SUVmax threshold score of 2.55 (p=0.02) for AE. There was no 90-day mortality in the patients with SUVmax < 2.55 (n=25). On the other hand, the 90-day mortality rate in patients with SUVmax ≥ 2.55 (n=6) was 33.3% (2 patients). 18F-FDG PET/CT may predict AE after lung resection and could be related to short-term survival in lung cancer patients with IIP. Further investigations are needed to improve the prognosis in patients with high SUVmax in the IIP area.

Analysis on risk factors of lung cancer complicated with pulmonary embolism

Pulmonary embolism (PE) is a potentially fatal complication and its morbidity together with fatalness will further increase when in patients with malignant tumors. Fast and accurate early diagnosis of PE thus seems considerably important. To explore the risk factors of lung cancer complicated with PE. A retrospective cohort study consisted of 40 lung cancer patients with PE (PE group) and 60 lung cancer patients without PE (non-PE group) were analyzed. The white blood cell (WBC) count, D-dimer and low-density lipoprotein (LDL) were higher in PE group than those in non-PE group (P<0.05), whereas the arterial partial pressure of oxygen (PaO2 ) in PE group was lower than that in non-PE group (P<0.05). Carcinoembryonic antigen (CEA) level between two groups also exhibited statistical difference (P<0.05). Those lung adenocarcinoma patients with stages III and IV tumor, coupled with deep venous thrombosis (DVT), having experienced bevacizumab treatment or platinum-based chemotherapy more likely suffered from PE (P<0.05). The multivariate analysis revealed that high D-dimer, chemotherapy, DVT, stages III to IV, adenocarcinoma were independent risk factors associated with PE (P<0.05). The overall survival time of patients in case group was significantly shorter than that in the control group with a median survival duration being 10.5months (95%CI, 8.95-12.05) and 16.8months (95%CI, 14.62-18.98), respectively, (P<0.01). High D-dimer, chemotherapy, DVT, stages III to IV and adenocarcinoma might have a positive correlation with PE, meanwhile, PE always predicted a poor prognosis in lung cancer patients.

Association between EGFR Gene Mutation and Antioxidant Gene Polymorphism of Non-Small-Cell Lung Cancer.

EGFR mutation status is considered as an important predictor of therapeutic responsiveness in non-small-cell lung carcinoma patients. Recent evidence suggests that antioxidant gene polymorphisms are potential predictors of lung cancer risk. Thus, stratification of EGFR mutation-related phenotypes by antioxidant gene polymorphism status can be an effective approach in terms of improving the prognosis of lung cancer patients. The present study was designed to evaluate the distribution frequency of antioxidant gene polymorphisms in lung adenocarcinoma, as well as its association with hotspot EGFR mutations. The study findings revealed that a statistically significant association exists between EGFR L858R mutation and AG + GG genotypes of SOD rs4880 polymorphism. Furthermore, the subgroup analysis data revealed that compared to AA genotype of SOD rs4880, AG + GG genotypes were significantly associated with advanced cancer stage and distant metastasis. Taken together, these findings can be utilized clinically to predict cancer aggressiveness, metastatic, potential and therapeutic responsiveness of lung cancer patients.

Preoperative Body Weight and Albumin Predict Survival in Patients With Resectable Lung Neoplasms: Role of COPD

IntroductionThe impact of preoperative nutritional status on survival in lung cancer (LC) patients with underlying chronic obstructive pulmonary disease (COPD) is still unclear. We hypothesized that presurgical nutritional assessment may differentially predict mortality in patients with resectable LC with moderate COPD and relatively well-preserved nutritional status. MethodsNutritional assessment [body mass index (BMI), blood parameters including albumin and protein levels, and body weight loss], and other clinical parameters [cigarette smoking (CS) history, LC staging and histological subtypes, COPD severity, lung function, and adjuvant therapy] were evaluated in 125 patients from the LC Mar Prospective Cohort: 87 LC-COPD patients and 38 LC patients without COPD before thoracotomy. Ten-year overall survival (OS) was analyzed in all patients. ResultsPrior to thoracotomy, in LC-COPD patients compared to LC, BMI and albumin declined relatively, low levels of the parameters BMI, albumin, and total proteins were associated with poorer 10-year survival, especially in the LC-COPD. CS burden also correlated with impaired survival. COPD per se worsened the prognosis in LC patients. ConclusionsIn the present cohort of LC patients with resectable tumors and relatively well-preserved nutritional status, the parameters BMI and blood albumin and protein levels measured prior to thoracotomy predicted OS, especially in those with COPD. These are clinically relevant findings, since values of those nutritional parameters were within the normal ranges in the majority of the analyzed patients. A thorough nutritional preoperative assessment should be included in the study of patients with resectable LC, particularly in those with chronic airway obstruction.

PRDX2 Promotes the Proliferation and Metastasis of Non-Small Cell Lung CancerIn VitroandIn Vivo

Purpose Previous studies have reported that the levels of PRDX2 were correlated with tumorigenicity, recurrence, and prognosis of patients with different cancers. We investigated the association between PRDX2 levels and the prognosis of lung cancer patients. We also measured PRDX2 expression of non-small cell lung cancer (NSCLC) cells and examined its roles in the proliferation and migration in vitro and in vivo. Methods We used the Kaplan–Meier plotter to analyze the survival of different levels of PRDX2 in lung cancer patients. The expression of PRDX2 in normal bronchial epithelial cell line and NSCLC cell lines was measured by qRT-PCR and western blot assays. Biological functions of NSCLC cells were detected by CCK8 and Transwell assays. We constructed tumor growth model using subcutaneously injection of nude mice and metastasis model by tail vein injection in vivo. The protein levels of proliferation related markers were measured by immunohistochemistry assay. Immunofluorescence method was used to detected EMT-related proteins. Results The high levels of PRDX2 were associated with bad prognosis in lung cancer patients, especially in patients with adenocarcinoma. The expression of PRDX2 in NSCLC cell lines was higher than normal bronchial epithelial cells. Knockdown of PRDX2 inhibited the proliferation, migration, and invasion in A549 cells, while overexpression of PRDX2 promoted the malignancy in NCI-H1299 cells in vitro. Silencing PRDX2 restrained tumor growth and repressed lung metastasis by EMT in vivo. Conclusion Our data indicates that PRDX2 functions as a protumor regulator and is involved in tumorigenesis and tumor progression of lung cancer.

Abstract 2991: Establishment of patient-derived cancer cell lines to elucidate the resistant mechanism of tyrosine kinase inhibitors

Abstract In non-small cell lung cancer (NSCLC), several somatic mutations such as EGFR and EML4-ALK have been identified in a significant subgroup of patients. Multiple clinical trials involving tyrosine kinase inhibitors (TKIs) have demonstrated significant improvement in the prognosis of lung cancer patients with these mutations. However, in clinic, lung cancer cells gradually acquire resistance to these inhibitors in a span of approximately 1 - 2 years. In TKI resistant lung cancer patients, next-generation sequencing of clinical samples from individual patients enables the detection of genetic alterations that contribute to drug resistance, such as EGFR T790M and EGFR C797S mutations. However, it does not always offer an appropriate treatment strategy for patients with acquired resistance. In contrast, the presence of living cancer cells allows researchers to biologically evaluate the roles of mutations or bypass pathways. For a thorough clarification of resistance mechanisms, living cancer cells, in addition to genomic information, are essential. In our report, we have established six patient-derived cancer cells (PDCs) from NSCLC patients who were treated with various TKIs and thereafter experienced disease progression. The success rate for PDCs was as high as 50% (6/12). Upon the established cell lines, 2 cases had EML4-ALK and the rest had EGFR mutation as an oncogene. After establishing the PDCs, TKI resistance was confirmed by MTS cell proliferation assay and 5 of 6 cases showed matched TKI resistance referring to the clinical background. To elucidate the adaptive resistant mechanisms in PDCs, Sanger sequence was performed and none of the gene mutations that have been previously reported to contribute to resistance to TKIs was detected. Next, to investigate the bypass pathway activation in these cell lines, we performed phospho-receptor tyrosine kinase (RTK) array screening. Interestingly, 4 of 5 cases showed activation of bypass RTK signaling and 3 of 4 cases obtained combined effectiveness with the additional RTK inhibitor. Furthermore, we have performed western blotting in 3 PDCs and detected that combination treatment attenuated the phosphorylation of the downstream molecules. In conclusion, by using PDCs, we have clarified the mechanism of acquired resistance and detected the treatment strategy to overcome these resistances. The findings suggest that PDCs may help develop precision medicine for TKI resistant patients. Citation Format: Tadashi Manabe, Hiroyuki Yasuda, Hideki Terai, Junko Hamamoto, Toshiki Ebisudani, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima. Establishment of patient-derived cancer cell lines to elucidate the resistant mechanism of tyrosine kinase inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2991.