Factor In Non-small Cell Lung Cancer Research Articles

Does High Standard Uptake Value on Positron Emission Tomography Preclude Sublobar Resection in Stage IA Non-Small Cell Lung Cancer ≤2cm?

Recent randomized trials have shown equivalent survival after sublobar resection (SLR) versus lobectomy in patients with clinical stage IA non-small cell lung cancer (NSCLC)≤2cm. High SUVmax is a known risk factor in NSCLC, yet limited data exists on whether a high SUV should preclude a SLR. This study aims to determine if there is an association between SUVmax and survival based on the extent of parenchymal resection. A retrospective review of a prospectively maintained institutional database was conducted to identify patients with clinical stage IA NSCLC≤2cm (2011-2020) treated with SLR or lobectomy. The primary outcome was cancer-specific survival (CSS). Secondary outcomes were overall survival (OS) and disease-free survival (DFS). 543 patients were identified; 36.8% had SLR and 63.2% had lobectomy. Baseline characteristics were similar. Patients who had SLR had significantly worse ECOG performance status and higher rates of comorbidities. 5-year CSS, OS, and DFS for the whole cohort were similar between SLR and lobectomy. A receiver operating characteristic curve estimated the SUVmax cutoff point to be 4.15. For the whole cohort, patients with SUVmax>4.15 had worse CSS compared to SUVmax≤4.15. However, there was no significant difference in 5-year CSS after SLR versus lobectomy in patients with SUVmax≤4.15 (98% in both groups; P=0.77) or patients with SUVmax>4.15 (90% versus 94% respectively; P=0.12). SUVmax may not be a useful clinical determinant of the extent of parenchymal resection in patients with cT1N0 NSCLC≤2cm. Patients treated by SLR had comparable survival to lobectomy, irrespective of PET avidity.

Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy

Anti-PD(L)-1 inhibition combined with platinum doublet chemotherapy (Chemo-IO) has become the most frequently used standard of care regimen in patients with non-small cell lung cancer (NSCLC). The negative impact of antibiotics on clinical outcomes prior to anti-PD(L)-1 inhibition monotherapy (IO) has been demonstrated in multiple studies, but the impact of antibiotic exposure prior to initiation of Chemo-IO is controversial. We assessed antibiotic exposures at two time windows: within 60 days prior to therapy (-60 d window) and within 60 days prior to therapy and 42 days after therapy (-60 + 42d window) in 2028 patients with advanced NSCLC treated with Chemo-IO and IO monotherapy focusing on objective response rate (ORR: rate of partial response and complete response), progression-free survival (PFS), and overall survival (OS). We also assessed impact of antibiotic exposure in an independent cohort of 53 patients. Univariable and multivariable analyses were conducted along with a meta-analysis from similar studies. For the -60 d window, in the Chemo-IO group (N = 769), 183 (24%) patients received antibiotics. Antibiotic exposure was associated with worse ORR (27% vs 40%, p = 0.001), shorter PFS (3.9 months vs. 5.9 months, hazard ratio [HR] 1.35, 95%CI 1.1,1.6, p = 0.0012), as well as shorter OS (10 months vs. 15 months, HR 1.50, 95%CI 1.2,1.8, p = 0.00014). After adjusting for known prognostic factors in NSCLC, antibiotic exposure was independently associated with worse PFS (HR 1.39, 95%CI 1.35,1.7, p = 0.002) and OS (HR 1.61, 95%CI 1.28,2.03, p < 0.001). Similar results were obtained in the -60 + 42d window, and also in an independent cohort. In a meta-analysis of patients with NSCLC treated with Chemo-IO (N = 4) or IO monotherapy (N = 13 studies) antibiotic exposure before treatment was associated with worse OS among all patients (n = 11,351) (HR 1.93, 95% CI 1.52, 2.45) and Chemo-IO-treated patients (n = 1201) (HR 1.54, 95% CI 1.28, 1.84). Thus, antibiotics exposure prior to Chemo-IO is common and associated with worse outcomes, even after adjusting for other factors. These results highlight the need to implement antibiotic stewardship in routine oncology practice.

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer

BackgroundEGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published.MethodsMedical records of patients with resectable NSCLC stage I–III diagnosed during 2015–2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher’s exact test. Survival analysis was done by cox-regression method.ResultsTotal 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity).ConclusionThe prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Prognostic value of lung immune prognostic index in non-small cell lung cancer patients receiving immune checkpoint inhibitors: a meta-analysis.

Until now, it has been difficult to accurately predict the efficacy of immunotherapy in patients with non-small cell lung cancer (NSCLC). A novel indicator, the lung immune prognostic index (LIPI), has shown relatively high prognostic value in patients with solid cancer. Therefore, this study aimed to further identify the association between LIPI and the survival of patients with NSCLC who receive immune checkpoint inhibitors (ICIs). Several electronic databases were searched for available publications up to April 23, 2023. Immunotherapy outcomes included overall survival (OS), progression-free survival (PFS), and hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analysis based on the study design and comparison of the LIPI was conducted. In this meta-analysis, 21 studies with 9,010 patients were included in this meta-analysis. The pooled results demonstrated that elevated LIPI was significantly associated with poor OS (HR = 2.50, 95% CI:2.09-2.99, p < 0.001) and PFS (HR = 1.77, 95% CI:1.64-1.91, p < 0.001). Subgroup analyses stratified by study design (retrospective vs. prospective) and comparison of LIPI (1 vs. 0, 2 vs. 0, 1-2 vs. 0, 2 vs. 1 vs. 0, 2 vs. 0-1 and 2 vs. 1) showed similar results. LIPI could serve as a novel and reliable prognostic factor in NSCLC treated with ICIs, and elevated LIPI predicts worse prognosis.

Zinc finger protein 263 upregulates interleukin 33 and suppresses autophagy to accelerate the malignant progression of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a complex disease that remains a major public health concern worldwide. One promising avenue for NSCLC treatment is the targeting of transcription factors that regulate key pathways involved in cancer progression. In this study, we investigated the role of the transcription factor ZNF263 in NSCLC and its impact on the regulation of IL33, apoptosis, and autophagy. Levels of ZNF263 in tissues and cell lines were identified, after which the effects of its knockdown on cellular malignant behaviors, apoptosis and autophagy were assessed. Based on bioinformatics analysis, ZNF263 was found to bind to IL33 promoter, their mutual relationship was confirmed, as well as the role of IL33 in the regulation of ZNF263. The involvement of ZNF263 in the growth of xenograft tumors was assessed using tumor-bearing nude mouse models. Experimental results revealed that ZNF263 was upregulated in NSCLC tissue samples and cell lines. Its expression level is positively correlated with cellular malignant behaviors. We further demonstrated that ZNF263 upregulated IL33 expression, which, in turn, promoted the proliferation and migration, inhibited apoptosis and autophagy in NSCLC cells. Furthermore, ZNF263 knockdown reduced the growth of xenograft tumors in nude mice. This finding suggests that the inhibition of ZNF263 or IL33 may represent a novel therapeutic strategy for NSCLC. Importantly, our results highlight the crucial role of transcription factors in NSCLC and their potential as therapeutic targets.

Populations particulières : patients de performance status 2 ou plus: Special populations: patients with performance status 2 or higher

Performance status (PS) is a measure of the patient’s overall condition. Karnofsky and ECOG (Eastern Cooperative Oncology Group) are the most widely used scales. A three-point conversion scale allows a strong correlation between both scores: ECOG 0-1 = Karnofsky 100-80 %, ECOG 2 = Karnofsky 60-70 %, ECOG 3-4 = Karnofsky 50-10 %. Numerous factors, whether linked to cancer or to comorbidities, can affect PS. PS remains a major independent prognostic factor in NSCLC (non small cell lung cancer) and SCLC (small cell lung cancer), despite its flawed reproducibility and the heterogeneity of cancer patients with poor PS. As a matter of fact, PS should be regarded as a stratification factor in research. All guidelines take PS into account as a therapeutic decision making tool, especially in the case of chemotherapy for metastatic NSCLC. Targeted therapy should be considered in case of metastatic disease with molecular targets regardless of PS, for its high effectiveness and good safety profile. Data regarding immunotherapy are rather sketchy. Tolerance seems to be fine. Findings regarding efficacy warrant careful selection of patients who might benefit from this therapy. In light of the European Medicines Agency call, let us build studies dedicated to patients as frail as they come and enroll them in clinical trials in such a way that they benefit, among others, from therapeutic advances. In order to apply clinical research findings to the general population, specific groups of patients should be more involved.1877-1203/© 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.

LncRNA PCBP1-AS1 mediated downregulation of ITGAL as a prognostic biomarker in lung adenocarcinoma.

Integrin alpha L (ITGAL) seemed to play a critical role in carcinogenesis and immune regulation. Nevertheless, the effects of ITGAL on non-small cell lung cancer (NSCLC) remain elusive. The present paper intended to determine the effects of ITGAL in NSCLC via the integration of bioinformatic analyses. In this study, we found that the mRNA and protein levels of ITGAL were downregulated in NSCLC tissues. Significantly, low ITGAL expression was related to poorer prognosis and increased malignancy of NSCLC. In addition, GO analysis and KEGG pathway analysis revealed that the coexpressed genes of ITGAL were predominantly associated with various immune-associated signaling pathways, like the T cell receptor signaling pathway, Th17 cell differentiation, chemokine signaling pathway, and NF-κB signaling pathway. Our result indicated that lncRNA-mediated downregulation of integrin alpha L expression was tightly related to immunocyte infiltration, immune modulators, and chemotactic factors in NSCLC, which potentially serves as a biomarker for clinical prognosis prediction and immunotherapy of NSCLC. This is the first comprehensive analysis of ITGAL in the prognosis, immune microenvironment, and immunotherapy of lung adenocarcinoma. ITGAL are promising biomarkers for predicting clinical outcomes and immunotherapy responses in patients with NSCLC.

Preoperative computed tomography-based tumoral radiomic features prediction for overall survival in resectable non-small cell lung cancer.

The purpose of this study was to evaluate whether preoperative radiomics features could meliorate risk stratification for the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. After rigorous screening, the 208 NSCLC patients without any pre-operative adjuvant therapy were eventually enrolled. We segmented the 3D volume of interest (VOI) based on malignant lesion of computed tomography (CT) imaging and extracted 1542 radiomics features. Interclass correlation coefficients (ICC) and LASSO Cox regression analysis were utilized to perform feature selection and radiomics model building. In the model evaluation phase, we carried out stratified analysis, receiver operating characteristic (ROC) curve, concordance index (C-index), and decision curve analysis (DCA). In addition, integrating the clinicopathological trait and radiomics score, we developed a nomogram to predict the OS at 1 year, 2 years, and 3 years, respectively. Six radiomics features, including gradient_glcm_InverseVariance, logarithm_firstorder_Median, logarithm_firstorder_RobustMeanAbsoluteDeviation, square_gldm_LargeDependenceEmphasis, wavelet_HLL_firstorder_Kurtosis, and wavelet_LLL_firstorder_Maximum, were selected to construct the radiomics signature, whose areas under the curve (AUCs) for 3-year prediction reached 0.857 in the training set (n=146) and 0.871 in the testing set (n=62). The results of multivariate analysis revealed that the radiomics score, radiological sign, and N stage were independent prognostic factors in NSCLC. Moreover, compared with clinical factors and the separate radiomics model, the established nomogram exhibited a better performance in predicting 3-year OS. Our radiomics model may provide a promising non-invasive approach for preoperative risk stratification and personalized postoperative surveillance for resectable NSCLC patients.

MiR-122-5p regulates the mevalonate pathway by targeting p53 in non-small cell lung cancer

The 5-year survival rate of non-small cell lung cancer (NSCLC) patients is very low. MicroRNAs (miRNAs) are involved in the occurrence of NSCLC. miR-122-5p interacts with wild-type p53 (wtp53), and wtp53 affects tumor growth by inhibiting the mevalonate (MVA) pathway. Therefore, this study aimed to evaluate the role of these factors in NSCLC. The role of miR-122-5p and p53 was established in samples from NSCLC patients, and human NSCLC cells A549 using the miR-122-5p inhibitor, miR-122-5p mimic, and si-p53. Our results showed that inhibiting miR-122-5p expression led to the activation of p53. This inhibited the progression of the MVA pathway in the NSCLC cells A549, hindered cell proliferation and migration, and promoted apoptosis. miR-122-5p was negatively correlated with p53 expression in p53 wild-type NSCLC patients. The expression of key genes in the MVA pathway in tumors of p53 wild-type NSCLC patients was not always higher than the corresponding normal tissues. The malignancy of NSCLC was positively correlated with the high expression of the key genes in the MVA pathway. Therefore, miR-122-5p regulated NSCLC by targeting p53, providing potential molecular targets for developing targeted drugs.

Antibiotic Treatment is an Independent Poor Risk Factor in NSCLC But Not in Melanoma Patients Who had Received Anti-PD-1/L1 Monotherapy

BackgroundAntibiotic treatment may reduce the efficacy of cancer immunotherapy by disrupting gut microbiome. We aimed to study the association of antibiotics and survival outcomes in advanced cutaneous melanoma and non–small-cell lung cancer (NSCLC) patients who had received anti-PD-1/L1 monotherapy. Patients and MethodsA total of 222 melanoma and 199 NSCLC patients had received anti-PD-1/L1 monotherapy in 5 Finnish hospitals between January 2014 and December 2020. Clinical characteristics, antibiotic and corticosteroid treatment, and survival outcomes were retrospectively collected from hospital and national medical records. ResultsThere were 32% of melanoma and 31% of NSCLC patients who had received antibiotic treatment (ABT) 3 months before to 1 month after the first anti-PD-1/L1 antibody infusion. In survival analyses, early antibiotic treatment was associated with inferior overall survival (OS) (ABT 19.2 [17.6-43.7] vs. no ABT 35.6 [29.3-NA] months, P = .033) but not with inferior progression-free survival (PFS) (ABT 5.8 [3.0-12.6] vs. no ABT 10.2 [7.7-15.3] months, P = .3) in melanoma patients and with inferior OS (ABT 8.6 [6.4-12.3] vs. no ABT 18.5 [15.1-21.6] months, P < .001) and PFS (ABT 2.8 [2.1-4.5] vs. no ABT 5.6 [4.4-8.0] months, P = .0081) in NSCLC patients. In multivariable analyses, ABT was not an independent risk-factor for inferior OS and PFS in melanoma but was associated with inferior OS (hazard ratio [HR] 2.12 [1.37-3.28]) and PFS (HR 1.65 [1.10-2.47]) in NSCLC after adjusted for other risk factors. ConclusionsEarly ABT was an independent poor risk factor in NSCLC patients who had received anti-PD-1/L1 monotherapy but not in melanoma patients. The weight of ABT as a poor risk factor might depend on other prognostic factors in different cancers.

Prognostic value of pretherapeutic FDG PET/CT in non-small cell lung cancer with pulmonary lymphangitic carcinomatosis

Pulmonary lymphangitic carcinomatosis (PLC) is associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). We sought to determine prognostic value of pretherapeutic fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in NSCLC with radiologically diagnosed PLC. We retrospectively reviewed 50 NSCLC patients with radiologically diagnosed PLC. Among eight clinical variables and five imaging parameters, metabolic PLC burden, which represents the overall tumor burden of PLC, and cPLC, which represents the location and extent of PLC in a three-grade system, were used. In multivariate analyses for progression-free survival, metabolic PLC burden (P = 0.0181), cPLC (P = 0.0401), and clinical stage (P = 0.0284) were identified as independent prognostic factors. High metabolic PLC burden had a worse prognosis, and the prognosis of cPLC3 was significantly worse than that of cPLC1 or cPLC2. In univariate analyses for overall survival, only age (P = 0.0073) was identified a prognostic factor. In conclusion, FDG PET/CT parameters were identified as independent prognostic factors in NSCLC with radiologically diagnosed PLC. Furthermore, a combination of anatomical and metabolic information about PLC obtained using FDG PET/CT provides insight into the overall tumor burden of PLC and is useful in predicting prognosis.

Populations particulières : patients de Performance Status 2 ou plus

Performance status (PS) is a measure of the patient’s overall condition. Karnofsky and ECOG (Eastern Cooperative Oncology Group) are the most widely used scales. A three-point conversion scale allows a strong correlation between both scores: ECOG 0-1 = Karnofsky 100-80%, ECOG 2 = Karnofsky 60-70%, ECOG 3-4 = Karnofsky 50-10%. Numerous factors, whether linked to cancer or to comorbidities, can affect PS. PS remains a major independent prognostic factor in NSCLC (non small cell lung cancer) and SCLC (small cell lung cancer), despite its flawed reproducibility and the heterogeneity of cancer patients with poor PS. As a matter of fact, PS should be regarded as a stratification factor in research. All guidelines take PS into account as a therapeutic decision making tool, especially in the case of chemotherapy for metastatic NSCLC. Targeted therapy should be considered in case of metastatic disease with molecular targets regardless of PS, for its high effectiveness and good safety profile. Data regarding immunotherapy are rather sketchy. Tolerance seems to be fine. Findings regarding efficacy warrant careful selection of patients who might benefit from this therapy. In light of the European Medicines Agency call, let us build studies dedicated to patients as frail as they come and enroll them in clinical trials in such a way that they benefit, among others, from therapeutic advances. In order to apply clinical research findings to the general population, specific groups of patients should be more involved.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Magnolol Induces Apoptosis Through Extrinsic/intrinsic Pathways and Attenuates NF-κB/STAT3 Signaling in Non-small-cell Lung Cancer Cells.

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear. Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4. Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins. Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC.

Dynamic monitoring circulating tumor DNA in plasma samples by PEAC technology for patients with early-stage non–small cell lung cancer after surgery.

8547 Background: Local recurrence or distant metastasis after surgery is not rare for early-stage Non-Small Cell Lung Cancer (NSCLC) patients. Present clinicopathological parameters, such as TNM stages and pathological subtype, are limited effective, as Positive Predictive Value (PPV) is low while Negative Predictive Value (NPV) is high. In recent years, circulating tumor DNA (ctDNA) has emerged as a noninvasive method for early diagnosis, prognostic stratification, disease surveillance, and treatment response evaluation. We assessed whether circulating tumor DNA (ctDNA) detected by PEAC technology could be a biomarker for minimal residual disease (MRD) and prediction of postoperative relapse in early-stage NSCLC. Methods: We enrolled 132 NSCLC patients with EGFR, KRAS, NRAS, BRAF and PIK3CA mutations, and obtained plasma samples at five perioperative time points (before surgery, 3-7 days, 6-months, 12-months and 18-months after surgery). Using PEAC technology, somatic mutations in plasma samples were identified and utilized for ctDNA-based MRD analysis. Clinical follow-ups were collected. Results: Our data showed that 32.0% (8 of 25) of patients with positive preoperative ctDNA experienced postoperative relapse, compared with 7.2% (6 of 83) in ctDNA negative patients, demonstrating that preoperative ctDNA status is an effective prognosis factor for NSCLC. In time point of 3-7 days after surgery, plasma samples were obtained from 47 patients, of which 33.3% (2 of 6) with positive ctDNA experienced postoperative relapse, while only 4.9% (2 of 41) in ctDNA negative patients. The result suggests that ctDNA positive in plasma samples of 3-7 days after surgery might be a strong biomarker for MRD detection and relapse prediction. For ctDNA surveillance, plasma samples from 6-months, 12-months and 18-months after surgery were collected and detected. At any one of the three tests ctDNA is positive, 20.0% (8 of 40) patients experienced clinical relapse, while 5.1% (3 of 59) patients with ctDNA negative status at all times relapse. A total of 14 recurrence events had occurred, ctDNA positivity precedes radiological recurrence by a median of 150.5 days (90.5 – 182, P = 0.006). Conclusions: Perioperative ctDNA analysis using PEAC technology is effective in early detection of MRD and relapse prediction, and hence could benefit NSCLC patient management in clinical settings. Clinical trial information: NCT03465241.

Interferon regulatory factor-1 regulates cisplatin-induced apoptosis and autophagy in A549 lung cancer cells

This study aimed to investigate the expression and function of interferon regulatory factor-1 (IRF-1) in non-small cell lung cancer (NSCLC). IRF-1 expression and its prognostic value were investigated through bioinformatic analysis. The protein expression levels of IRF-1, cleaved caspase 3, and LC3-I/II were analyzed by western blotting. A lentiviral vector was used to overexpress or knockdown IRF-1 in vitro. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. ATP, SOD, MDA, cell viability, LDH release, and caspase 3 activity were evaluated using commercial kits. Compared to the levels in normal tissues, IRF-1 expression was significantly lower in lung cancer tissues and was a prognostic factor for NSCLC. Cisplatin treatment-induced IRF-1 activation, ROS production, ATP depletion, SOD consumption, and MDA accumulation in A549 lung cancer cells. IRF-1 overexpression promoted mitochondrial depolarization, oxidative stress, and apoptotic cell death and inhibited autophagy in A549 cells, and these effects could be reversed by IRF-1 knockdown. These data suggest that IRF-1 regulates apoptosis, autophagy and oxidative stress, which might be served as a potential target for increasing chemotherapy sensitivity of lung cancer.

Identifying common signatures and potential therapeutic biomarkers in COPD and lung cancer using miRNA-mRNA co-expression networks

The association between non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) is now well established, as people with COPD are more likely to develop lung carcinoma. However, the evidence for this relationship is inconclusive and there is currently little information on the underlying molecular mechanisms. MicroRNAs (miRNAs) are one of the regulatory factors in NSCLC and COPD that their functions are widely studied in many chronic diseases and cancers. In this study, we applied systems biology approaches to identify and predict miRNAs that potentially play regulatory roles between COPD and NSCLC. We performed differential expression analysis on public miRNA and mRNA expression datasets, for both of diseases, and then we reconstructed two miRNA-mRNA co-expression networks and merged these two co-expression networks into a community co-expression network. Results indicated the existence of very common miRNAs (ex. hsa-miR-326 and hsa-miR-1293) and mRNAs (such as FAT2, ALOX5AP, and LDB2) between the two mentioned diseases. Moreover, we discovered specific miRNAs (hsa-miR-574-3p) that targeted common mRNAs. We utilized drug-target interaction networks to identify candidate drugs for common mRNAs, which can be considered in the treatment of two diseases (e.g. iloperidone). Generally, our study highlighted common miRNAs between COPD and NSCLC that as new signatures or biomarkers for therapeutic purposes. Investigating the miRNA biomarkers in this study improves our understanding about the shared mechanisms between COPD and NSCLC.

Pretreatment Albumin-to-Alkaline Phosphatase Ratio Is a Prognostic Marker in Lung Cancer Patients: A Registry-Based Study of 7077 Lung Cancer Patients.

Simple SummarySince the albumin-to-alkaline phosphatase ratio (AAPR) has shown promising prognostic prediction in cancer patients, the prognostic value of the AAPR was evaluated in a large cohort of 7077 lung cancer patients. We combined patient data from the Danish Lung Cancer Registry and the clinical laboratory information system (LABKA) and showed that a low AAPR was independently associated with an inferior median overall survival in non-small cell lung cancer patients and small cell lung cancer patients. Furthermore, data indicated a level-dependent correlation between the AAPR and survival and that the AAPR added additional prognostic value to the already well-established prognostic markers in lung cancer. Therefore, if our findings are validated in the future, the AAPR should be incorporated as a factor in the general prognostication of lung cancer patients.The albumin-to-alkaline phosphatase ratio (AAPR) is a novel promising prognostic marker in cancer patients. However, the evidence for its significance in lung cancer is scarce. Therefore, we assessed the prognostic value of the AAPR in a large cohort of lung cancer patients. Data on lung cancer patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and combined with data on the pretreatment serum AAPR level extracted from the clinical laboratory information system (LABKA). AAPR tertiles were applied as cutoffs. Cox proportional hazard models assessed the prognostic value of the AAPR. In total, 5978 non-small cell lung cancer (NSCLC) patients and 1099 small cell lung cancer (SCLC) patients were included. Decreasing AAPR level was significantly associated with declining median overall survival (OS) in NSCLC patients (medium vs. low AAPR, adjusted HR = 0.73 (95% confidence interval (CI) 0.68–0.79); high vs. low AAPR, adjusted HR = 0.68 (95% CI 0.62–0.73)) and in SCLC patients (medium vs. low AAPR, adjusted HR = 0.62 (95% CI 0.52–0.74); high vs. low, adjusted HR = 0.59 (95% CI 0.50–0.70)). In conclusion, the AAPR was an independent prognostic factor in NSCLC and SCLC patients. The correlation seems to be level dependent, with reducing survival found to be associated with decreasing AAPR level.

RETRACTED ARTICLE: Reduced LINC00467 elevates microRNA-125a-3p to suppress cisplatin resistance in non-small cell lung cancer through inhibiting sirtuin 6 and inactivating the ERK1/2 signaling pathway.

The non-coding RNAs have been identified as potential biomarkers in cancers. This study aimed to investigate the effect of long intergenic non-protein coding RNA 467 (LINC00467)/microRNA (miR-125a-3p)/sirtuin 6 (SIRT6) axis on non-small cell lung cancer (NSCLC). Expression of LINC00467, miR-125a-3p, SIRT6, and ERK1/2 signaling pathway-related factor in NSCLC was assessed. A549 and H1299 cells were induced by cisplatin (DDP) to establish DDP-resistant cell lines, and the drug resistance was detected. DDP-resistant cells were transfected with relative oligonucleotides and/or plasmids to observe the effects of LINC00467 and miR-125a-3p on NSCLC cells. The interaction among LINC00467, miR-125a-3p, and SIRT6 was detected using dual luciferase reporter gene assay and RNA pull-down assay. A tumor xenograft model was established, and Ki67 expression was detected in tumors. LINC00467 and SIRT6 were upregulated, miR-125a-3p was suppressed, and the ERK1/2 pathway was activated in NSCLC. LINC00467 or SIRT6 inhibition or miR-125a-3p elevation restricted malignancy and DDP resistance of NSCLC cells. Reduced miR-125a-3p reversed the effect of inhibited LINC00467 on NSCLC cells. LINC00467 competitively bound to miR-125a-3p, and miR-125a-3p targeted SIRT6. Inhibiting LINC00467 and SIRT6 or upregulating miR-125a-3p repressed tumor formation in vivo. LINC00467 silencing upregulates miR-125a-3p to decrease DDP resistance in NSCLC cells via inhibiting SIRT6 and inactivating the ERK1/2 signaling pathway.

TPD7 inhibits the non-small cell lung cancer HCC827 cell growth by regulating EGFR signalling pathway

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and is characterized by more insensitivity to chemotherapy and poor prognosis. Epidermal growth factor receptor (EGFR) has been confirmed as a tumorigenic driving factor of NSCLC. Taspine has been proved effective in the inhibition of malignant tumours. Here, we found TPD7, a novel taspine derivative, exerted most inhibitory effect on EGFR-dependent HCC827 cells and investigated the underling mechanism. In addition, TPD7 could block cell cycle at G0/G1 phase of HCC827 cells by regulating the expression of cyclin D1 and cyclin E. Furthermore, TPD7 induced HCC827 cell apoptosis by regulating the expression of BCL-2 family proteins. Further study revealed that TPD7 could down-regulate the phosphorylation of EGFR and downstream members. TPD7 might present a potential EGFR inhibitor in the treatment of NSCLC.

The circular RNA circ_GRHPR promotes NSCLC cell proliferation and invasion via interactions with the RNA-binding protein PCBP2.

As the most common malignancy, lung cancer is characterised by high rates of occurrence and mortality. Although circular RNAs (circRNAs) are known to act as important regulators in cancer, their role in lung cancer remains poorly understood. In this study, circ_GRHPR expression was found to be significantly upregulated in the serum of five patients with non‐small cell lung cancer (NSCLC), compared to that in healthy controls. It is expressed at high levels in NSCLC cell lines, as revealed by qRT‐PCR analysis. Functionally, we demonstrated that circ_GRHPR promotes NSCLC proliferation and invasion in vitro and in vivo by cell proliferation, transwell, cell cycle, and tumour‐forming assays. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays showed that circ_GRHPR interacts with the RNA‐binding protein poly(rC)‐binding protein 2 (PCBP2) and regulates its subcellular localisation by forming the circ_GRHPR/PCBP2 complex, localizing PCBP2 mainly in the cytoplasm and reducing the proportion found in the nucleus. Furthermore, we demonstrated that four‐and‐a‐half LIM‐only protein 3 (FHL3) is a tumour‐stimulating factor in NSCLC that interacts with and is influenced by PCBP2. Circ_GRHPR increased FHL3 expression in the nucleus of NSCLC cells by decreasing PCBP2 expression therein and promoting the proliferation and invasion of NSCLC cells. Therefore, our study identified that circ_GRHPR promotes NSCLC proliferation and invasion, providing a possible explanation for its mechanism of action.