Translational lung cancer research最新文献

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and accounts for about 40% of all lung cancer cases. This research aims to investigate the effects of miR-9-3p on ferroptosis in LUAD cells and to elucidate its regulatory mechanisms. Studies have shown that LUAD is related to ferroptosis, and specific microRNAs (miRNA) are also related to ferroptosis. However, further research is needed to elucidate the mechanisms by which miR-9-3p induces ferroptosis in LUAD.

Methods: Our study comprehensively analyzed multiple databases to investigate miR-9-3p expression in LUAD tissues. Quantitative polymerase chain reaction (qPCR) was utilized to detect miR-9-3p levels in LUAD cells and tissues, examining its prognostic significance. Reactive oxygen species (ROS) and superoxide dismutase (SOD) assays assessed the impact of miR-9-3p on lipid peroxidation in LUAD cells. Dual-luciferase reporter assays were conducted to evaluate the binding affinity between miR-9-3p and target genes, while Western blotting and immunofluorescence were used to examine the regulation of miR-9-3p on downstream signaling pathways.

Results: We observed that miR-9-3p was upregulated in LUAD cells by qPCR, and the ferroptosis of LUAD cells increased upon treatment with erastin following the transfection of miR-9-3p inhibitor. Cell Counting Kit-8 (CCK-8), ROS, and SOD activity assays confirmed that inhibiting miR-9-3p enhanced lipid peroxidation in LUAD cells, contributing to higher rates of ferroptosis. Subsequent dual-luciferase reporter assays validated spermidine/spermine N1-acetyltransferase 1 (SAT1) as a target gene of miR-9-3p. Further Western blot confirmed that miR-9-3p regulated the expression of SAT1 and p53 proteins in p53 wild-type (WT) LUAD cells. Rescue experiments demonstrated that SAT1 was necessary for miR-9-3p to promote cell proliferation and suppress ferroptosis in p53 WT LUAD cells. Additionally, the effect of miR-9-3p on ferroptosis in LUAD cells was regulated by p53 signaling pathway.

Conclusions: Overall, these findings demonstrate that miR-9-3p negatively regulates ferroptosis in LUAD cells through SAT1 and p53 signaling pathway, suggesting that miR-9-3p plays a crucial role in LUAD pathogenesis and targeting this miRNA with an inhibitor exhibits promising potential for the treatment of LUAD.

Background: Despite the importance of early diagnosis of lung cancer and wide availability of chest radiography, the detection of operable stage lung cancer on chest radiographs (CXRs) remains challenging. This study aimed to investigate the effectiveness of artificial intelligence (AI)-based CXR analysis for detecting operable lung cancers.

Methods: Patients who underwent lung cancer surgery at two referral hospitals between March 2020 and February 2021 were retrospectively included in this study. Preoperative CXRs of the patients were analyzed using commercial AI-based lesion detection software, and the results of lesion location and types obtained using the software were reviewed by radiologists and pulmonologists, with computed tomography (CT) as a reference standard for determining nodule characteristics. Factors influencing AI detection of lung cancer on CXR were assessed using logistic regression analysis.

Results: Among the 594 patients who underwent surgery for lung cancer (median age: 65 years, 51.3% male), the sensitivity of AI for detecting lung cancer on CXR was 57.7%, and it identified 86% of CXR-visible lung cancers. Detection rates of lung cancer by AI increased according to the disease stage: 42.5% for stage IA, 86.3% for stage IB, and 90.9% for stages II-III. The detection rate increased to over 60% from stage IA2 onwards when tumor size exceeded 1 cm. Regarding lesion type on CT, 8.3%, 46.8%, and 77.3% of non-solid, part-solid, and solid nodules, respectively, were detected by AI. Multivariable analysis showed that nodule location in the upper zone [odds ratio (OR) 2.78, P<0.001], peripheral region (OR 4.59, P<0.001), and solid lesion diameter (OR 1.20, P<0.001) were significantly associated with AI detection of lung cancer.

Conclusions: AI could be an effective tool for detecting operable lung cancer on CXRs, particularly when lesions are larger and located in the upper and peripheral regions.

Background: Patients diagnosed with non-small cell lung cancer (NSCLC) usually have a poor prognosis, so it is critical to identify effective biomarkers for prognosis prediction. The aim of this study is to establish a nomogram to evaluate the prognostic significance of blood markers in patients with NSCLC and provide reference for clinical work.

Methods: A total of 486 patients with NSCLC who were admitted to hospital from January 2009 to December 2019 were retrospectively analyzed. The cohort was divided into a training set (n=340) and a validation set (n=146). Eleven blood indicators were selected as prognostic parameters by the least absolute shrinkage and selection operator (LASSO) model to establish tumor marker inflammatory nutrition (TMIN) score. Univariate and multivariate regression analyses were performed to establish a TMIN-nomogram model for predicting overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic (ROC) survival curve, calibration curve and clinical decision curve analysis (DCA) were used to evaluate the predictive performance of the TMIN-nomogram model.

Results: The TMIN score were constructed for 11 of the most valuable prognostic variables, including white blood cells (WBCs), neutrophils (N), platelets (PLT), albumin (ALB), globulin (GLB), prealbumin (PAB), carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA21-1), fibrinogen (FIB), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR), and patients were divided into low-risk and high-risk groups using optimal cutovers. The TMIN score showed good predictive value for both OS and PFS. In addition, The TMIN score and sex, smoke, pathological classification, American Joint Committee on Cancer stage (AJCC stage), tumor diameter and Eastern Cooperative Oncology Group-performance status (ECOG-PS) and other clinical indicators showed a strong correlation. Univariate and multivariate analyses confirmed that TMIN score was an independent risk factor for OS and PFS in NSCLC patients. It is worth noting that the TMIN nomogram model of OS and PFS based on multivariate analysis combined with TMIN score has very good prognostic value for NSCLC patients.

Conclusions: TMIN is a promising predictor for PFS and OS in NSCLC patients. The TMIN-nomogram prediction model can be used as an effective tool for the comprehensive prognosis evaluation of NSCLC patients.

Background: The tumor immune microenvironment of anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma (LUAD) stratified by ALK fusion variants is poorly pictured. Hence, in this study, we aim to explore the immune heterogeneity of ALK⁺ LUAD across different ALK fusion variants and further investigate their significance on clinical prognosis.

Methods: A retrospective analysis was conducted on ALK⁺ LUAD patients (N=68). DNA and RNA-based next-generation sequencing (NGS) was performed to clarify the specific ALK fusion variants. Clinical and pathological characteristics were compared between long and short ALK variants. To research the immune heterogeneity, multi-fluorescence was carried out to explore the differences in immune properties, such as tumor-infiltrating lymphocyte (TIL) number, TIL subset, and tertiary lymphoid structures (TLS) development, between long and short ALK variants. Furthermore, the prognostic value of these characteristics was analyzed. Finally, the expression of lymphocyte-activation gene-3 (LAG3), one novel immune therapy target, was assessed across ALK⁺ LUAD.

Results: LUAD patients with short ALK fusion variant-driven tumors exhibited higher American Joint Committee on Cancer (AJCC) stage as well as larger tumor size than those with long ALK fusion variant-driven tumors. Compared to long ALK fusion variants, there were more TILs, especially natural killer (NK) cells, within short ALK variants. However, fewer TLS were established in cancers harboring short ALK variants than those with long ALK variants. In advanced-stage LUAD patients with ALK fusion, short ALK variants, hot immune status, and high-level NK cells were identified to be adverse prognostic factors, while high-level B cells, as well as the development of TLS, served as positive prognostic factors. As for LAG3 expression, LAG3⁺ immune cells were more enriched in short ALK variants than in long ALK variants.

Conclusions: LUAD patients with short ALK fusion variant-driven tumors exhibited worse prognosis than those with long ALK fusion variant-driven tumors. The tumor immune microenvironments are heterogeneous across different ALK fusion variants with short variants characterized by higher levels of TIL, especially NK cells, but by less TLS development than long variants ALK⁺ LUAD, which disfavor disease outcomes.

Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) among them. The KEAP1 gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The STK11 gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The STK11 gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of STK11 or KEAP1 abnormalities with the KRAS mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of STK11 and KEAP1 genes mutations with the KRAS gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with STK11-, KEAP1- and KRAS-mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.

Background: Perioperative treatment of locally advanced non-small cell lung cancer (NSCLC) is attracting attention. The effect of neoadjuvant tyrosine kinase inhibitor (TKI) therapy on postoperative long-term outcomes in patients with driver gene mutations remains unclear. The aim of this study was to clarify the long-term survival outcomes of patients with stage III NSCLC harboring driver gene mutations who received preoperative TKI therapy.

Methods: Between January 2016 and December 2018, 10 patients with clinical stage III NSCLC with driver gene mutations were treated with TKIs [epidermal growth factor receptor (EGFR) mutation, n=9; anaplastic lymphoma kinase (ALK) fusion, n=1]. One patient refused surgery. The remaining nine patients received sequential chemotherapy followed by surgery. Postoperatively, six patients received adjuvant chemotherapy, and TKIs were readministered in four patients.

Results: The main adverse events of TKIs were grade 3 liver damage and grade 3 skin rash, which required a change in the drug from gefitinib to afatinib and dose reduction, respectively. In all 10 patients, the radiological response to TKIs was greater than the partial response, and nine patients underwent radical surgery. Although viable cancer cells remained in all patients with EGFR mutations, a pathological complete response was obtained in the patient with ALK fusion. No mortality or major morbidity was observed perioperatively. Of the patients who underwent surgery, 3 were alive without recurrence, while 6 had distant metastasis, including 5 with brain metastasis. Seven of the nine patients who underwent surgery were still alive after a median follow-up period of 77.2 months.

Conclusions: Successful long-term outcomes were achieved after sequential targeted therapy and chemotherapy, followed by surgery for stage III NSCLC. However, it is noteworthy that postoperative treatment may have also contributed to minimizing postoperative recurrence.

Background: Anti-angiogenic agents, such as nintedanib and ramucirumab, when combined with docetaxel, are subsequent treatment options in patients with non-small cell lung cancer (NSCLC) who have failed on first-line chemotherapy or immunochemotherapy. However, to date, there are no validated predictive biomarkers for efficacy of anti-angiogenic therapies in this setting. The aim of this study was to explore whether genetic or genomic markers, alone or combined with clinical covariates, could be used to predict overall survival (OS) in patients with NSCLC who are eligible for treatment with nintedanib plus docetaxel.

Methods: LUME-BioNIS (NCT02671422) was a prospective, non-interventional study that assessed the efficacy and safety of nintedanib plus docetaxel in patients with relapsed/refractory NSCLC. The primary outcome was OS in relation to exploratory molecular biomarkers, alone or in combination with clinical covariates. Exploratory multivariate and univariate analyses were undertaken on putative biomarkers including clinical variables, somatic mutations, gene expression, immunological, and proliferation markers. Sub-analyses in patients with prior immunotherapy were performed.

Results: Of 260 enrolled patients, most patients received nintedanib plus docetaxel in the second-line (68.8%) or third-line (25.8%). After a median follow-up of 19.7 months, median OS was 8.1 months (95% confidence interval: 7.1-9.5). Univariate subgroup analysis indicated that the presence of liver/adrenal metastases, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥1, time since start of first-line therapy (<9 months), and response to first-line therapy had potential prognostic significance for OS. In multivariate analysis, the presence of brain/liver metastases and the presence of >2 metastatic sites at baseline were associated with OS. In univariate analyses in patients with prior immunotherapy, RNA expression levels of genes involved in cell proliferation, DNA damage repair, interferon signaling, and abundance of neutrophils had potential prognostic significance for OS.

Conclusions: Nintedanib plus docetaxel had promising activity and manageable safety in a real-world clinical setting. No new predictive biomarkers were identified to help select patients who may particularly benefit from anti-angiogenic therapy.

Background: Previous studies reported significant relationships between obesity and pulmonary dysfunction. Here, we investigated genetic alterations in the lung tissues of high fat diet (HFD) induced obese mouse through transcriptomic and molecular analyses.

Methods: Eight-week-old male C57BL/6J mice were fed either a normal chow diet (NCD) or HFD for 12 weeks. We performed RNA sequencing, functional analysis of altered genes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway data, Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, protein network analysis, quantitative real-time polymerase chain reaction, and Western blotting.

Results: We performed RNA sequencing analysis in the lung tissue of HFD mice. GO and KEGG pathway data presented higher expressions of genes related to lung fibrosis, and the changes of several pathways including regulation of nitrogen compound metabolic process, G protein-coupled receptor signaling, cancer pathway, and small cell lung cancer pathway. DAVID analysis and protein network analysis showed the changes of vascular endothelial growth factor, hypoxia-inducible factor-1 and rat sarcoma virus signaling related to vascular permeability, and protein network of MYC proto-oncogene gene related to cancer. In addition, we found increased protein and mRNA levels of the growth/differentiation factor 15 and alpha smooth muscle actin genes related to lung fibrosis in lung tissue of HFD mice.

Conclusions: HFD contributes to an increased risk of lung fibrosis and lung cancer. Thus, we propose that the genetic modulation and the molecular regulation of target pathways are essential to suppress pulmonary fibrosis in obese patients.