The Interaction of Calcium-Sensing Receptor with KIF11 Enhances Cisplatin Resistance in Lung Adenocarcinoma via BRCA1/cyclin B1 pathway.

Cisplatin (DDP) is commonly used in the treatment of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), and the primary cause for its clinical inefficacy is chemoresistance. Here, we aimed to investigate a novel mechanism of chemoresistance in LUAD cells, focusing on the calcium-sensing receptor (CaSR). In this study, high CaSR expression was detected in DDP-resistant LUAD cells, and elevated CaSR expression is strongly correlated with poor prognosis in LUAD patients receiving chemotherapy. LUAD cells with high CaSR expression exhibited decreased sensitivity to cisplatin, and the growth of DDP-resistant LUAD cells was inhibited by cisplatin treatment in combination with CaSR suppression, accompanied by changes in BRCA1 and cyclin B1 protein expression both in vitro and in vivo. Additionally, an interaction between CaSR and KIF11 was identified. Importantly, suppressing KIF11 resulted in decreased protein levels of BRCA1 and cyclin B1, enhancing the sensitivity of DDP-resistant LUAD cells to cisplatin with no obvious decrease in CaSR. Here, our findings established the critical role of CaSR in promoting cisplatin resistance in LUAD cells by modulating cyclin B1 and BRCA1 and identified KIF11 as a mediator, highlighting the potential therapeutic value of targeting CaSR to overcome chemoresistance in LUAD.

m6A modification of CDC5L promotes lung adenocarcinoma progression through transcriptionally regulating WNT7B expression.

Cell division cycle 5-like (CDC5L) protein is implicated in the development of various cancers. However, its role in the progression of lung adenocarcinoma (LUAD) remains uncertain. Our findings revealed frequent upregulation of CDC5L in LUAD, which correlated with poorer overall survival rates and advanced clinical stages. In vitro experiments demonstrated that CDC5L overexpression stimulated the proliferation, migration, and invasion of LUAD cells, whereas CDC5L knockdown exerted suppressive effects on these cellular processes. Furthermore, silencing CDC5L significantly inhibited tumor growth and metastasis in a xenograft mouse model. Mechanistically, CDC5L activates the Wnt/ß-catenin signaling pathway by transcriptionally regulating WNT7B, thereby promoting LUAD progression. Besides, METTL14-mediated m6A modification contributed to CDC5L upregulation in an IGF2BP2-dependent manner. Collectively, our study uncovers a novel molecular mechanism by which the m6A-induced CDC5L functions as an oncogene in LUAD by activating the Wnt/ß-catenin pathway through transcriptional regulation of WNT7B, suggesting that CDC5L may serve as a promising prognostic marker and therapeutic target for LUAD.

CT morphological features and histogram parameters to predict micropapillary or solid components in stage IA lung adenocarcinoma.

Objectives: This study aimed to construct prediction models based on computerized tomography (CT) signs, histogram and morphology features for the diagnosis of micropapillary or solid (MIP/SOL) components of stage IA lung adenocarcinoma (LUAC) and to evaluate the models' performance. Methods: This clinical retrospective study included image data of 376 patients with stage IA LUAC based on postoperative pathology, admitted to Putian First Hospital from January 2019 to June 2023. According to the presence of MIP/SOL components in postoperative pathology, patients were divided into MIP/SOL+ and MIP/SOL- groups. Cases with tumors ≤ 3 cm and ≤ 2 cm were separately analyzed. Each subgroup of patients was then randomly divided into a training set and a test set in a ratio of 7:3. The training set was used to build the prediction model, and the test set was used for internal validation. Results: For tumors ≤ 3 cm, ground-glass opacity (GGO) [odds ratio (OR) = 0.244; 95% confidence interval (CI): 0.103-0.569; p = 0.001], entropy (OR = 1.748; 95% CI: 1.213-2.577; p = 0.004), average CT value (OR = 1.002; 95% CI: 1.000-1.004; p = 0.002), and kurtosis (OR = 1.240; 95% CI: 1.023-1.513; p = 0.030) were independent predictors of MIP/SOL components of stage IA LUAC. The area under the ROC curve (AUC) of the nomogram prediction model for predicting MIP/SOL components was 0.816 (95% CI: 0.756-0.877) in the training set and 0.789 (95% CI: 0.689-0.889) in the test set. In contrast, for tumors ≤ 2 cm, kurtosis was no longer an independent predictor. The nomogram prediction model had an AUC of 0.811 (95% CI: 0.731-0.891) in the training set and 0.833 (95% CI: 0.733-0.932) in the test set. Conclusion: For tumors ≤ 3 cm and ≤ 2 cm, GGO, average CT value, and entropy were the same independent influencing factors in predicting MIP/SOL components of stage IA LUAC. The nomogram prediction models have potential diagnostic value for identifying MIP/SOL components of early-stage LUAC.

Based on machine learning, CDC20 has been identified as a biomarker for postoperative recurrence and progression in stage I & II lung adenocarcinoma patients.

Objective: By utilizing machine learning, we can identify genes that are associated with recurrence, invasion, and tumor stemness, thus uncovering new therapeutic targets. Methods: To begin, we obtained a gene set related to recurrence and invasion from the GEO database, a comprehensive gene expression database. We then employed the Weighted Gene Co-expression Network Analysis (WGCNA) to identify core gene modules and perform functional enrichment analysis on them. Next, we utilized the random forest and random survival forest algorithms to calculate the genes within the key modules, resulting in the identification of three crucial genes. Subsequently, one of these key genes was selected for prognosis analysis and potential drug screening using the Kaplan-Meier tool. Finally, in order to examine the role of CDC20 in lung adenocarcinoma (LUAD), we conducted a variety of in vitro and in vivo experiments, including wound healing assay, colony formation assays, Transwell migration assays, flow cytometric cell cycle analysis, western blotting, and a mouse tumor model experiment. Results: First, we collected a total of 279 samples from two datasets, GSE166722 and GSE31210, to identify 91 differentially expressed genes associated with recurrence, invasion, and stemness in lung adenocarcinoma. Functional enrichment analysis revealed that these key gene clusters were primarily involved in microtubule binding, spindle, chromosomal region, organelle fission, and nuclear division. Next, using machine learning, we identified and validated three hub genes (CDC45, CDC20, TPX2), with CDC20 showing the highest correlation with tumor stemness and limited previous research. Furthermore, we found a close association between CDC20 and clinical pathological features, poor overall survival (OS), progression-free interval (PFI), progression-free survival (PFS), and adverse prognosis in lung adenocarcinoma patients. Lastly, our functional research demonstrated that knocking down CDC20 could inhibit cancer cell migration, invasion, proliferation, cell cycle progression, and tumor growth possibly through the MAPK signaling pathway. Conclusion: CDC20 has emerged as a novel biomarker for monitoring treatment response, recurrence, and disease progression in patients with lung adenocarcinoma. Due to its significance, further research studying CDC20 as a potential therapeutic target is warranted. Investigating the role of CDC20 could lead to valuable insights for developing new treatments and improving patient outcomes.

Histones Methyltransferase NSD3 Inhibits Lung Adenocarcinoma Glycolysis Through Interacting with PPP1CB to Decrease STAT3 Signaling Pathway.

Histones methyltransferase NSD3 targeting H3K36 is frequently disordered and mutant in various cancers, while the function of NSD3 during cancer initiation and progression remains unclear. In this study, it is proved that downregulated level of NSD3 is linked to clinical features and poor survival in lung adenocarcinoma. In vivo, NSD3 inhibited the proliferation, immigration, and invasion ability of lung adenocarcinoma. Meanwhile, NSD3 suppressed glycolysis by inhibiting HK2 translation, transcription, glucose uptake, and lactate production in lung adenocarcinoma. Mechanistically, as an intermediary, NSD3 binds to PPP1CB and p-STAT3 in protein levels, thus forming a trimer to dephosphorylate the level of p-STAT3 by PPP1CB, leading to the suppression of HK2 transcription. Interestingly, the phosphorylation function of PPP1CB is related to the concentration of carbon dioxide and pH value in the culture environment. Together, this study revealed the critical non-epigenetic role of NSD3 in the regulation of STAT3-dependent glycolysis, providing a piece of compelling evidence for targeting the NSD3/PPP1CB/p-STAT3 in lung adenocarcinoma.

PFN1 Knockdown Aggravates Mitophagy to Retard Lung Adenocarcinoma Initiation and M2 Macrophage Polarization.

Tumor-associated macrophages (TAM) are considered as crucial influencing factors of lung adenocarcinoma (LUAD) carcinogenesis and metastasis. Profilin 1 (PFN1) has been proposed as a potent driver of migration and drug resistance in LUAD. The focus of this work was to figure out the functional mechanism of PFN1 in macrophage polarization in LUAD. PFN1 expression and its significance in patients' survival were detected by ENCORI and Kaplan-Meier Plotter. RT-qPCR and western blotting examined PFN1 expression in LUAD cells. CCK-8 assay and colony formation assay detected cell proliferation. Flow cytometry detected cell apoptosis. Relevant assay kit tested caspase3 concentration. Western blotting analyzed the expression of proliferation- and apoptosis-related proteins. RT-qPCR and immunofluorescence staining measured M1 and M2 macrophages markers. Mitophagy was assessed by MitoTracker Red staining, immunofluorescence staining, and western blotting. PFN1 expression was increased in LUAD tissues and cells and correlated with the poor survival rate of LUAD patients. Deficiency of PFN1 hindered the proliferation, whereas facilitated the apoptosis of LUAD cells. Additionally, PFN1 interference impaired M2 macrophage polarization. Moreover, PFN1 knockdown exacerbated the mitophagy in LUAD cells and mitophagy inhibitor mitochondrial division inhibitor 1 (Mdivi-1) notably reversed the effects of PFN1 down-regulation on the proliferation, apoptosis as well as macrophage polarization in LUAD cells. To sum up, activation of mitophagy initiated by PFN1 depletion might obstruct the occurrence and M2 macrophage polarization in LUAD.

Overexpression of ESYT3 improves radioimmune responses through activating cGAS-STING pathway in lung adenocarcinoma.

BACKGROUND: Radiotherapy can modulate systemic antitumor immunity, while immune status in the tumor microenvironment also influences the efficacy of radiotherapy, but relevant molecular mechanisms are poorly understood in lung adenocarcinoma (LUAD). METHODS: In this study, we innovatively proposed a radiotherapy response classification for LUAD, and discovered ESYT3 served as a tumor suppressor and radioimmune response sensitizer. ESYT3 expression was measured both in radioresistant and radiosensitive LUAD tissues and cells. The influence of ESYT3 on radiotherapy sensitivity and resistance was then investigated. Interaction between ESYT3 and STING was evaluated through multiple immunofluorescent staining and coimmunoprecipitation, and downstream molecules were further analyzed. In vivo models were constructed to assess the combination treatment efficacy of ESYT3 overexpression with radiotherapy. RESULTS: We found that radioresistant subtype presented immunosuppressive state and activation of DNA damage repair pathways than radiosensitive subtype. ESYT3 expression was remarkably attenuated both in radioresistant LUAD tissues and cells. Clinically, low ESYT3 expression was linked with radioresistance. Overexpression of ESYT3 enabled to alleviate radioresistance, and sensitize LUAD cells to DNA damage induced by irradiation. Mechanically, ESYT3 directly interacted with STING, and activated cGAS-STING signaling, subsequently increasing the generation of type I IFNs as well as downstream chemokines CCL5 and CXCL10, thus improving radioimmune responses. The combination treatment of ESYT3 overexpression with radiotherapy had a synergistic anticancer effect in vitro and in vivo. CONCLUSIONS: In summary, low ESYT3 expression confers resistance to radiotherapy in LUAD, and its overexpression can improve radioimmune responses through activating cGAS-STING-dependent pathway, thus providing an alternative combination therapeutic strategy for LUAD patients.

A disulfidptosis-related glucose metabolism and immune response prognostic model revealing the immune microenvironment in lung adenocarcinoma.

Background: Lung adenocarcinoma accounts for the majority of lung cancer cases and impact survival rate of patients severely. Immunotherapy is an effective treatment for lung adenocarcinoma but is restricted by many factors including immune checkpoint expression and the inhibitory immune microenvironment. This study aimed to explore the immune microenvironment in lung adenocarcinoma via disulfidptosis. Methods: Public datasets of lung adenocarcinoma from the TCGA and GEO was adopted as the training and validation cohort. Based on the differences in the expression of disulfidptosis -related genes, a glucose metabolism and immune response prognostic model was constructed. The prognostic value and clinical relationship of the model were further explored. Immune-related analyses were performed according to CIBERSORT, ssGSEA, TIDE, IPS. Results: We verified that the model could accurately predict the survival expectancy of lung adenocarcinoma patients. Patients with lung adenocarcinoma and a low-risk score had better survival outcomes according to the model. Moreover, the high-risk group tended to have an immunosuppressive effect, as reflected by the immune cell components, phenotypes and functions. We also found that the clinically relevant immune checkpoint CTLA-4 was significantly higher in low-risk group (P<0.05), indicating that the high-risk group may suffer worse tumor immunotherapy efficacy. Finally, we found that this model has accurate predictive value for the efficacy of immune checkpoint blockade in non-small cell lung cancer (P<0.05). Conclusion: The prognostic model demonstrated the feasibility of predicting survival and immunotherapy efficacy via disulfidptosis-related genes and will facilitate the development of personalized anticancer therapy.

Identifying potential therapeutic targets in lung adenocarcinoma: a multi-omics approach integrating bulk and single-cell RNA sequencing with Mendelian randomization.

Our research aimed to identify new therapeutic targets for Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer known for its low 5-year survival rate of 22%. By employing a comprehensive methodological approach, we analyzed bulk RNA sequencing data from 513 LUAD and 59 non-tumorous tissues, identifying 2,688 differentially expressed genes. Using Mendelian randomization (MR), we identified 74 genes with strong evidence for a causal effect on risk of LUAD. Survival analysis on these genes revealed significant differences in survival rates for 13 of them. Our pathway enrichment analysis highlighted their roles in immune response and cell communication, deepening our understanding. We also utilized single-cell RNA sequencing (scRNA-seq) to uncover cell type-specific gene expression patterns within LUAD, emphasizing the tumor microenvironment's heterogeneity. Pseudotime analysis further assisted in assessing the heterogeneity of tumor cell populations. Additionally, protein-protein interaction (PPI) network analysis was conducted to evaluate the potential druggability of these identified genes. The culmination of our efforts led to the identification of five genes (tier 1) with the most compelling evidence, including SECISBP2L, PRCD, SMAD9, C2orf91, and HSD17B13, and eight genes (tier 2) with convincing evidence for their potential as therapeutic targets.

In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma.

The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.

Enhanced CT-Based Intratumoral and Peritumoral Radiomics Nomograms Predict High-Grade Patterns of Invasive Lung Adenocarcinoma.

RATIONALE AND OBJECTIVES: Extraction of intratumoral and peritumoral radiomics features combined with clinical factors to establish nomograms to predict high-grade patterns (micropapillary and solid) of invasive adenocarcinoma of the lung (IAC). MATERIALS AND METHODS: A retrospective study was conducted on 463 patients with pathologically confirmed IAC. Patients were randomized in a 7:3 ratio into a training cohort (n = 324) and a testing cohort (n = 139). A total of 2154 CT-based radiomic features were extracted from each of the four regions: gross tumor volume (GTV) and gross peritumoral tumor volume (GPTV3, GPTV6, GPTV9) containing peri-tumor regions of 3 mm, 6 mm, and 9 mm. A radiomics nomogram was constructed based on the optimal radiomics model and clinically independent predictors. RESULTS: The GPTV3 radiomics model showed better predictive performance in the testing group compared to the GTV (0.840), GPTV6 (0.843), and GPTV9 (0.734) models, with an AUC value of 0.889 in the testing group. In the clinical model, tumor density and the presence of a spiculation sign were identified as independent predictors. The nomogram, which combined these independent predictors with the GPTV3-Radscore, proved to be clinically useful. CONCLUSION: The GPTV3 radiomics model was superior to the GTV, GPTV6, and GPTV9 radiomics models in predicting high-grade patterns (HGP) of IAC. In addition, nomograms based on GPTV3 radiomics features and clinically independent predictors can further improve the prediction efficiency.

Optimal treatment strategies for hepatoid adenocarcinoma of the lung: insights from a comprehensive analysis.

BACKGROUND: Hepatoid adenocarcinoma of the lung (HAL) is a distinctly uncommon subtype of lung adenocarcinoma (LAC), characterized by hepatoid features and an alarmingly low 5-year survival rate of approximately 8%. The scarcity of information on this condition has contributed to the absence of standardized treatment protocols, and the molecular underpinnings of its pathogenesis remain largely unexplored. To bridge these gaps, this study compiled data from 191 primary HAL patients to delineate treatment patterns, prognostic factors, and potential pathogenic mechanisms. METHODS: This study was divided into two cohorts: cohort 1, comprising 110 patients extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and cohort 2, consisting of 70 patients identified through a comprehensive literature review via the PubMed, Web of Science, and Scopus databases, in addition to 11 patients from Tongji Hospital. The Cox proportional hazards regression model was employed to identify independent prognostic factors. Kaplan-Meier survival curves were generated to assess the impact of treatment modalities centered around surgery and chemotherapy. Moreover, this study evaluated the efficacy of first-line treatment regimens and conducted Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses on identified mutated genes. RESULTS: The demographic and clinical profile of HAL patients typically comprises older individuals who are smokers, with a predisposition for diagnosis at advanced disease stages, culminating in a high mortality rate. Key prognostic indicators identified included disease stage, chemotherapy and surgical interventions. The study suggests a treatment strategy that advocates chemotherapy for patients with stage IV HAL and surgery for those with non-stage IV disease. The combination of paclitaxel and platinum-based chemotherapy emerged as an efficacious first-line treatment, with the integration of immunotherapy and targeted therapies showing potential benefits. Genetic analysis underscored similarities between HAL and LAC, particularly highlighting aberrant kinase activity (serine, threonine, and tyrosine) and the activation of PI3K-Akt and MAPK signaling pathways as contributing factors to HAL pathogenesis. CONCLUSION: Despite its relatively rare occurrence, this study underscores the significance of treatment strategies and concludes probable prognostic factors. Due to limited reports, a deeper understanding of the molecular mechanisms driving tumorigenesis and progression in HAL is needed.

Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

The Effect of Intracranial Control After Intracranial Local Therapy on the Prognosis of Patients with Brain Metastasis of Lung Adenocarcinoma.

Purpose: The aim of the present study was to assess the clinical outcomes and prognostic factors of lung adenocarcinoma patients with brain metastases (BMs) after intracranial local therapy. Patients and Methods: A total of 83 lung adenocarcinoma patients with BMs who underwent craniotomy combined with radiotherapy or intracranial radiotherapy alone were retrospectively analyzed. The intracranial tumor response was determined according to the Response Assessment in Neuro-Oncology of Brain Metastases (RANO-BM) criteria. The median overall survival (OS), intracranial progression-free survival (iPFS), and related prognostic factors were analyzed with the Kaplan‒Meier estimator method and Cox proportional hazards regression model. Results: Among 83 patients, 20 patients received craniotomy combined with radiotherapy, and 63 patients received intracranial radiotherapy alone. Following intracranial local therapy, 11 patients (13.3%) achieved complete response (CR); among them, 8 patients underwent neurosurgical resection. In addition, 32 patients (38.55%) achieved partial response (PR), 32 patients (38.55%) experienced stable disease (SD), and 8 (9.6%) experienced progressive disease (PD). The median follow-up period was 25.4 months (range 0.8-49.6 months). The median follow-up time for the iPFS was 16.2 months (range 0.6-41.2 months). The median OS, iPFS were 28.2 months and 24.7 months. Epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) mutations (HR 3.216, 95% confidence interval (CI) 1.269-8.150, p = 0.014) and iPFS (HR 0.881, 95% CI 0.836-0.929, p < 0.001) were found to be beneficial factors for OS. An intracranial-tumor CR was associated with a longer iPFS (PR: HR 0.052, 95% CI 0.009-0.297, p = 0.001; SD: HR 0.081, 95% CI 0.025-0.259, p < 0.001; PD: HR 0.216, 95% CI 0.077-0.606, p = 0.004). Conclusion: Prolonged iPFS was associated with better OS in lung adenocarcinoma patients with BMs following intracranial local therapy, and mutations of EGFR / ALK or an intracranial-tumor CR are independent prognostic factors for prolonged survival.

Ubiquitin-Specific Protease 22 Plays a Key Role in Increasing Extracellular Vesicle Secretion and Regulating Cell Motility of Lung Adenocarcinoma.

Tumor-derived extracellular vesicles (EVs) are potential biomarkers for tumors, but their reliable molecular targets have not been identified. The previous study confirms that ubiquitin-specific protease 22 (USP22) promotes lung adenocarcinoma (LUAD) metastasis in vivo and in vitro. Moreover, USP22 regulates endocytosis of tumor cells and localizes to late endosomes. However, the role of USP22 in the secretion of tumor cell-derived EVs remains unknown. In this study, it demonstrates that USP22 increases the secretion of tumor cell-derived EVs and accelerates their migration and invasion, invadopodia formation, and angiogenesis via EV transfer. USP22 enhances EV secretion by upregulating myosin IB (MYO1B). This study further discovers that USP22 activated the SRC signaling pathway by upregulating the molecule KDEL endoplasmic reticulum protein retention receptor 1 (KDELR1), thereby contributing to LUAD cell progression. The study provides novel insights into the role of USP22 in EV secretion and cell motility regulation in LUAD.

N6-methyladenosine-modified SRPK1 promotes aerobic glycolysis of lung adenocarcinoma via PKM splicing.

BACKGROUND: The RNA N6-methyladenosine (m6A) modification has become an essential hotspot in epigenetic modulation. Serine-arginine protein kinase 1 (SRPK1) is associated with the pathogenesis of various cancers. However, the m6A modification of SRPK1 and its association with the mechanism of in lung adenocarcinoma (LUAD) remains unclear. METHODS: Western blotting and polymerase chain reaction (PCR) analyses were carried out to identify gene and protein expression. m6A epitranscriptomic microarray was utilized to the assess m6A profile. Loss and gain-of-function assays were carried out elucidate the impact of METTL3 and SRPK1 on LUAD glycolysis and tumorigenesis. RNA immunoprecipitation (RIP), m6A RNA immunoprecipitation (MeRIP), and RNA stability tests were employed to elucidate the SRPK1's METTL3-mediated m6A modification mechanism in LUAD. Metabolic quantification and co-immunoprecipitation assays were applied to investigate the molecular mechanism by which SRPK1 mediates LUAD metabolism. RESULTS: The epitranscriptomic microarray assay revealed that SRPK1 could be hypermethylated and upregulated in LUAD. The main transmethylase METTL3 was upregulated and induced the aberrant high m6A levels of SRPK1. Mechanistically, SRPK1's m6A sites were directly methylated by METTL3, which also stabilized SRPK1 in an IGF2BP2-dependent manner. Methylated SRPK1 subsequently promoted LUAD progression through enhancing glycolysis. Further metabolic quantification, co-immunoprecipitation and western blot assays revealed that SRPK1 interacts with hnRNPA1, an important modulator of PKM splicing, and thus facilitates glycolysis by upregulating PKM2 in LUAD. Nevertheless, METTL3 inhibitor STM2457 can reverse the above effects in vitro and in vivo by suppressing SRPK1 and glycolysis in LUAD. CONCLUSION: It was revealed that in LUAD, aberrantly expressed METTL3 upregulated SRPK1 levels via an m6A-IGF2BP2-dependent mechanism. METTL3-induced SRPK1 fostered LUAD cell proliferation by enhancing glycolysis, and the small-molecule inhibitor STM2457 of METTL3 could be an alternative novel therapeutic strategy for individuals with LUAD.

Resected lung adenocarcinoma with lymph node metastasis: is ground glass opacity component a prognostic factor?

Background: Ground glass opacity (GGO)-featured lung adenocarcinoma generally has excellent prognosis, and here is rarely the occurrence of lymph node metastasis. We conducted a retrospective cohort study to explore the prognostic impact of GGO component in node-positive lung adenocarcinomas. Methods: A total of 669 patients with pathologic N1/N2 lung adenocarcinoma receiving R0 resection and systemic lymph node dissection from 2008 to 2015 were reviewed, including 635 solid and 34 part-solid lesions. Propensity score matching (PSM) was performed to compare survival outcomes of solid and part-solid lesions, in order to determine the prognostic value of GGO component. Cox proportional hazard model was performed to identify significant prognostic factors for resected node positive lung adenocarcinoma. Results: About 5.1% (34 of 669) of resected node-positive lung adenocarcinoma presented as part-solid nodules on computed tomography (CT) images in this cohort. The median nodule size on CT of the 34 part-solid lesions was 31 mm (range, 15-68 mm), median solid component size on CT was 24 mm (range, 12-62 mm), and median consolidation/tumor ratio was 0.8 (range, 0.64-0.95). After 1:4 PSM, 136 patients and 34 patients were matched from the solid and part-solid groups. No significant difference in either recurrence-free survival (RFS) (P=0.71) or overall survival (OS) (P=0.82) was found between the solid and part-solid groups. Multivariable Cox regression showed that pN stage was the strongest prognostic factor for RFS and OS. GGO component was not an independent prognostic factor toward for RFS [P=0.75; hazard ratio (HR) =0.93; 95% confidence interval (CI): 0.59-1.46] or OS (P=0.53; HR =1.19; 95% CI: 0.69-2.05). Conclusions: A minority of resected node-positive lung adenocarcinoma presents as GGO component on CT. The presence of GGO component does not predict better prognosis in node-positive lung adenocarcinoma.

Lymph node dissection of station 8 improves the survival of T≤3 cmN0M0 lung adenocarcinoma patients.

Background: Mediastinal station 8 lymph node dissection (8LND) is recommended by guidelines but not routinely performed in real world clinical practice. This study aimed to investigate the effect of 8LND on the prognosis of pT≤3 cmN0M0 lung adenocarcinoma. Methods: Patients undergoing lobectomy were retrospectively enrolled from West China Hospital from 2011 to 2019. Kaplan-Meier method and log-rank test were used to investigate the effects of 8LND on the progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). Propensity score matching (PSM) was used to reduce the confounding effects. Multivariable analysis was conducted to evaluate the effect of 8LND in the matched patients. Subgroup analyses were conducted to further identify patients who might benefit from 8LND. Results: A total of 1,209 patients were enrolled and 261 (21.59%) patients underwent 8LND. Before PSM, for patients who received 8LND (8LND+ patients) and who did not (8LND- patients), the 5-year PFS was 91.34%, 88.03% (P=0.03) respectively, the 5-year OS was 97.10%, 92.78% (P=0.03) respectively, and the 5-year CSS was 97.67%, 93.59% (P=0.05) respectively. After PSM, 8LND+ patients still had better PFS (P=0.006), OS (P=0.01), and CSS (P=0.03) as compared to 8LND- patients. Multivariable analyses showed that 8LND was associated with lower risk of disease progression [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.26-0.80; P=0.007], and lower risk of death (HR: 0.33; 95% CI: 0.13-0.85; P=0.02). The survival benefit of 8LND was still found in subgroup analyses in male patients, smokers, patients with a pT2 tumor (≤3 cm), and patients with a poorly differentiated tumor. Conclusions: 8LND could improve the survival of T≤3 cmN0M0 lung adenocarcinoma patients. Routine 8LND is recommended, especially in male, smokers, patients with a pT2 tumor (≤3 cm), and patients with a poorly differentiated tumor.

Sublobar resection for lung adenocarcinoma less than 2 cm containing solid or micropapillary components radiologically presented as consolidation-to-tumor ratio (CTR) ≤0.25 [ground-glass opacity (GGO)].

Background: The suitability of sublobar resection as a surgical approach for early-stage non-small cell lung cancer (NSCLC) remains unclear. This study investigated the feasibility of sublobar resection in patients with pathological-stage IA adenocarcinoma less than 2 cm characterized by a high-risk pathological subtype but exhibiting radiologically noninvasive features. Methods: We conducted a retrospective review of patients diagnosed with pathological stage IA lung adenocarcinoma who underwent surgical intervention between 2013 and 2017. The inclusion criteria included a maximum tumor diameter of 2.0 cm or less, a consolidation-to-tumor ratio (CTR) of 0.25 or less, and a histopathological confirmation of a solid or micropapillary component. Patients were categorized into sublobar resection and lobectomy groups, and propensity score matching was employed to mitigate potential confounders. The primary endpoints were lung cancer-specific survival (LCSS) and overall survival (OS). Results: The study comprised 149 patients, with 84 in the lobectomy group and 65 in the limited resection group. In the overall cohort, the 5-year LCSS was 100% for both groups, while the 5-year OS was 97.6% (95% CI: 94.41-100.00%) in the lobectomy group and 100% in the sublobar resection group (P=0.21). After propensity score matching, the LCSS remained at 100% for both groups, and the 5-year OS was 97.14% in the lobectomy group and 100% in the sublobar resection group (P=0.32). Conclusions: Based on our experience, for lung adenocarcinoma containing solid/micropapillary subtype, a size less than 2 cm, and a CTR ≤0.25, the oncological outcomes appeared to be comparable between sublobar resection and lobectomy, suggesting that sublobar resection might serve as an equivalent alternative to lobectomy for such lesions.

Identification of Biomarkers for Lung Adenocarcinoma With Qi Deficiency and Phlegm Dampness.

BACKGROUND: Qi deficiency and phlegm dampness (QPD) is one of the most common traditional Chinese medicine (TCM) syndromes in lung adenocarcinoma (LUAD). This study aimed to identify syndrome-specific biomarkers for LUAD with QPD syndrome. METHODS: Peripheral blood mononuclear cells (PBMCs) from LUAD patients with QPD, LUAD patients with non-QPD (N-QPD), and healthy control (H) were collected and analyzed with RNA-seq to identify differentially expressed genes (DEGs). The area under the receiver operator characteristic curve (AUC) of each DEG was calculated, and the top 10 highest AUC DEGs were validated by qRT-PCR. Logistic regression analysis was used to develop a diagnostic model evaluated with AUC. RESULTS: A total of 135 individuals were enrolled in this study (training set: 15 QPD, 15 N-QPD, 15 H; validation set: 30 QPD, 30 N-QPD, 30 H). A total of 1480 DEGs were identified between QPD and N-QPD. The qRT-PCR results showed that the expression of DDR2 was downregulated, and PPARG was upregulated, which was in line with the finding of the training set. We developed a diagnostic model with these two genes. The AUC of the diagnostic model in the training cohort and validation cohort was 0.891 and 0.777, respectively. CONCLUSIONS: We identified the two genes (DDR2 and PPARG) as syndrome-specific biomarkers for LUAD with QPD syndrome and developed a novel diagnostic model, which may help to improve the accuracy and sensibility of clinical diagnosis and provide a new target for natural drug treatment of LUAD.