METTL1/FOXM1 promotes lung adenocarcinoma progression and gefitinib resistance by inhibiting PTPN13 expression.

INTRODUCTION: Lung adenocarcinoma (LUAD) is the most common malignant tumor in respiratory system. Methyltransferase-like 1 (METTL1) is a driver of m7G modification in mRNA. This study aimed to demonstrate the role of METTL1 in the proliferation, invasion and Gefitinib-resistance of LUAD. METHODS: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells. RESULTS: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G-dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up-regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD.

Knockdown of GNL3 inhibits LUAD cell growth by regulating Wnt-ß-catenin pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of tumor-associated mortality, and it is needed to find new target to combat this disease. Guanine nucleotide-binding -protein-like 3 (GNL3) mediates cell proliferation and apoptosis in several cancers, but its role in LUAD remains unclear. OBJECTIVE: To explore the expression and function of Guanine nucleotide-binding protein-like 3 (GNL3) in lung adenocarcinoma (LUAD) and its potential mechanism in inhibiting the growth of LUAD cells. METHODS: We evaluated the expression of GNL3 in LUAD tissues and its association with patient prognosis using databases and immunohistochemistry. Cell proliferation was assessed by CCK-8 assay as well as colony formation, while apoptosis was evaluated by FCM. The effect of GNL3 knockdown on the Wnt/ß-catenin axis was investigated by Immunoblot analysis. RESULTS: GNL3 is overexpressed in LUAD tissues and is correlated with poor prognosis. Knockdown of GNL3 significantly inhibited the growth as well as induced apoptosis in A549 as well as H1299 cells. Furthermore, we found that the inhibitory effect of GNL3 knockdown on LUAD cell growth is associated with the downregulation of the Wnt/ß-catenin axis. CONCLUSION: GNL3 is key in the progression of LUAD by metiating Wnt/ß-catenin axis. Targeting GNL3 may represent a novel therapeutic method for LUAD treatment.

Successful Treatment of Switching EGFR-TKIs for Advanced Lung Adenocarcinoma Due to Interstitial Lung Disease: A Case Report.

INTRODUCTION: Icotinib and almonertinib are efficacious for non-small cell lung cancer (NSCLC) factor patients with epidermal growth receptor (EGFR)-mutation. Patients who previously used EGFR tyrosine kinase inhibitor (EGFR TKI) may switch to another one due to the adverse events. CASE PRESENTATION: Here, we report a case of a 73-year-old male patient with advanced lung adenocarcinoma in which an EGFR (exon 21 L858R substitution) was found. Icotinib (125mg three times daily) was administered initially. He achieved partial response two months later but developed acute interstitial lung disease (grade 2) with dry cough and chest tightness five months later. Icotinib was discontinued, and treatment with methylprednisolone improved the interstitial lung disease. Chemotherapy with pemetrexed, carboplatin, and bevacizumab was initiated as subsequent therapy. Considering the effectiveness of EGFR-TKIs, we decided cautiously to rechallenge the third-generation TKI almonertinib administration. The patient successfully received almonertinib for almost one year without the recurrence of interstitial lung disease and tumor progression. ILD was an infrequent but often life-threatening reaction associated with icotinib. CONCLUSION: This is the first reported case of successful switching from icotinib to another EGFR TKI because of interstitial lung disease associated with icotinib, suggesting that EGFR-TKIs rechallenge because of adverse events rather than progression might provide a significant benefit in patients with EGFR driver positive NSCLC.

Computed tomography radiomics study of invasion and instability of lung adenocarcinoma manifesting as ground glass nodule.

Background: Ground-glass nodule (GGN) is the most common manifestation of lung adenocarcinoma on computed tomography (CT). Clinically, the success rate of preoperative diagnosis of GGN by puncture biopsy and other means is still low. The aim of this study is to investigate the clinical and radiomics characteristics of lung adenocarcinoma presenting as GGN on CT images using radiomics analysis methods, establish a radiomics model, and predict the classification of pathological tissue and instability of GGN type lung adenocarcinoma. Methods: This study retrospectively collected 249 patients with 298 GGN lesions who were pathologically confirmed of having lung adenocarcinoma. The images were imported into the Siemens scientific research prototype software to outline the region of interest and extract the radiomics features. Logistic model A (a radiomics model to identify the infiltration of lung adenocarcinoma manifesting as GGNs) was established using features after the dimensionality reduction process. The receiver operating characteristic (ROC) curve of the model on training set and the verification set was drawn, and the area under the curve (AUC) was calculated. Second, a total of 112 lesions were selected from 298 lesions originating from CT images of at least two occasions, and the time between the first CT and the preoperative CT was defined as not less than 90 days. The mass doubling time (MDT) of all lesions was calculated. According to the different MDT diagnostic thresholds instability was predicted. Finally, their AUCs were calculated and compared. Results: There were statistically significant differences in age and lesion location distribution between the "noninvasive" lesion group and the invasive lesion group (P<0.05), but there were no statistically significant differences in sex (P>0.05). Model A had an AUC of 0.89, sensitivity of 0.75, and specificity of 0.86 in the training set and an AUC of 0.87, sensitivity of 0.63, and specificity of 0.90 in the validation set. There was no significant difference statistically in MDT between "noninvasive" lesions and invasive lesions (P>0.05). The AUCs of radiomics models B1, B2 and B3 were 0.89, 0.80, and 0.81, respectively; the sensitivities were 0.71, 0.54, and 0.76, respectively; the specificities were 0.83, 0.77, and 0.60, respectively; and the accuracies were 0.78, 0.65, and 0.69, respectively. Conclusions: There were statistically significant differences in age and location of lesions between the "noninvasive" lesion group and the invasive lesion group. The radiomics model can predict the invasiveness of lung adenocarcinoma manifesting as GGNs. There was no significant difference in MDT between "noninvasive" lesions and invasive lesions. The radiomics model can predict the instability of lung adenocarcinoma manifesting as GGN. When the threshold of MDT was set at 813 days, the model had higher specificity, accuracy, and diagnostic efficiency.

KLRB1 expression is associated with lung adenocarcinoma prognosis and immune infiltration and regulates lung adenocarcinoma cell proliferation and metastasis through the MAPK/ERK pathway.

Background: Lung cancer is the most common primary malignant tumor of the lung, and as one of the malignant tumors that pose the greatest threat to the health of the population, the incidence rate has remained high in recent years. Previous studies have shown that KLRB1 is transcriptionally repressed in lung adenocarcinoma and correlates with lung adenocarcinoma prognosis. The objective of this study is to investigate the intrinsic mechanisms by which KLRB1 affects the malignant phenotypes of lung adenocarcinoma such as immune infiltration, proliferation, growth and metastasis. Methods: We assessed the expression levels of KLRB1 in publicly available databases and investigated its associations with clinical and pathological variables. Enrichment analysis was subsequently conducted to investigate possible signaling pathways and their associated biological functions. Statistical analysis, including Spearman correlation and the application of multigene prediction models, was utilized to assess the relationship between the expression of KLRB1 and the infiltration of immune cells. The diagnostic and prognostic value of KLRB1 was evaluated using Kaplan-Meier survival curves, diagnostic receptor operating characteristic (ROC) curves, histogram models, and Cox regression analysis. Specimens from lung adenocarcinoma (LUAD) patients were collected, the expression level of KLRB1 was detected by protein blotting analysis, and the expression level of KLRB1 was detected at the mRNA level by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Small interfering RNA (siRNA) was used to silence gene expression, and Transwell, Cell Counting Kit-8 (CCK-8) and colony formation assays were subsequently performed to analyze the effects of KLRB1 on LUAD cell migration, invasion and proliferation. Results: KLRB1 expression was lower in lung cancer tissue than in surrounding healthy tissue. Genes differentially expressed in the low and high KLRB1 expression groups were found to be significantly enriched in pathways related to immunity. KLRB1 exerted an impact on the MAPK/ERK signaling pathway, thereby modulating the growth and proliferation of LUAD cells. KLRB1 expression is linked to prognosis, immune infiltration, and cell migration and proliferation in LUAD. Conclusions: The evidence revealed a correlation between KLRB1 and both prognosis and immune infiltration in LUAD patients.

CALU promotes lung adenocarcinoma progression by enhancing cell proliferation, migration and invasion.

BACKGROUND: Lung cancer is the second most common cancer with the highest mortality in the world. Calumenin as a molecular chaperone that not only binds various proteins within the endoplasmic reticulum but also plays crucial roles in diverse processes associated with tumor development. However, the regulatory mechanism of calumenin in lung adenocarcinoma remains elusive. Here, we studied the impact of calumenin on lung adenocarcinoma and explored possible mechanisms. METHODS: 5-ethynyl-2'-deoxyuridine assay, colony formation, transwell and wound healing assays were performed to explore the effects of calumenin on the proliferation and migration of lung adenocarcinoma cells. To gain insights into the underlying mechanisms through which calumenin knockdown inhibits the migration and proliferation of lung adenocarcinoma, we performed Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis and Ingenuity Pathway Analysis based on transcriptomics by comparing calumenin knockdown with normal A549 cells. RESULTS: The mRNA and protein levels of calumenin in lung adenocarcinoma are highly expressed and they are related to an unfavorable prognosis in this disease. Calumenin enhances the proliferation and migration of A549 and H1299 cells. Gene Set Enrichment Analysis revealed that knockdown of calumenin in A549 cells significantly inhibited MYC and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog signaling pathways while activating interferon signals, inflammatory signals, and p53 pathways. Ingenuity pathway analysis provided additional insights, indicating that the interferon and inflammatory pathways were prominently activated upon calumenin knockdown in A549 cells. CONCLUSIONS: The anti-cancer mechanism of calumenin knockdown might be related to the inhibition of MYC and KRAS signals but the activation of interferon signals, inflammatory signals and p53 pathways.

Knockdown of miR-1293 attenuates lung adenocarcinoma angiogenesis via Spry4 upregulation-mediated ERK1/2 signaling inhibition.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Angiogenesis plays a pivotal role in LUAD progression via supplying oxygen and nutrients for cancer cells. Non-coding miR-1293, a significantly up-regulated miRNA in LUAD tissues, can be potentially used as a novel biomarker for predicting the prognosis of LUAD patients. However, little information is available about the function of miR-1293 in LUAD progression especially cancer-induced angiogenesis. Herein, we found that miR-1293 knockdown could obviously attenuate LUAD-induced angiogenesis in vitro and down-regulate two most important pro-angiogenic cytokines VEGF-A and bFGF expression and secretion. Indeed, miR-1293 abrogation inactivated the angiogenesis-promoting ERK1/2 signaling characterized by decreased ERK1/2 phosphorylation and translocation from nucleus to cytoplasm. Next we found that miR-1293 knockdown reactivated the endogenous ERK1/2 pathway inhibitor Spry4 expression and Spry4 perturbance with specific siRNA transfection abolished the inhibition of ERK1/2 pathway and LUAD-induced angiogenesis by miR-1293 knockdown. Finally, with in vivo assay, we found obvious Spry4 up-regulation and VEGF-A, bFGF, ERK1/2 phosphorylation, micro-vessel density marker CD31 expression down-regulation in vivo, respectively. Collectively, these results indicated that miR-1293 knockdown could significantly attenuate LUAD angiogenesis via Spry4-mediated ERK1/2 signaling inhibition, which might be helpful for uncovering more functions of miR-1293 in LUAD and providing experimental basis for possible LUAD therapeutic strategy targeting miR-1293.

Peptidyl-prolyl isomerase F as a prognostic biomarker associated with immune infiltrates and mitophagy in lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is among the most prevalent malignancies worldwide, with unfavorable treatment outcomes. Peptidyl-prolyl isomerase F (PPIF) is known to influence the malignancy traits of tumor progression by modulating the bioenergetics and mitochondrial permeability in cancer cells; however, its role in LUAD remains unclear. Our study seeks to investigate the clinical significance, tumor proliferation, and immune regulatory functions of PPIF in LUAD. Methods: The expression of PPIF in LUAD tissues and cells was assessed using bioinformatics analysis, immunohistochemistry (IHC), and Western blotting. Survival curve analysis was conducted to examine the prognostic association between PPIF expression and LUAD. The immunomodulatory role of PPIF in LUAD was assessed through the analysis of PPIF expression and immune cell infiltration. A series of gain- and loss-of-function experiments were conducted on PPIF to investigate its biological functions in LUAD both in vitro and in vivo. The mechanisms underlying PPIF's effects on LUAD were delineated through functional enrichment analysis and Western blotting assays. Results: PPIF exhibited overexpression in LUAD tissues compared to normal controls. Survival curve analysis revealed that patients with LUAD exhibiting higher PPIF expression demonstrated decreased overall survival and a shorter progression-free interval. PPIF was implicated in modulating immune cell infiltration, particularly in regulating the T helper 1-T helper 2 cell balance. Functionally, PPIF was discovered to promote tumor cell proliferation and advance cell-cycle progression. Furthermore, PPIF could impede mitophagy by targeting the FOXO3a/PINK1-Parkin signaling pathway. Conclusions: The findings of this study indicate that the prognosis-related gene PPIF may have a significant role in the regulation of LUAD cell proliferation, tumor-associated immune cell infiltration, and mitophagy, and thus PPIF may be a promising therapeutic target of LUAD.

Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma.

Background: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Methods: Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. Results: We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Conclusions: Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

PSME3 promotes lung adenocarcinoma development by regulating the TGF-ß/SMAD signaling pathway.

Background: Lung adenocarcinoma (LUAD) is one of the most common types of cancer worldwide. Proteasome activator subunit 3 (PSME3) is a subunit of a proteasome activator, and changes in PSME3 can lead to the development of many diseases in organisms. However, the specific mechanism of PSME3 in LUAD has not yet been elucidated. This study initially revealed the mechanism of PSME3 promoting the progression of lung adenocarcinoma, which provided a potential molecular target for clinical treatment. Methods: PSME3 expression in LUAD cells and tissues was assessed by bioinformatics analysis, immunohistochemistry (IHC), Western blotting (WB), and quantitative real time polymerase chain reaction (qRT-PCR). A series of functional experiments were used to evaluate the effects of PSME3 knockdown and overexpression on LUAD cell proliferation, migration, and apoptosis. The potential mechanism of PSME3 was explored by transcriptome sequencing and WB experiments. Results: In this study, our initial findings indicated that PSME3 expression was abnormally high in LUAD and was associated with poor patient prognosis. Further, we found that the downregulation of PSME3 significantly inhibited LUAD cell proliferation, an effect that was verified by subcutaneous tumor formation experiments in nude mice. Similarly, the rate of invasion and migration of LUAD cells significantly decreased after the downregulation of PSME3. Using flow cytometry, we found that the knockdown of PSME3 caused cell cycle arrest at the G1/S phase. Through transcriptome sequencing, we found that the transforming growth factor-beta (TGF-ß)/SMAD signaling pathway was closely related to LUAD, and we then validated the pathway using WB assays. Conclusions: We demonstrated that PSME3 was abnormally highly expressed in LUAD and related to poor patient prognosis; therefore, targeting PSME3 in the treatment of LUAD may represent a novel therapeutic approach.

Bioinformatics analysis of an immunotherapy responsiveness-related gene signature in predicting lung adenocarcinoma prognosis.

Background: Immune therapy has become first-line treatment option for patients with lung cancer, but some patients respond poorly to immune therapy, especially among patients with lung adenocarcinoma (LUAD). Novel tools are needed to screen potential responders to immune therapy in LUAD patients, to better predict the prognosis and guide clinical decision-making. Although many efforts have been made to predict the responsiveness of LUAD patients, the results were limited. During the era of immunotherapy, this study attempts to construct a novel prognostic model for LUAD by utilizing differentially expressed genes (DEGs) among patients with differential immune therapy responses. Methods: Transcriptome data of 598 patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) database, which included 539 tumor samples and 59 normal control samples, with a mean follow-up time of 29.69 months (63.1% of patients remained alive by the end of follow-up). Other data sources including three datasets from the Gene Expression Omnibus (GEO) database were analyzed, and the DEGs between immunotherapy responders and nonresponders were identified and screened. Univariate Cox regression analysis was applied with the TCGA cohort as the training set and GSE72094 cohort as the validation set, and least absolute shrinkage and selection operator (LASSO) Cox regression were applied in the prognostic-related genes which fulfilled the filter criteria to establish a prognostic formula, which was then tested with time-dependent receiver operating characteristic (ROC) analysis. Enriched pathways of the prognostic-related genes were analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and tumor immune microenvironment (TIME), tumor mutational burden, and drug sensitivity tests were completed with appropriate packages in R (The R Foundation of Statistical Computing). Finally, a nomogram incorporating the prognostic formula was established. Results: A total of 1,636 DEGs were identified, 1,163 prognostic-related DEGs were extracted, and 34 DEGs were selected and incorporated into the immunotherapy responsiveness-related risk score (IRRS) formula. The IRRS formula had good performance in predicting the overall prognoses in patients with LUAD and had excellent performance in prognosis prediction in all LUAD subgroups. Moreover, the IRRS formula could predict anticancer drug sensitivity and immunotherapy responsiveness in patients with LUAD. Mechanistically, immune microenvironments varied profoundly between the two IRRS groups; the most significantly varied pathway between the high-IRRS and low-IRRS groups was ribonucleoprotein complex biogenesis, which correlated closely with the TP53 and TTN mutation burdens. In addition, we established a nomogram incorporating the IRRS, age, sex, clinical stage, T-stage, N-stage, and M-stage as predictors that could predict the prognoses of 1-year, 3-year, and 5-year survival in patients with LUAD, with an area under curve (AUC) of 0.718, 0.702, and 0.68, respectively. Conclusions: The model we established in the present study could predict the prognosis of LUAD patients, help to identify patients with good responses to anticancer drugs and immunotherapy, and serve as a valuable tool to guide clinical decision-making.

Correlation analysis between driver gene mutation and clinicopathological features in lung adenocarcinoma based on real-world cumulative clinical data.

Background: Driver genes are essential predictors of targeted therapeutic efficacy. Detecting driver gene mutations in lung adenocarcinoma (LUAD) patients can help to screen for targeted drugs and improve patient survival benefits. This study aims to investigate the mutation characterization of driver genes and their correlation with clinicopathological features in LUAD. Methods: A total of 440 LUAD patients were selected from Sir Run Run Shaw Hospital between July 2019 and September 2022. Postoperative tissue specimens were analyzed for gene mutations using next-generation sequencing technology, focusing, including epidermal growth factor receptor EGFR, ALK, ROS1, RET, KRAS, MET, BRAF, HER2, PIK3CA and NRAS. At the same time, clinicopathological data were collected and organized for multidimensional correlation analysis. Results: Of 440 LUAD patients, driver gene mutations were not detected in 48 patients. The proportion of patients with driver gene mutations was as high as 89.09%. The top three driver genetic mutations were EGFR, KRAS, and MET. Sixty-nine types of EGFR mutations were detected and distributed in the protein tyrosine kinase catalytic domain (56, 81.16%), Furin-like cysteine-rich region (9, 13.04%), receptor binding domain (3, 4.35%), and EGFR transmembrane domain (1, 1.45%). Single gene locus mutation occurred in 343 LUAD patients, but the mutation gene types covered all tested genes. Our findings showed that EGFR mutations were more commonly observed in non-smoking and female patients (P<0.01), KRAS mutations were more prevalent in male patients and smokers (P<0.01), ROS1 mutations had larger tumor diameters (P<0.01) and RET mutations were more prevalent in smokers (P<0.05). Conclusions: LUAD patients exhibit diverse genetic mutations, which may co-occur simultaneously. Integrated analysis of multiple mutations is essential for accurate diagnosis and effective treatment of the disease. The use of NGS can significantly expand our understanding of gene mutations and facilitate integrated analysis of multiple gene mutations, providing critical evidence for targeted treatment methods.

EGFR kinase domain duplication in lung adenocarcinoma with systemic and intracranial response to a double-dose of furmonertinib: a case report and literature review.

Background: EGFR kinase domain duplication (EGFR-KDD) is an infrequent oncogenic driver mutation in lung adenocarcinoma. It may be a potential target benefit from EGFR-tyrosine kinase inhibitors (TKIs) treatment. Case presentation: A 66-year-old Chinese male was diagnosed with lung adenocarcinoma in stage IVb with brain metastases. Next-generation sequencing revealed EGFR-KDD mutation. The patient received furmonertinib 160mg daily for anti-cancer treatment and obtained therapeutic efficacy with partial response (PR). Progression-free survival (PFS) duration from monotherapy was 16 months. With slow progressions, combined radiotherapy and anti-vascular targeted therapy also brought a continuous decrease in the tumors. The patient has an overall survival (OS) duration of more than 22 months and still benefits from double-dose furmonertinib. Conclusions: This report provided direct evidence for the treatment of EGFR-KDD to use furmonertinib. A Large-scale study is needed to confirm this preliminary finding.

Proteomics shows that brain metastases of lung adenocarcinoma overexpress ribosomal proteins in response to gamma knife radiosurgery.

Gamma knife radiosurgery (GKRS) is recommended as the first-line treatment for brain metastases of lung adenocarcinoma (LUAD) in many guidelines, but its specific mechanism is unclear. We aimed to study the changes in the proteome of brain metastases of LUAD in response to the hyperacute phase of GKRS and further explore the mechanism of differentially expressed proteins (DEPs). Cancer tissues were collected from a clinical trial for neoadjuvant stereotactic radiosurgery before surgical resection of large brain metastases (ChiCTR2000038995). Five brain metastasis tissues of LUAD were collected within 24 h after GKRS. Five brain metastasis tissues without radiotherapy were collected as control samples. Proteomics analysis showed that 163 proteins were upregulated and 25 proteins were downregulated. GO and KEGG enrichment analyses showed that the DEPs were closely related to ribosomes. Fifty-three of 70 ribosomal proteins were significantly overexpressed, while none of them were underexpressed. The risk score constructed from 7 upregulated ribosomal proteins (RPL4, RPS19, RPS16, RPLP0, RPS2, RPS26 and RPS25) was an independent risk factor for the survival time of LUAD patients. Overexpression of ribosomal proteins may represent a desperate response to lethal radiotherapy. We propose that targeted inhibition of these ribosomal proteins may enhance the efficacy of GKRS.

Pan-cell death-related signature reveals tumor immune microenvironment and optimizes personalized therapy alternations in lung adenocarcinoma.

This study constructed a comprehensive analysis of cell death modules in eliminating aberrant cells and remodeling tumor microenvironment (TME). Consensus analysis was performed in 490 lung adenocarcinoma (LUAD) patients based on 4 types of cell death prognostic genes. Intersection method divided these LUAD samples into 5 cell death risk (CDR) clusters, and COX regression analysis were used to construct the CDR signature (CDRSig) with risk scores. Significant differences of TME phenotypes, clinical factors, genome variations, radiosensitivity and immunotherapy sensitivity were observed in different CDR clusters. Patients with higher risk scores in the CDRSig tended to be immune-excluded or immune-desert, and those with lower risk scores were more sensitive to radiotherapy and immunotherapy. The results from mouse model showed that intense expression of the high-risk gene PFKP was associated with low CD8+ T cell infiltration upon radiotherapy and anti-PD-L1 treatment. Deficient assays in vitro confirmed that PFKP downregulation enhanced cGAS/STING pathway activation and radiosensitivity in LUAD cells. In conclusion, our studies originally performed a comprehensive cell death analysis, suggesting the importance of CDR patterns in reprogramming TME and providing novel clues for LUAD personalized therapies.

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BACKGROUND: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare. CASE PRESENTATION: An 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases. CONCLUSION: As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

Cuproptosis-Related lncRNA Predict Prognosis and Immune Response of LUAD.

Background: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs. Methods: First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results. Results: 7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis. Conclusion: The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.

Low Expression of SCN4B Predicts Poor Prognosis in Non-Small Cell Lung Cancer.

BACKGROUND: Sodium voltage-gated channel beta subunit 4 (SCN4B) plays a suppressive role in various tumors. However, the role of SCN4B in non-small cell lung cancer (NSCLC) is not yet clear. This study aims to investigate the expression of SCN4B in NSCLC patients and its correlation with prognosis. METHODS: Firstly, the expression of SCN4B in non-small cell lung cancer (NSCLC) was analyzed using The Cancer Genome Atlas (TCGA) database. Then, differential expression genes (DEGs) were identified using R software. Next, DEG enrichment pathways were analyzed using the R package clusterProfiler. Protein-protein interaction networks were revealed through STRING analysis. A heatmap showed significant differential expression of SCN4B. Further analysis included examining SCN4B expression in a pan-cancer context and its correlation with 24 types of immune cells in NSCLC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blot, immunohistochemistry, and clinical data were used to validate SCN4B expression and prognostic value in NSCLC patients. RESULTS: SCN4B mRNA expression in non-small cell lung cancer tissues was significantly lower than in adjacent normal tissues (p < 0.001). Clinical correlation analysis confirmed its association with clinical pathology. Gene set enrichment analysis (GSEA) and tumor immune-related analyses indicated that SCN4B is involved in NSCLC-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and participates in immune infiltration. qRT-PCR, Western Blot, and immunohistochemistry also confirmed that SCN4B is downregulated in NSCLC patients and is associated with poor prognosis. CONCLUSION: SCN4B is downregulated in tumor tissues of NSCLC patients and is associated with a poor prognosis.

Elevated RACGAP1 Expression Enhances Malignant Potential in Lung Adenocarcinoma and Serves as a Prognostic Factor.

Background: While RACGAP1 is identified as a potential oncogene, its specific role in lung adenocarcinoma (LUAD) remains unclear. Methods: First, we conducted a comprehensive analysis of the role of RACGAP1 across 33 types of cancer. Subsequently, we investigated the expression levels of RACGAP1 and its impact on prognosis using data from The Cancer Genome Atlas (TCGA) database. We utilized single-cell sequencing data to explore the tumor-related processes of RACGAP1 in LUAD and validated our findings through experimental verification. Employing a consensus clustering (CC) approach, we subdivided LUAD patients into two subtypes based on RACGAP1 cell cycle-related genes (RrCCGs). These subtypes exhibited significant differences in tumor characteristics, lymph node metastasis, and recurrence. Furthermore, we evaluated the prognostic influence of RrCCGs using univariate Cox regression and least absolute shrinkage and selection operator regression models (LASSO), successfully establishing a prognostic model. Results: RACGAP1 is frequently overexpressed in various tumors and can impact the prognosis of patients with LUAD. Additionally, experimental evidence has demonstrated that low expression of RACGAP1 favors tumor cell apoptosis and restoration of the cell cycle, while high expression promotes invasion and metastasis. Through CC analysis of RrCCGs, patients were classified into two groups, with survival analysis revealing distinct prognoses and stages between the two groups. Furthermore, Cox and LASSO regression successfully constructed a prognostic model with robust predictive capability.