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1.
Mol Cancer ; 23(1): 182, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39218851

RESUMO

BACKGROUND: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days. METHODS: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets. RESULTS: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options. CONCLUSIONS: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.


Assuntos
Adenocarcinoma de Pulmão , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/metabolismo , Análise por Conglomerados , Genômica/métodos , Mutação , Biomarcadores Tumorais/genética , Feminino , Masculino , Sequenciamento Completo do Genoma , Prognóstico , Terapia de Alvo Molecular , Perfilação da Expressão Gênica , Idoso , Pessoa de Meia-Idade , Multiômica
2.
Oncol Res ; 32(9): 1439-1452, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39220139

RESUMO

Objectives: The pro-oncogenic effects of NCAPD2 have been extensively studied across various tumor types; however, its precise role within the context of lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the biological functions of NCAPD2 in LUAD and unravel the underlying mechanistic pathways. Methods: Utilizing bioinformatics methodologies, we explored the differential expression of NCAPD2 between normal and tumor samples, along with its correlations with clinical-pathological characteristics, survival prognosis, and immune infiltration. Results: In the TCGA-LUAD dataset, tumor samples demonstrated significantly elevated levels of NCAPD2 expression compared to normal samples (p < 0.001). Clinically, higher NCAPD2 expression was notably associated with advanced T, N, and M stages, pathologic stage, gender, smoking status, and diminished overall survival (OS). Moreover, differentially expressed genes (DEGs) associated with NCAPD2 were predominantly enriched in pathways related to cell division. Immune infiltration analysis revealed that NCAPD2 expression levels were linked to the infiltration of memory B cells, naïve CD4+ T cells, activated memory CD4+ T cells, and M1 macrophages. In vitro experiments demonstrated that silencing NCAPD2 suppressed LUAD cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cell cycle progression. Conclusions: In summary, NCAPD2 may represent a promising prognostic biomarker and novel therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Biomarcadores Tumorais , Ciclo Celular , Movimento Celular , Proliferação de Células , Neoplasias Pulmonares , Humanos , Proliferação de Células/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Prognóstico , Movimento Celular/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Ciclo Celular/genética , Invasividade Neoplásica , Feminino , Masculino , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Biologia Computacional/métodos
3.
Front Immunol ; 15: 1347770, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39267750

RESUMO

Introduction: The connection between aging and cancer is complex. Previous research has highlighted the association between the aging process of lung adenocarcinoma (LUAD) cells and the immune response, yet there remains a gap in confirming this through single-cell data validation. Here, we aim to develop a novel aging-related prognostic model for LUAD, and verify the alterations in the genome and immune microenvironment linked to cellular senescence. Methods: We integrated a comprehensive collection of senescence genes from the GenAge and CellAge databases and employed the least absolute shrinkage and selection operator (LASSO) Cox analysis to construct and validate a novel prognostic model for LUAD. This model was then utilized to examine the relationship between aging, tumor somatic mutations, and immune cell infiltration. Additionally, we explored the heterogeneity of senescence and intercellular communication within the LUAD tumor microenvironment (TME) through single-cell transcriptomic data analysis. Results: By exploring the expression profiles of 586 cellular senescence-related genes in 428 LUAD patients, we constructed an aging-related genes (ARGs) risk model included 10 ARGs and validated it as an independent prognostic predictor for LUAD patients. Notably, patients with low aging scores (LAS group) exhibited better survival, lower tumor mutation burden (TMB), lower somatic mutation frequency, lower tumor proliferation rate, and an immune activated phenotype compared to patients with high aging scores (HAS group). While the HAS group was enriched in tumor cells and showed a lower infiltration of CD8-CCR7, CD8- CXCL13, CD8-GNLY, FCGR3A NK cells, XCL1 NK cells, plasma cell (PC) and other immune subsets. Furthermore, the SPP1 and TENASCIN pathways, associated with tumor immune escape and tumor progression, were also enriched in the HAS group. Additionally, our study also indicated that senescence levels were heterogeneous in the LUAD tumor microenvironment (TME), especially with tumor cells in the LAS group showing higher age scores compared to those in the HAS group. Conclusions: Collectively, our findings underscore that ARRS through ARGs serves as a robust biomarker for the prognosis in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Senescência Celular , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Senescência Celular/genética , Senescência Celular/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Prognóstico , Biomarcadores Tumorais/genética , Mutação , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Idoso , Envelhecimento/imunologia , Envelhecimento/genética
4.
Sci Rep ; 14(1): 21451, 2024 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271782

RESUMO

Based on the joint analysis of multi-omic data and the biological experiments, we demonstrate that FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via regulating MFAP4/FAK signal axis in this study. The levels of FOXF1 and MFAP4 are significantly down-regulated in LUAD, and the increased levels of two genes can improve the clinical prognosis of LUAD patients. Fluorescein reporter gene determination, chromatin immunoprecipitation and gene co-expression analysis indicate that MFAP4 level is positively regulated by transcription factor FOXF1. The function enrichment analysis shows that the levels of FOXF1 and MFAP4 are closely associated with an enrichment of tumor metastasis signatures. FOXF1 can inhibit the migration and invasion of LAUD cells by transcriptionally activating MFAP4 expression. And the overexpression of FOXF1/MFAP4 can reduce focal adhesion kinase (FAK) phosphorylation, while their knockdown result in the opposite effects. The increased levels of FOXF1/MFAP4 enhance the antitumor immunity by increasing the infiltration of dendritic cells and CD4+ T cells, and the interactions between LUAD cells and immune cells, and activating multiple anti-tumor immunity-related pathways. In conclusion, our study reveals the potential function of FOXF1/MFAP4/FAK signal axis in inhibiting metastasis of LUAD cells and modulating anti-tumor immunity of LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Fatores de Transcrição Forkhead , Neoplasias Pulmonares , Invasividade Neoplásica , Transdução de Sinais , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Movimento Celular , Camundongos , Animais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo
5.
Narra J ; 4(2): e1024, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39280288

RESUMO

Previous studies have associated tumor size with metastasis and prognosis in lung carcinoma; however, a precise cut-off for predicting distant metastasis in lung adenocarcinoma remains unclear. The aim of this study was to determine the cut-off point for predicting distant metastasis in lung adenocarcinoma. A cross-sectional study was conducted at Dr. Moewardi Hospital, Surakarta, Indonesia, from January 2022 to September 2023. Total sampling was employed, involving patients over 18 years old with a confirmed diagnosis of lung adenocarcinoma based on lung computed tomography (CT) scan findings, who had not yet received chemotherapy and had confirmed metastasis outside the lung. The study's dependent variable was the incidence of distant metastasis, while the independent variable was lung adenocarcinoma size. Two experienced thoracic radiologists measured lung adenocarcinoma size by assessing the longest axis using chest multi-slice computed tomography (MSCT) in the lung window setting. Receiver operating characteristic (ROC) curve analysis determined the optimal tumor size cut-off for predicting distant metastasis. Of 956 thoracic cancer patients, 108 were diagnosed with lung adenocarcinoma. After applying the inclusion and exclusion criteria, 89 patients were eligible. In the present study, tumor size predicted 68.1% of distant metastasis cases, with a cut-off point of 7.25 cm, yielding a sensitivity of 61.9% and a specificity of 61.5%. Tumors >7.25 cm had a 2.60-fold higher risk of distant metastasis compared to smaller tumors, with larger tumors more likely to spread to various sites. In conclusion, lung adenocarcinomas larger than 7.25 cm have a 2.60-fold increased risk of distant metastasis, making tumor size a crucial predictive factor. The study provides valuable insights for radiologists and can improve diagnosis accuracy and treatment planning by emphasizing tumor size as a key factor in managing lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos Transversais , Indonésia/epidemiologia , Idoso , Metástase Neoplásica , Prognóstico , Adulto , Curva ROC , Valor Preditivo dos Testes
6.
Biol Direct ; 19(1): 82, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285446

RESUMO

BACKGROUND: Armadillo Repeat Containing X-Linked 1 (ARMCX1), a member of the ARM Repeat X-linked protein family, exerts inhibitory function in various tumors. However, its biological role in lung adenocarcinoma (LUAD) and the underlying molecular mechanisms require further exploration. METHODS: LUAD tissue microarrays and bioinformatic databases were used to evaluate the relationship between ARMCX1 and clinicopathological features. The influence of ARMCX1 on LUAD cell proliferation, migration, and invasion in vitro was determined by colony formation, CCK-8, EdU incorporation, cell cycle, wound healing, and Transwell assays. The impact of ARMCX1 on LUAD cell growth and metastasis in vivo was determined by subcutaneously transplanted tumor and pulmonary metastasis assays. Western blot, immunoprecipitation, immunofluorescence, cycloheximide, and proteasome inhibitor assays were finally conducted to explore the potential underlying molecular mechanisms. RESULTS: ARMCX1 expression was downregulated in clinical LUAD samples due to which patient prognoses were poor. Functional experiments indicated that ARMCX1 overexpression inhibited the growth and metastasis of LUAD cells in vitro and in vivo. The molecular mechanism suggested that ARMCX1 recruits the E3 ubiquitin ligase FBXW7 for mediating ubiquitinated degradation of c-Myc, suppressing its nuclear accumulation, and ultimately inactivating cell cycle and epithelial-mesenchymal transition (EMT) signals. CONCLUSION: ARMCX1 inhibits LUAD cell proliferation and metastasis by interacting with c-Myc and enhancing its ubiquitination and degradation. Consequently, it can act as a tumor suppressor in this disease. These results suggest that ARMCX1 is a potential target in the treatment of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Proteína 7 com Repetições F-Box-WD , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-myc , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Proteólise , Progressão da Doença , Movimento Celular , Masculino , Camundongos Nus , Feminino , Regulação Neoplásica da Expressão Gênica
7.
Mol Cancer ; 23(1): 185, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39232758

RESUMO

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Linfócitos do Interstício Tumoral , Macrófagos , Microambiente Tumoral , Humanos , Prognóstico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/mortalidade , Microambiente Tumoral/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/metabolismo , Análise de Célula Única/métodos
8.
World J Surg Oncol ; 22(1): 235, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39232762

RESUMO

BACKGROUND: Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components. MATERIALS AND METHODS: We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination. RESULTS: Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components. CONCLUSION: MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy.


Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Neoplasias Pulmonares , Mutação , Estadiamento de Neoplasias , Humanos , Masculino , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/mortalidade , Estudos Retrospectivos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Pessoa de Meia-Idade , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/mortalidade , Prognóstico , Idoso , Taxa de Sobrevida , Seguimentos , Quimioterapia Adjuvante/métodos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/genética , Pneumonectomia , Adulto
9.
Integr Cancer Ther ; 23: 15347354241273962, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39223822

RESUMO

BACKGROUND: The traditional Chinese medicine (TCM) Xiaoliu Pingyi recipe (XLPYR) has been clinically used for several decades, demonstrating favorable therapeutic effects. However, the underlying regulatory mechanisms remain unclear. The aim of this study was to explore the anti-tumor effects of XLPYR and its regulatory role in the vascular microenvironment through in vivo and in vitro experiment. MATERIALS AND METHODS: In the in vivo study, a C57BL/6J mouse model of lung adenocarcinoma (LUAD) allografts was established, and various interventions were administered for 14 days (Model group: administered normal saline via oral gavage; Pemetrexed (PEM) group: intraperitoneally injected with a solution of pemetrexed, once every 3d; XLPYR group: administered XLPYR via oral gavage; Combination (COMBI) group: received XLPYR via oral gavage simultaneously with intraperitoneal injection of pemetrexed solution). Tumor volume and weight were then compared among the groups. The impact of XLPYR on the tumor vascular microenvironment was assessed using immunohistochemistry staining. In the in vitro study, XLPYR-containing serum was prepared by oral administration to SD rats. The CCK-8 assay evaluated the effect of the serum on the proliferation of normal lung epithelial BEAS-2B cells and LUAD A549 cells, determining the optimal intervention concentrations. The cell migration and invasion abilities were evaluated using the wound-healing assay and Transwell assay, respectively. Finally, ELISA assay measured VEGF secretion levels in the LUAD cell supernatant, and RT-qPCR and Western Blot were employed to detect differences in HIF-1α, VEGFA, Ang-2, and PI3K/Akt mRNA and protein expression levels in both in vivo and in vitro experiments. RESULTS: In the in vivo study, XLPYR significantly inhibited the growth of mice LUAD allografts, with enhanced anti-tumor effects observed with prolonged drug intervention. Immunohistochemistry staining revealed reduced MVD and increased pericyte coverage in all intervention groups. Regarding vascular function, FITC-Dextran extravasation in the tumor tissues of the Model group was significantly higher than in the intervention groups, particularly with lower extravasation in the COMBI group compared to the PEM group. In the in vitro study, XLPYR demonstrated a time- and concentration-dependent inhibitory effect on LUAD cells, and with greater sensitivity in inhibiting LUAD cells compared to BEAS-2B cells. The wound-healing assay and Transwell assay confirmed that XLPYR significantly suppressed the migration and invasion abilities of LUAD cells. ELISA experiments further revealed a significant decrease in VEGF expression in the supernatant of each intervention group. RT-qPCR and Western Blot results showed consistent findings between the in vivo and in vitro experiments. HIF-1α, VEGFA, and Ang-2 mRNA and protein expression levels were significantly downregulated in the PEM group, XLPYR group, and COMBI group. There were no significant differences in the expression of PI3K and Akt mRNA and total protein, but the expression levels of phosphorylated p-PI3K and p-Akt were notably downregulated. CONCLUSION: XLPYR significantly inhibited C57BL/6J mouse LUAD allograft growth and improved the vascular microenvironment, thereby intervening in tumor angiogenesis and inducing vascular normalization. It suppressed LUAD cell proliferation, migration, and invasion, while reducing VEGF concentration in the cell supernatant. The regulatory mechanism may involve inhibiting PI3K/Akt protein phosphorylation and downregulating angiogenesis-related factors, such as HIF-1α, VEGF, and Ang-2.


Assuntos
Adenocarcinoma de Pulmão , Medicamentos de Ervas Chinesas , Neoplasias Pulmonares , Camundongos Endogâmicos C57BL , Microambiente Tumoral , Animais , Medicamentos de Ervas Chinesas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Humanos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Masculino , Pemetrexede/farmacologia , Neovascularização Patológica/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos
10.
Sci Rep ; 14(1): 20482, 2024 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227650

RESUMO

Lung cancer is the leading cause of cancer-related death globally. Metastasis is the most common reason of mortality in which hypoxia is suggested to have a pivotal role. However, the effect of hypoxia on the metastatic potential and migratory activity of cancer cells is largely unexplored and warrants detailed scientific investigations. Accordingly, we analyzed changes on cell proliferation and migratory activity both in single-cell migration and invasion under normoxic and hypoxic conditions in lung adenocarcinoma cell lines. Alterations in crucial genes and proteins associated with cellular response to hypoxia, epithelial-mesenchymal transition, proliferation and apoptosis were also analyzed. Generally, we observed no change in proliferation upon hypoxic conditions and no detectable induction of apoptosis. Interestingly, we observed that single-cell motility was generally reduced while invasion under confluent conditions using scratch assay was enhanced by hypoxia in most of the cell lines. Furthermore, we detected changes in the expression of EMT markers that are consistent with enhanced motility and metastasis-promoting effect of hypoxia. In summary, our study indicated cell line-, time of exposure- and migrational type-dependent effects of hypoxia in cellular proliferation, motility and gene expression. Our results contribute to better understanding and tackling cancer metastasis.


Assuntos
Adenocarcinoma de Pulmão , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Linhagem Celular Tumoral , Apoptose , Hipóxia Celular , Regulação Neoplásica da Expressão Gênica , Células A549
11.
Trials ; 25(1): 582, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227966

RESUMO

INTRODUCTION: Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis. METHODS: In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection. CONCLUSIONS: Our findings do not support a genetic association between HPV infection and lung cancer.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Análise da Randomização Mendeliana , Infecções por Papillomavirus , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/virologia , Neoplasias Pulmonares/epidemiologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Fatores de Risco , Medição de Risco , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/epidemiologia , Proteínas E7 de Papillomavirus/genética , Predisposição Genética para Doença , Adenocarcinoma/genética , Adenocarcinoma/virologia , Adenocarcinoma/epidemiologia , Papillomavirus Humano 18/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/virologia , Polimorfismo de Nucleotídeo Único , Fenótipo , Papillomavirus Humano
12.
J Cancer Res Clin Oncol ; 150(9): 409, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39230677

RESUMO

PURPOSE: Invasive mucinous adenocarcinoma (IMA) of the lungs is a rare subtype of lung adenocarcinoma with a limited understanding of its prognosis, particularly in advanced stages. This study aimed to assess the prognosis of patients with advanced IMA by focusing on treatment modalities. METHODS: This single-center retrospective study evaluated 33 patients with IMAs diagnosed with advanced-stage disease or disease progression after curative treatment between 2011 and 2021. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). OS and PFS were calculated from the date of the diagnosis of advanced IMA. RESULTS: The study cohort included 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Treatment modalities included conventional chemotherapy in 24 patients (72.7%), targeted therapy in seven (21.2%), immunotherapy in 13 (39.4%), and local ablative therapy (LAT) in 13 (39.4%). The median OS was 32 months (95% confidence interval [CI], 2.9-61.0), with LAT significantly associated with improved OS compared to non-LAT treatment (not reached vs. 11.3 months, p = 0.001). However, there was no significant difference in OS based on conventional chemotherapy (p = 0.396), targeted therapy (p = 0.655), or immunotherapy (p = 0.992). In multivariate analysis, LAT remained an independent prognostic factor for OS (hazard ratio, 0.125; 95% CI, 0.026-0.608; p = 0.01). PFS was 8.6 months (95% CI, 3.6-13.7), with no significant differences observed among the treatment modalities. CONCLUSION: Our findings suggest that LAT may provide favorable survival outcomes in patients with advanced IMA.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Adulto , Idoso de 80 Anos ou mais , Prognóstico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/terapia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/cirurgia , Invasividade Neoplásica , Intervalo Livre de Progressão , Estadiamento de Neoplasias , Taxa de Sobrevida
13.
Braz J Med Biol Res ; 57: e13885, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39258674

RESUMO

NLRP1, the first identified inflammasome-forming sensor, is thought to be involved in cancer, yet its definite function in lung adenocarcinoma (LUAD) remains unclear. Herein, we explored the expression and function of NLRP1 in LUAD. Decreased NLRP1 expression was identified in LUAD, which was associated with a poor prognosis. Overexpression of NLRP1 inhibited tumor growth in vitro and in vivo. Mechanically, this effect was observed regardless of inflammasome activation. Further studies revealed that overexpression of NLRP1 downregulated the phosphorylation of DRP1 and promoted mitochondrial fusion, which was mediated by inhibition of NF-κB activity. NF-κB agonist could neutralize the effect of NLRP1 on mitochondrial dynamics. In addition, LUAD sensitivity to cisplatin was enhanced by decreased mitochondrial fission resulting from up-regulated NLRP1. In conclusion, our findings demonstrated an unexpected role of NLRP1 in LUAD by modulating mitochondrial activities, which provides strong evidence for its potential in LUAD treatment.


Assuntos
Adenocarcinoma de Pulmão , Inflamassomos , Neoplasias Pulmonares , Mitocôndrias , Proteínas NLR , Humanos , Inflamassomos/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Proteínas NLR/metabolismo , Animais , Mitocôndrias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/fisiologia , Camundongos , Masculino , Proliferação de Células/efeitos dos fármacos , Feminino
14.
Medicine (Baltimore) ; 103(22): e38387, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-39259093

RESUMO

A family of molecular chaperone complexes called chaperonin-containing T-complex protein 1 (TCP-1) subunit genes (CCTs) aids in the folding of numerous proteins. With regard to lung adenocarcinoma (LUAD), this study provided a thorough understanding of the diagnostic and prognostic use of CCTs. The expression of CCTs in LUAD was evaluated by using databases including UALCAN and the Gene Expression Omnibus. Immunohistochemistry (IHC) was conducted to validate the expression of CCTs in LUAD. The mutation in the CCTs was identified through the cBioPortal database, while promoter methylation was measured by the UALCAN database. The prognostic value of CCTs was evaluated using the PrognoScan analysis. The GEPIA2.0 database was used to measure the prognostic value of CCTs and associated Hub genes. Correlation analysis between CCTs expression in LUAD was based on the GEPIA2.0 database. The ROC curves, clinical correlation analysis, gene ontology, Kyoto Encyclopedia of Genes and Genome analysis, and immune cell infiltration analysis were downloaded from The Cancer Genome Atlas database and then analyzed and visualized using the R language. The STRING database was used for protein-protein interaction analysis. Upregulation of CCTs expression in patients with LUAD indicated advanced diseases and a poor prognosis. ROC curve analysis revealed that the CCTs may serve as diagnostic indicators. The functional enrichment analysis showed that CCTs were involved in the mitosis-mediated cell cycle process. Additionally, 10 hub genes associated with CCTs that were linked to LUAD prognosis and tumor progression were identified. Immune cell infiltration analysis showed that CCTs expression in tumor tissues tends to be related to T helper type 2 cell infiltration. This study revealed that CCTs may serve as valuable biomarkers for the diagnosis and targeted therapy of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Biomarcadores Tumorais , Chaperonina com TCP-1 , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/imunologia , Chaperonina com TCP-1/genética , Chaperonina com TCP-1/metabolismo , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Regulação Neoplásica da Expressão Gênica , Mutação , Masculino , Feminino
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(8): 1529-1536, 2024 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-39276048

RESUMO

OBJECTIVE: To explore the correlation of baseline CCL19+ dendritic cell (CCL19+ DC) infiltration in lung adenocarcinoma microenvironment with immunotherapy efficacy and CD8+ T cell infiltration. METHODS: We retrospectively analyzed the data of patients with lung adenocarcinoma hospitalized at First Affiliated Hospital of Henan University of Science and Technology from January, 2020 to December, 2023, and collected tissue samples from 96 patients undergoing immunotherapy for assessing CCL19+ DC and CD8+ T cell infiltration using immunofluorescence assay. We evaluated the predictive value of baseline CCL19+ DCs for patient responses to immunotherapy using receiver-operating characteristics (ROC) curves and analyzed the correlations of baseline CCL19+ DC expression with immunotherapy efficacy and CD8+ T cell and cytotoxic T lymphocyte (CTL) infiltrations. In co-culture systems of lung adenocarcinoma PC9 cells, CD8+ T cells and DCs (overexpressing CCL19 with or without anti PD-1 antibody treatment), the expressions of granzyme B, perforin, IFN-γ, and Ki-67 in T cells were analyzed using flow cytometry. RESULTS: The patients with partial or complete remission following immunotherapy had a significantly higher baseline CCL19+ DC infiltration level in lung adenocarcinoma tissues than those with poor responses. CCL19+ DC infiltration had an area under ROC curve of 0.785, a sensitivity of 75.6%, and a specificity of 62.8% for predicting immunotherapy efficacy. The expression of CD8+ T cell surface molecules Granzyme B (P<0.01), Perforin (P<0.01), IFN-γ (P<0.01) and Ki-67 (P<0.001) in patients with high expression of CCL19+ DC were higher than those in patients with low expression of CCL19+ DC. The baseline CCL19+ DC infiltration level was positively correlated with immunotherapy efficacy (P=0.003), CTL infiltration of (r=0.6657, P<0.001) and CD8+ T cell infiltration (P=0.007). In the co-cultured cells, CCL19 overexpression combined with anti-PD1 treatment of the DCs more strongly enhanced cytotoxicity and proliferation of CD8+ T lymphocytes than either of the single treatments (P<0.01 or 0.001). CONCLUSION: The baseline CCL19+ DC infiltration level in lung adenocarcinoma microenvironment is positively correlated with immunotherapy efficacy and CTL infiltration and can thus predict the response to immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Quimiocina CCL19 , Células Dendríticas , Imunoterapia , Neoplasias Pulmonares , Humanos , Células Dendríticas/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Quimiocina CCL19/metabolismo , Imunoterapia/métodos , Adenocarcinoma de Pulmão/terapia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Estudos Retrospectivos , Microambiente Tumoral/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Granzimas/metabolismo
16.
BMC Med Imaging ; 24(1): 240, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39272029

RESUMO

BACKGROUND: To design a pulmonary ground-glass nodules (GGN) classification method based on computed tomography (CT) radiomics and machine learning for prediction of invasion in early-stage ground-glass opacity (GGO) pulmonary adenocarcinoma. METHODS: This retrospective study included pulmonary GGN patients who were histologically confirmed to have adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma cancer (IAC) from 2020 to 2023. CT images of all patients were automatically segmented and 107 radiomic features were obtained for each patient. Classification models were developed using random forest (RF) and cross-validation, including three one-versus-others models and one three-class model. For each model, features were ranked by normalized Gini importance, and a minimal subset was selected with a cumulative importance exceeding 0.9. These selected features were then used to train the final models. The models' performance metrics, including area under the curve (AUC), accuracy, sensitivity, and specificity, were computed. AUC and accuracy were compared to determine the final optimal method. RESULTS: The study comprised 193 patients (mean age 54 ± 11 years, 65 men), including 65 AIS, 54 MIA, and 74 IAC, divided into one training cohort (N = 154) and one test cohort (N = 39). The final three-class RF model outperformed three individual one-versus-others models in distinguishing each class from the other two. For the multiclass classification model, the AUC, accuracy, sensitivity, and specificity were 0.87, 0.79, 0.62, and 0.88 for AIS; 0.90, 0.79, 0.54, and 0.89 for MIA; and 0.87, 0.69, 0.73, and 0.67 for IAC, respectively. CONCLUSIONS: A radiomics-based multiclass RF model could effectively differentiate three types of pulmonary GGN, which enabled early diagnosis of GGO pulmonary adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Aprendizado de Máquina , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Feminino , Masculino , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/patologia , Idoso , Invasividade Neoplásica/diagnóstico por imagem , Sensibilidade e Especificidade , Radiômica
17.
Int J Mol Sci ; 25(17)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39273283

RESUMO

BACKGROUND: Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells. METHODS: Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 mM for 2 h. Angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) transfection was performed 6 h prior to ropivacaine administration. Cell proliferation and migration were assessed with cell counting kit 8 (CCK-8) and a wound healing assay at 0 and 24 h after anesthesia exposure. PCR arrays were performed, followed by PCR validation. RESULTS: Ropivacaine administration inhibited A549 cell proliferation and migration in a concentration-dependent manner, with ACE2 upregulation and HIF1α (hypoxia-inducible factor 1α) downregulation. The anticancer effect of ropivacaine was canceled out via ACE2 siRNA transfection. PCR arrays showed specific gene change patterns in the ropivacaine and respective ACE2-knockdown groups. EGFR (epidermal growth factor receptor), BAX (Bcl-2-associated X protein) and BCL2 (B-cell/CLL lymphoma 2) were suppressed with ropivacaine administration; these effects were reversed via ACE2 siRNA induction. CONCLUSION: Ropivacaine administration inhibited A549 cell biology in conjunction with ACE2 upregulation via the inhibition of the Wnt1 (wingless/Integrated 1) pathway.


Assuntos
Adenocarcinoma de Pulmão , Enzima de Conversão de Angiotensina 2 , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Ropivacaina , Humanos , Ropivacaina/farmacologia , Proliferação de Células/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Movimento Celular/efeitos dos fármacos , Células A549 , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Wnt1/metabolismo , Proteína Wnt1/genética , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
18.
Int J Mol Sci ; 25(17)2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39273449

RESUMO

Lung adenocarcinoma (LUAD) poses significant challenges due to its complex biological characteristics and high recurrence rate. The high recurrence rate of LUAD is closely associated with cellular dormancy, which enhances resistance to chemotherapy and evasion of immune cell destruction. Using single-cell RNA sequencing (scRNA-seq) data from LUAD patients, we categorized the cells into two subclusters: dormant and active cells. Utilizing high-density Weighted Gene Co-expression Network Analysis (hdWGCNA) and pseudo-time cell trajectory, aberrant expression of genes involved in protein O-glycosylation was detected in dormant cells, suggesting a crucial role for O-glycosylation in maintaining the dormant state. Intercellular communication analysis highlighted the interaction between fibroblasts and dormant cells, where the Insulin-like Growth Factor (IGF) signaling pathway regulated by O-glycosylation was crucial. By employing Gene Set Variation Analysis (GSVA) and machine learning, a risk score model was developed using hub genes, which showed high accuracy in determining LUAD prognosis. The model also demonstrated robust performance on the training dataset and excellent predictive capability, providing a reliable basis for predicting patient clinical outcomes. The group with a higher risk score exhibited a propensity for adverse outcomes in the tumor microenvironment (TME) and tumor mutational burden (TMB). Additionally, the 50% inhibitory concentration (IC50) values for chemotherapy exhibited significant variations among the different risk groups. In vitro experiments demonstrated that EFNB2, PTTG1IP, and TNFRSF11A were upregulated in dormant tumor cells, which also contributed greatly to the diagnosis of LUAD. In conclusion, this study highlighted the crucial role of O-glycosylation in the dormancy state of LUAD tumors and developed a predictive model for the prognosis of LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Aprendizado de Máquina , Microambiente Tumoral , Humanos , Glicosilação , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Prognóstico , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Redes Reguladoras de Genes
19.
BMC Cancer ; 24(1): 1138, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267056

RESUMO

PURPOSE: Lung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches. METHODS: We constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts. RESULTS: We developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells. CONCLUSION: We have identified malignant cell-associated ligand-receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/genética , Imunoterapia , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Feminino , Análise de Célula Única/métodos , Masculino , Transcriptoma , Aprendizado de Máquina , Multiômica
20.
Tuberk Toraks ; 72(3): 197-207, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39275932

RESUMO

Introduction: Platelets (PLT) and host systemic inflammatory response (SIR) are known to be effective in the aggregation of cancer cells and the formation of metastasis. There are studies pointing out to the prognostic efficacy of lymphocyte-monocyte ratio (LMR) showing SIR activation and mean platelet volume (MPV) values indicating platelet activation in various cancer types. We predict that easy-to-access hemogram parameters such as MPV, MPV/PLT, and LMR can be guiding in the clinical follow-up period of patients with epidermal growth factor receptor (EGFR) positive mutation and who received EGFR, tyrosine kinase inhibitor (TKI) in the first-line treatment in predicting the progression of the disease, predicting the survival time of the patients, and evaluating the response to treatment. Materials and Methods: The study is retrospective and included patients with stage III and stage IV pulmonary adenocarcinoma with positive EGFR mutations and for whom TKI was used in the first-line treatment between January 2011 and January 2021. MPV, MPV/PLT, and LMR values of the patients were calculated before treatment. Age, sex, comorbidity, smoking history, TNM stage, metastasis localizations, EGFR mutation types, TKI treatments used in first-line treatment, and MPV, MPV/PLT, and LMR values at the 1st month of treatment were recorded. With Kaplan-Meier, six-month, one-year, three-year, and five-year survival rates, average life expectancy, and 95% confidence intervals for these periods were calculated. Variables that may affect progression and overall survival (OS) were determined by performing univariate and multivariate Cox regression analysis. Result: One hundred and two patients were included in the study. The mean age of the patients was 64.30 ± 12.6 years. Eighty-four patients were in stage IV at the time of diagnosis. The expected mean progression-free survival (PFS) period of the cases was found to be 13.3 months. The mean life expectancy of the cases was found to be 35.1 months. Web-based Cutoff Finder algorithm written in the R program (http://molpath.charite.de/cutoff) was used to determine the ideal cut points for MPV, MPV/PLT, and LMR. The cut-off values were found to be 7.55 fL for MPV, 0.251 for MPV/PLT, and 2.615 for LMR, respectively. In univariate Cox regression analysis, LMR level lower than 2.615 increased the rate of progression 1.747 times (95% confidence interval: 1.129-2.705) and the death rate 2.056 times (95% confidence interval: 1.217-3.475) (p= 0.012, p= 0.007). The mean PFS LMR cut-off value was 10.3 months, and 15.3 months, and mean OS durations were 25.1 months and 40.8 months for the groups with low and high cut-off values respectively (p= 0.011, p= 0.006 log-rank test). According to the results of multivariate Cox regression analysis, MPV/PLT < 0.251, smoking, presence of pleural and adrenal metastases, and gefitinib treatment were independent factors in determining PFS. The independent factors determining OS in multivariate Cox regression analysis were being male, platelet increase, MPV > 7.55, gefitinib treatment, and smoking. Conclusions: MPV, MPV/PLT, and LMR are potential biomarkers that can be used for the clinical follow-up of lung ADC patients receiving EGFR-TKI treatment.


Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Neoplasias Pulmonares , Volume Plaquetário Médio , Inibidores de Proteínas Quinases , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/patologia , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Prognóstico , Mutação , Monócitos , Plaquetas , Linfócitos
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