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1.
Nat Commun ; 15(1): 4195, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760351

RESUMO

Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Ferritinas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Ferritinas/metabolismo , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/genética , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Camundongos , Cobre/metabolismo , Autofagia/efeitos dos fármacos , Camundongos Nus , Indóis , Pirimidinas
2.
Ther Adv Med Oncol ; 15: 17588359231210678, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38028145

RESUMO

Background: The profile of immune-related adverse events (irAEs) due to programmed death-1 (PD-1) inhibitors-based combination therapy in advanced non-small cell lung cancer (NSCLC) and its relationship with survival have not been fully described. Objective: Designed to capture the spectrum of irAEs and explore the association between irAEs and clinical outcomes in patients with NSCLC. Design: This retrospective single-center study included patients with advanced NSCLC treated with PD-1 inhibitors (mainly in combination with chemotherapy) at Jiangsu Cancer Hospital. Methods: The relationship between irAEs and survival was explored using landmark analysis and time-dependent Cox regression. The subgroup analyses focused on investigating the effects of organ-specific irAE, irAE grade, and steroid dose used to treat irAE. Results: This study included 301 patients, 199 of whom received PD-1 inhibitors plus chemotherapy. The most common irAEs were skin toxicity (19.3%), endocrinopathy (21.3%), and pneumonitis (17.6%). In the entire cohort, the median progression-free survival (PFS) for patients developing and not developing irAE was 12.3 and 10.7 months (p < 0.001), and the median overall survival (OS) was 23.5 months and 20.1 months (p = 0.137), respectively. Subgroup analyses indicated that grade 3 or higher irAE, high steroid dose, and immune-related pneumonitis were detrimental to OS, whereas skin toxicity was beneficial to survival. These findings were further corroborated by both landmark analyses and Cox regression models conducted over four time points (1, 3, 6, and 12 months). Conclusion: In the real world, NSCLC patients receiving PD-1 inhibitor-based combination therapy (particularly combined with chemotherapy) experience longer PFS with irAE, though not necessarily OS. Immune-related skin toxicity is associated with a better prognosis, whereas pneumonitis grade ⩾3 irAE and high steroid dose compromise survival. Clinicians should remain cognizant of the organ-specific manifestations of irAE and take proactive measures to mitigate the progression of irAE.

3.
Cancer Sci ; 114(12): 4607-4621, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37770420

RESUMO

Evaluating the accuracy of pulmonary nodule diagnosis avoids repeated low-dose computed tomography (LDCT)/CT scans or invasive examination, yet remains a main clinical challenge. Screening for new diagnostic tools is urgent. Herein, we established a nomogram based on the diagnostic signature of five circulating tsRNAs and CT information to predict malignant pulmonary nodules. In total, 249 blood samples of patients with pulmonary nodules were selected from three different lung cancer centers. Five tsRNAs were identified in the discovery and training cohorts and the diagnostic signature was established by the randomForest algorithm (tRF-Ser-TGA-003, tRF-Val-CAC-005, tRF-Ala-AGC-060, tRF-Val-CAC-024, and tiRNA-Gln-TTG-001). A nomogram was developed by combining tsRNA signature and CT information. The high level of accuracy was identified in an internal validation cohort (n = 83, area under the receiver operating characteristic curve [AUC] = 0.930, sensitivity 100.0%, specificity 73.8%) and external validation cohort (n = 66, AUC = 0.943, sensitivity 100.0%, specificity 86.8%). Furthermore, the diagnostic ability of our model discriminating invasive malignant ones from noninvasive lesions was assessed. A robust performance was achieved in the diagnosis of invasive malignant lesions in both training and validation cohorts (discovery cohort: AUC = 0.850, sensitivity 86.0%, specificity 81.4%; internal validation cohort: AUC = 0.784, sensitivity 78.8%, specificity 78.1%; and external validation cohort: AUC = 0.837, sensitivity 85.7%, specificity 84.0%). This novel circulating tsRNA-based diagnostic model has potential significance in predicting malignant pulmonary nodules. Application of the model could improve the accuracy of pulmonary nodule diagnosis and optimize surgical plans.


Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Nomogramas , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Tomografia Computadorizada por Raios X/métodos , Pulmão/patologia , Estudos Retrospectivos
4.
Cell Death Differ ; 30(11): 2365-2381, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37689814

RESUMO

The clinical efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) is limited by the emergence of drug resistance. We hypothesise that restoring dysregulated circular RNAs under initial treatment with EGFR-TKIs may enhance their effectiveness. Through high-throughput screening, we identify that combining circular RNA IGF1R (cIGF1R) with EGFR-TKIs significantly synergises to suppress tumour regrowth following drug withdrawal. Mechanistically, cIGF1R interacts with RNA helicase A (RHA) to depress insulin-like growth factor 1 receptor (IGF1R) mRNA splicing, negatively regulating the parent IGF1R signalling pathway. This regulation is similar to that of IGF1R inhibitor, which induces drug-tolerant persister (DTP) state with activated mitophagy. The cIGF1R also encodes a peptide C-IGF1R that reduces Parkin-mediated ubiquitination of voltage-dependent anion channel 1 (VDAC1) to restrict mitophagy, acting as a molecular switch that promotes the transition of DTP to apoptosis. Our study shows that combining cIGF1R with EGFR-TKIs efficiently reduces the emergence of DTP.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Mitofagia , Receptores ErbB/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1
5.
Cell Death Dis ; 14(8): 551, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37620336

RESUMO

Super-enhancers (SEs) are regulatory element clusters related to cell identity and disease. While the studies illustrating the function of SE-associated long noncoding RNAs (lncRNAs) in lung adenocarcinoma (LUAD) remains few. In our research, a SE-driven lncRNA, LINC00880, was identified, which showed higher expression in LUAD compared to normal tissues and indicated worse outcomes in stage I LUADs. We found that the transcription factor (TF) FOXP3 could simultaneously occupy the promoter and SE regions of LINC00880 to promote its transcription. The oncogenic function of LINC00880 was validated both in vitro and in vivo. Mechanically, LINC00880 binds to the protein CDK1 to increase its kinase activity, which rely on the phosphorylation state of pT161 in CDK1. LINC00880 also promotes the interaction between CDK1 and PRDX1. Moreover, LINC00880 interacts with PRDX1, which indicates that LINC00880 acts as a protein scaffold between CDK1 and PRDX1 to form a ternary complex, thereby resulting in the activation of PI3K/AKT to promote malignancy. Our results reveal that the SE-associated lncRNA LINC00880 regulates the CDK1/PRDX1 axis to sustain the malignancy of LUAD, providing a novel therapeutic target.


Assuntos
Adenocarcinoma , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Fosfatidilinositol 3-Quinases , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição , Adenocarcinoma/genética , Pulmão , Peroxirredoxinas , Proteína Quinase CDC2/genética
6.
PeerJ ; 11: e15672, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37456863

RESUMO

A growing body of evidence suggests that anesthetics impact the outcome of patients with cancer after surgical intervention. However, the optimal dose and underlying mechanisms of co-administered anesthetics in lung tumor therapy have been poorly studied. Here, we aimed to investigate the role of combined anesthetics propofol, sufentanil, and rocuronium in treating lung cancer using an orthogonal experimental design and to explore the optimal combination of anesthetics. First, we evaluated the effects of the three anesthetics on the proliferation and invasion of A-549 cells using Cell Counting Kit 8 and Transwell migration and invasion assays. Subsequently, we applied the orthogonal experimental design (OED) method to screen the appropriate concentrations of the combined anesthetics with the most effective antitumor activity. We found that all three agents inhibited the proliferation of A-549 cells in a dose- and time-dependent manner when applied individually or in combination, with the highest differences in the magnitude of inhibition occurring 24 h after combined drug exposure. The optimal combination of the three anesthetics that achieved the strongest reduction in cell viability was 1.4 µmol/L propofol, 2 nmol/L sufentanil, and 7.83 µmol/L rocuronium. This optimal 3-drug combination produced a more beneficial result at 24 h than either single drug. Our results provide a theoretical basis for improving the efficacy of lung tumor treatment and optimizing anesthetic strategies.


Assuntos
Anestésicos Combinados , Neoplasias Pulmonares , Humanos , Anestésicos Combinados/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Propofol/farmacologia , Rocurônio/farmacologia , Sufentanil/farmacologia
7.
J Immunother Cancer ; 11(6)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37369391

RESUMO

BACKGROUND: It has been reported that smoking history as a predictor of immunotherapy efficacy in patients with advanced lung cancer, however, the underlying mechanisms of this phenomenon remain largely unknown. METHODS: The patients with lung adenocarcinoma's (LUAD) cohort and the orthotopical transplanted mouse model were used to explore the correlation between smoking status and tertiary lymphoid structure (TLS) and chemokine CCL21, respectively. Cell adhesion and co-immunoprecipitation assays were performed to explore the interaction between CD4+T cells and CD20+B cells under tobacco exposure. Chromatin immunoprecipitation-PCR was used to dissect the mechanism of upregulated CCL21 secretion in tobacco treatment. Serum CCL21 level was recorded in patients with LUAD treated with immunotherapy. RESULTS: Here we observed that individuals with a smoking history exhibit an increased quantity and maturation level of TLS compared with non-smokers, along with higher levels of CCL21 secretion. Tobacco exposure promoted CCL21 expression in an epithelial cell-intrinsic manner, of which BaP, the main component of tobacco, facilitated the nuclear retention of the aryl hydrocarbon receptor that occupied the promoter of CCL21. Additionally, the activated CCL21/CCR7 axis increased the CD11a expression of CD4+T cells, boosting the interaction with CD20+B cells dependent on ICAM1, which potentially induced the TLSs formation. Patients with elevated serum levels of CCL21 benefited more from immunotherapy. CONCLUSIONS: Patients with a smoking history exhibited higher levels of TLS via the CCL21-dependent mechanism, serum CCL21 was identified as a reliable biomarker for predicting the efficacy of immunotherapy.


Assuntos
Quimiocina CCL21 , Estruturas Linfoides Terciárias , Animais , Camundongos , Linhagem Celular Tumoral , Quimiocina CCL21/metabolismo , Imunoterapia , Humanos
8.
Cancers (Basel) ; 14(22)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36428729

RESUMO

Cancer ranks as the second leading cause of death worldwide, and, being a genetic disease, it is highly heritable. Over the past few decades, genome-wide association studies (GWAS) have identified many risk-associated loci harboring hundreds of single nucleotide polymorphisms (SNPs). Some of these cancer-associated SNPs have been revealed as causal, and the functional characterization of the mechanisms underlying the cancer risk association has been illuminated in some instances. In this review, based on the different positions of SNPs and their modes of action, we discuss the mechanisms underlying how SNPs regulate the expression of target genes to consequently affect tumorigenesis and the development of cancer.

9.
Oncogenesis ; 11(1): 61, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36216804

RESUMO

Lung adenocarcinoma (LUAD) exhibits high heterogeneity and is well known for its high genetic variation. Recently, the understanding of non-genetic variation provides a new perspective to study the heterogeneity of LUAD. Little is known about whether super-enhancers (SEs) may be primarily responsible for the inter-tumor heterogeneity of LUAD. We used super-enhancer RNA (seRNA) levels of a large-scale clinical well-annotated LUAD cohort to stratify patients into three clusters with different prognosis and other malignant characteristics. Mechanistically, estrogen-related receptor alpha (ERRα) in cluster 3-like cell lines acts as a cofactor of BRD4 to assist SE-promoter loops to activate glycolysis-related target gene expression, thereby promoting glycolysis and malignant progression, which confers a therapeutic vulnerability to glycolytic inhibitors. Our study identified three groups of patients according to seRNA levels, among which patients in cluster 3 have the worst prognosis and vulnerability of glycolysis dependency. We also proposed a 3-TF index model to stratify patients with glycolysis-addicted tumors according to tumor SE stratification.

10.
J Hematol Oncol ; 15(1): 114, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982471

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) is the leading cause of death worldwide. However, the roles of long noncoding RNAs (lncRNAs) hijacked by super-enhancers (SEs), vital regulatory elements of the epigenome, remain elusive in the progression of LUAD metastasis. METHODS: SE-associated lncRNA microarrays were used to identify the dysregulated lncRNAs in LUAD. ChIP-seq, Hi-C data analysis, and luciferase reporter assays were utilized to confirm the hijacking of LINC01977 by SE. The functions and mechanisms of LINC01977 in LUAD were explored by a series of in vitro and in vivo assays. RESULTS: We found that LINC01977, a cancer-testis lncRNA, was hijacked by SE, which promoted proliferation and invasion both in vitro and in vivo. LINC01977 interacted with SMAD3 to induce its nuclear transport, which facilitated the interaction between SMAD3 and CBP/P300, thereby regulating the downstream target gene ZEB1. Additionally, SMAD3 up-regulated LINC09177 transcription by simultaneously binding the promoter and SE, which was induced by the infiltration of M2-like tumor-associated macrophages (TAM2), subsequently activating the TGF-ß/SMAD3 pathway. Moreover, LINC01977 expression was positively correlated with TAM2 infiltration and SMAD3 expression, especially in early-stage LUAD. Higher chromatin accessibility in the SE region of LINC01977 was observed with high expression of TGF-ß. Early-stage LUAD patients with high LIN01977 expression had a shorter disease-free survival. CONCLUSIONS: TAM2 infiltration induced a rich TGF-ß microenvironment, activating SMAD3 to bind the promoter and the SE of LINC01977, which up-regulated LINC01977 expression. LINC01977 also promoted malignancy via the canonical TGF-ß/SMAD3 pathway. LINC01977 hijacked by SE could be a valuable therapeutic target, especially for the treatment of early-stage LUAD.


Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
11.
J Cell Mol Med ; 26(2): 436-448, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34877770

RESUMO

TP53 mutation is the most widespread mutation in lung adenocarcinoma (LUAD). Meanwhile, p53 (encoded by TP53) has recently been implicated in immune responses. However, it is still unknown whether TP53 mutation remodels the tumour microenvironment to influence tumour progression and prognosis in LUAD. In this study, we developed a 6-gene immune-related risk model (IRM) to predict the survival of patients with LUAD in The Cancer Genome Atlas (TCGA) cohort based on TP53 status, and the predictive ability was confirmed in 2 independent cohorts. TP53 mutation led to a decreased immune response in LUAD. Further analysis revealed that patients in the high-index group had observably lower relative infiltration of memory B cells and regulatory T cells and significantly higher relative infiltration of neutrophils and resting memory CD4+ T cells. Additionally, the IRM index positively correlated with the expression of critical immune checkpoint genes, including PDCD1 (encoding PD-1) and CD274 (encoding PD-L1), which was validated in the Nanjing cohort. Furthermore, as an independent prognostic factor, the IRM index was used to establish a nomogram for clinical application. In conclusion, this IRM may serve as a powerful prognostic tool to further optimize LUAD immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Prognóstico , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
BMC Cancer ; 21(1): 1098, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641822

RESUMO

BACKGROUND: This study aimed to develop a reliable immune signature based on B-cell proportion to predict the prognosis and benefit of immunotherapy in LUAD. METHODS: The proportion of immune cells in the TCGA-LUAD dataset was estimated using MCP-counter. The Least Absolute Shrinkage and Selector Operation was used to identify a prognostic signature and validated in an independent cohort. We used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) data and formalin-fixed paraffin-embedded (FFPE) specimens immunohistochemistry to illustrate the correlation between prognostic signature and leukocyte migration. RESULTS: We found that the relative abundance of B lineage positively correlated with overall survival. Then, we identified a 13-gene risk-score prognostic signature based on B lineage abundance in the testing cohort and validated it in a cohort from the GEO dataset. This model remained strongly predictive of prognoses across clinical subgroups. Further analysis revealed that patients with a low-risk score were characterized by B-cell activation and leukocyte migration, which was also confirmed in FFPE specimens by qRT-PCR and immunohistochemistry. Finally, this immune signature was an independent prognostic factor in the composite nomogram of clinical characteristics. CONCLUSIONS: In conclusion, the 13-gene immune signature based on B-cell proportion may serve as a powerful prognostic tool in LUAD.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos B/citologia , Perfilação da Expressão Gênica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/citologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/terapia , Movimento Celular , Bases de Dados Genéticas , Feminino , Humanos , Imunidade Celular , Imuno-Histoquímica , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Masculino , Nomogramas , Inclusão em Parafina , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Análise de Sequência de RNA
13.
Mol Ther Nucleic Acids ; 23: 355-368, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33425493

RESUMO

Aberrant expression of circular RNAs (circRNAs) is involved in cancer progression through interaction with RNA-binding proteins (RBPs). Herein, we screened circRNA expression of A549 cells in circBase and the crosslinking immunoprecipitation (CLIP) data of human antigen R (HuR), an extensively studied RBP, and identified a circRNA, circ-defective in cullin neddylation 1 domain containing 4 (circDCUN1D4), originating from the DCUN1D4 gene transcript. circDCUN1D4 is downregulated in tumor samples under the mediation of DExH-box helicase 9 (DHX9), which inhibits the formation of circRNA by binding inverted repeat Alus (IRAlus) in flanking sequences. circDCUN1D4 depletion promoted invasion in vitro and metastasis in vivo. Importantly, the interaction between circDCUN1D4 and HuR increased the transportation of HuR to the cytoplasm. circDCUN1D4 acts as a scaffold to facilitate the interaction between the HuR protein and thioredoxin-interacting protein (TXNIP) mRNA, which enhances the stability of the TXNIP mRNA. Additionally, circDCUN1D4 directly interacts with TXNIP mRNA through base complementation, indicating the formation of the circDCUN1D4/HuR/TXNIP RNA-protein ternary complex. Furthermore, circDCUN1D4 suppressed metastasis and glycolysis of lung cancer cells in a TXNIP-dependent manner. Clinically, the downregulated expression of circDCUN1D4 was more prevalent in lymph node metastatic tissues and served as an independent risk factor for the overall survival of lung adenocarcinoma (LUAD) patients. These findings demonstrated that a novel circRNA, circDCUN1D4, is involved in the metastasis and glycolysis of LUAD.

14.
Front Oncol ; 10: 573534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324550

RESUMO

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.

15.
Cell Death Dis ; 11(11): 1010, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239613

RESUMO

Mutation or downregulation of p53 (encoded by TP53) accelerates tumorigenesis and malignant progression in esophageal squamous cell carcinoma (ESCC). However, it is still unknown whether circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, participate in the regulation of this progress. In this study, we explored the expression profiles of circRNAs in three paired samples of ESCC and identified cCNTNAP3, which is a circRNA that originates from the CNTNAP3 gene transcript and is highly expressed in normal human esophageal tissue. However, we found that the cCNTNAP3 expression level was significantly downregulated in ESCC tissues. In vitro and in vivo studies revealed that cCNTNAP3 inhibited proliferation and increased apoptosis in p53 wild-type ESCC cells, but not in mutant cells. Mechanistically, we found that cCNTNAP3 promotes the expression of p53 by sponging miR-513a-5p. Rescue assay confirmed that the suppressive function of cCNTNAP3 was dependent on miR-513a-5p. We also observed that p53/RBM25 participated in the formation of cCNTNAP3, which implied the existence of a positive feedback loop between cCNTNAP3 and p53. Furthermore, the downregulation of cCNTNAP3 was significantly correlated with later T stage and thus can serve as an independent risk factor for the overall survival of patients with p53 wild-type ESCC. In conclusion, the cCNTNAP3-TP53 positive feedback loop may provide a potential target for the management of ESCC, which also reveals the important role of circRNAs in the regulation of p53.


Assuntos
Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , RNA Circular/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Xenoenxertos , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas do Tecido Nervoso/metabolismo , RNA Circular/genética , Transfecção , Proteína Supressora de Tumor p53/genética
16.
Oncogenesis ; 9(10): 92, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33070167

RESUMO

Lung adenocarcinoma (LUAD) relies on dysregulated gene expression to sustain its infinite growth and progression. Emerging evidence indicates that aberrant transcriptional program results from core transcriptional regulatory circuitry (CRC) which is driven by super-enhancers (SEs). In this study, by integrating profiles of H3K27Ac chromatin immunoprecipitation sequencing (ChIP-seq) from normal adult lung and LUAD cell lines, we revealed that widespread alterations of the super-enhancer were presence during lung carcinogenesis. With SE-based modeling of regulatory circuits and assessments of transcription factor (TF) dependencies, we reconstructed an interconnected transcriptional regulation network formed by three master TFs, including ELF3, EHF, and TGIF1, all of which promoted each other's expression that confirmed by ChIP-qPCR and western blot. Loss-of function assay revealed that each of them is essential for LUAD cells survival, invasion and metastasis. Meanwhile, the rescue assay also illustrated the transacting transcriptional regulatory circuitry. In addition, the mRNA levels of ELF3, EHF, and TGIF1 were differentially expressed in LUAD tumors and peritumoral tissue. IHC of serial sections revealed that high expressions of CRC (ELF3/EHF/TGIF1-High) were closely associated with high proliferative activity in tumor tissue and poor prognosis on patients with LUAD. Finally, we used small molecular inhibitors to perturb the transcriptional circuitry, also exhibited a prominent anti-cancer effect in vitro. Our findings reveal the mechanism of the transcriptional dysregulation and addiction of LUAD.

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