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1.
Zhonghua Yi Xue Za Zhi ; 100(45): 3614-3621, 2020 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-33333686

RESUMO

Objective: To investigate the feasibility of circulating tumor DNA (ctDNA) in detecting small cell lung cancer (SCLC) gene mutations and its prognostic value in chemotherapy and/or radiotherapy for SCLC patients. Methods: A total of 77 SCLC patients who were admitted to the Department of Thoracic Medical Oncology and the Department of Thoracic Radiation Oncology of Zhejiang Cancer Hospital from July 2016 to November 2019 were included. There were 66 males and 11 females, with a median age of 60 years. Among them, 42 cases were in limited stage (LS) and 35 cases were in extensive stage (ES). Next-generation sequencing (NGS) of patients' plasma ctDNA was performed before treatment. The differences of mutated genes and signaling pathways between LS and ES patients were analyzed and compared. Blood-based tumor mutation burden (bTMB) was calculated according to detected somatic cell mutations. Patients were divided into the high bTMB and the low bTMB groups according to the optimal threshold calculated by R software. Log-rank tests were used to compare progression-free survival (PFS) between the high bTMB and the low bTMB groups. Results: Among the 77 patients, 76 patients had gene mutations detected in their plasma, and the positive rate of ctDNA test was 98%. Among the 76 patients, the genes with the highest mutation frequency were TP53 (89%), RB1 (70%), LRP1B (34%), CREBBP (21%), MLL3 (21%), MLL2 (16%), NOTCH1 (13%), ROS1 (13%), BRCA2 (12%), and PTPRD (12%). The most common mutated genes in LS patients were TP53 (90%), RB1 (68%), LRP1B (24%), MLL2 (22%), and BRCA2 (17%); the most common mutated genes in ES patients were TP53 (89%), RB1 (71%), LRP1B (46%), CREBBP (31%), and MLL3 (29%). The mutation rates of NOTCH1 and CREBBP genes were significantly higher in ES patients (31.4% and 22.9%) than those in LS patients (11.9% and 4.8%) (both P<0.05). Signaling pathway analysis showed that there were more NOTCH pathway gene variations in ES patients. Among LS patients, patients in the high bTMB group (≥ 6.96 mutations/Mb) had a longer PFS than that in the low bTMB group (<6.96 mutations/Mb) (P=0.033); but no such difference was noted in ES patients. Conclusion: Plasma ctDNA sequencing detected SCLC gene mutation profiles similar to those reported in previous literature, thus ctDNA could be used as a tool to study SCLC genomics; the mutation spectra of ES-SCLC and LS-SCLC were different. bTMB has potential prognostic value in LS-SCLCs treated with chemoradiotherapy.


Assuntos
DNA Tumoral Circulante , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Biomarcadores Tumorais/genética , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Carcinoma de Pequenas Células do Pulmão/genética
2.
Am J Clin Oncol ; 43(9): 670-675, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889839

RESUMO

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non-small cell lung cancer and conversely, patients with non-small cell lung cancer have had transformation to small cell lung cancer or other non-small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Transformação Celular Neoplásica , Receptores ErbB/genética , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia
3.
J Cancer Res Clin Oncol ; 146(10): 2519-2534, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32648226

RESUMO

PURPOSE: Metastasis is an unavoidable event happened among almost all small cell lung cancer (SCLC) patients. However, the molecular driven factors have not been elucidated. Recently, a novel hydrolase called cell migration inducing hyaluronidase (CEMIP) triggered both migration and invasion in many tumors but not SCLC. Therefore, in this study, we verified that CEMIP promoted migration and invasion in SCLC and applied proteomics analysis to screen out potential target profiles and the signaling pathway related to CEMIP regulation. METHOD: Immunofluorescence was conducted to exam the expression of CEMIP on SCLC and paired adjacent normal tissues among enrollment. RT-qPCR and Western blot (WB) assays were conducted to valuate cellular protein and mRNA expression of CEMIP and EMT markers. Lentivirus-CEMIP-shRNAs and CEMIP plasmid were used for expression manipulating. Changes of cellular migration and invasion were tested through transwell assays. Tandem Mass Tag (TMT) peptide labeling coupled with LC-MS/MS was used for quantifying proteins affected by reducing expression of CEMIP on H446 cells. RESULTS: The expression of CEMIP showed 1.64 ± 0.16-fold higher in SCLC tissues than their normal counterpart. Decreasing the expression of CEMIP on SCLC cells H446 regressed both cellular migration and invasion ability, whereas the promoting cellular migration and invasion was investigated through over-expressing CEMIP on H1688. Proteomic and bioinformatics analysis revealed that total 215 differentially expressed proteins (DEPs) that either their increasing or decreasing relative expression met threshold of 1.2-fold changes with p value ≤ 0.05. The dramatic up-regulated DEPs included an unidentified peptide sequence (encoded by cDNA FLJ52096) SPICE1 and CRYAB, while the expression of S100A6 was largely down-regulated. DEPs mainly enriched on caveolae of cellular component, calcium ion binding of biological process and epithelial cell migration of molecular function. KEGG enrichment indicated that DEPs mainly exerted their function on TGF-ß, GABAergic synapse and MAPK signaling pathway. CONCLUSION: It is the first report illustrating that CEMIP might be one of the metastatic triggers in SCLC. And also, it provided possible molecular mechanism cue and potential downstream target on CEMIP-induced cellular migration and invasion on SCLC.


Assuntos
Hialuronoglucosaminidase/metabolismo , Neoplasias Pulmonares/metabolismo , Proteoma/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Idoso , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Feminino , Imunofluorescência , Humanos , Hialuronoglucosaminidase/biossíntese , Hialuronoglucosaminidase/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
4.
Mol Carcinog ; 59(8): 967-979, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32424979

RESUMO

Drug resistance is the leading cause for rapid progression and relapse in small-cell lung cancer (SCLC) patients. Thus overcoming drug resistance still remains to be urgently resolved during SCLC treatment. Here, we found p62/SQSTM1 was enriched in SCLC spheroids, a subpopulation possessing cancer stem-like properties, which is responsible for cancer relapse and metastasis. Subsequent functional assays in vitro showed that short hairpin RNA (shRNA)-mediated p62 knockdown increased sensitivity of SCLC cell lines to cisplatin (DDP), whereas lentivirus-mediated p62 ectopic overexpression diminished DDP-induced cytotoxicity in both NCI-H446 and NCI-H1688 cell lines. Moreover, ectopic p62 overexpression promoted DDP resistance of NCI-H446 cells-derived tumor xenografts in immunodeficient mice in vivo, as indicated by accelerated tumor growth rate and reduced fluorescent activity of cleaved caspase-3. Gene expression profiling analysis revealed that p62 was positively correlated with neuronal precursor cell-expressed, developmentally downregulated gene 9 (NEDD9) expression level. Consistently, NEDD9 messenger RNA (mRNA) level was decreased upon p62 suppression by small interfering RNA (siRNA) and increased with p62 transient overexpression in SCLC cell lines, suggesting that p62 positively regulated NEDD9 mRNA. Depletion of NEDD9 by siRNA, to a large extent, reversed p62-overexpressed SCLC cells to DDP-induced cytotoxicity, implying NEDD9 might act as a downstream target which was in charge of p62-mediated DDP resistance. Taken together, our findings uncovered a previously unknown role of p62 in the regulation of SCLC drug resistance, assigning p62 as an attractive target for SCLC treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Sequestossoma-1/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Interferente Pequeno/genética , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Eur J Cancer ; 132: 24-34, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325417

RESUMO

BACKGROUND: Dissemination of non-small-cell lung cancer (NSCLC) in the central nervous system is a frequent and challenging clinical problem. Systemic or local therapies rarely prolong survival and have modest activity regarding local control. Alterations in gene expression in brain metastasis versus primary tumour may increase aggressiveness and impair therapeutic efforts. METHODS: We identified 25 patients with surgically removed NSCLC brain metastases in two different patient cohorts. For 13 of these patients, primary tumour samples were available. Gene expression analysis using the nCounter® PanCancer Immune Profiling gene expression panel (nanoString technologies Inc.) was performed in brain metastases and primary tumour samples. Identification of differentially expressed genes was conducted on normalized data using the nSolver analysis software. RESULTS: We compared gene expression patterns in brain metastases with primary tumours. Brain metastasis samples displayed a distinct clustering pattern compared to primary tumour samples with a statistically significant downregulation of genes related to immune response and immune cell activation. Results from KEGG term analysis on differentially expressed genes revealed a concomitant enrichment of multiple KEGG terms associated with the immune system. We identified a 12-gene immune signature that clearly separated brain metastases from primary tumours. CONCLUSIONS: We identified a unique gene downregulation pattern in brain metastases compared with primary tumours. This finding may explain the lower intracranial efficacy of systemic therapy, especially immunotherapy, in brain metastasis of patients with NSCLC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Transcriptoma , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia
6.
Gene ; 745: 144629, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32229158

RESUMO

Small-cell lung cancer (SCLC) is the most invasive of all lung cancer subtypes, and is characterized by its rapid response to chemotherapy resistance. Overcoming chemotherapy resistance is therefore the key to treating SCLC. P53 is mutated in most SCLCs, which has an effect of enhancing chemotherapy resistance. Regulation of p53 proteins by a variety of post-translational modifications, such as acetylation, which affects their function. Acetylation and deacetylation of p53 may be potential targets for modulating chemosensitivity. Recent studies have shown that SIRT3 acts as a deacetylase that regulates acetylation of p53. However, whether SIRT3 can regulate the post-translational modification of mutant p53 has not been studied. In the present study, we found that SIRT3 can deacetylate mutant p53, thus reducing its expression, inducing apoptosis in SCLC cells, and increasing SCLC chemosensitivity. The relationship between SIRT3 and mutant p53 could be the basis of a new SCLC treatment approach.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Sirtuína 3/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mutação , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Res ; 80(11): 2355-2367, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32265224

RESUMO

The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.


Assuntos
CDC2-CDC28 Quinases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteína do Retinoblastoma/deficiência , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , CDC2-CDC28 Quinases/genética , CDC2-CDC28 Quinases/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas de Ligação a Retinoblastoma/deficiência , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Biochem Biophys Res Commun ; 524(4): 803-809, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32037090

RESUMO

The carcinogenic function of arachidonate lipoxygenase12 (Alox12) has been reported in various cancers. However, little is known on the role of Alox12 in lung cancer. Here, we demonstrate that Alox12 is upregulated and contributes to biological activities of lung cancer through multiple mechanisms. We found that Alox12 mRNA and protein levels were increased by 2.5-fold in a panel of lung cancer cell lines compared to normal lung cells. The expression of Alox12 varied among lung cancer cell lines. The immunohistochemistry analysis on paired normal and tumor lung tissues from twenty patients showed that Alox12 protein level is higher in lung cancer than normal lung tissues from the majority of patients. We further observed the upregulation of Alox12-12-HETE signaling axis in lung cancer tissues. Overexpression of Alox12 promoted growth and migration in normal lung cells and lung cancer cells. In contrast, Alox12 inhibition via genetic and pharmacological approaches suppressed growth and migration, induced apoptosis, and sensitized lung cancer cells to chemotherapy. This is through suppressing RhoA signaling, inhibiting epithelial-to-mesenchymal transition (EMT) and NF-κB activity. Our work reveals the therapeutic value of inhibiting Alox12 in overcoming chemoresistance in lung cancer.


Assuntos
Araquidonato 12-Lipoxigenase/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , NF-kappa B/genética , Carcinoma de Pequenas Células do Pulmão/genética , Proteína rhoA de Ligação ao GTP/genética , Apoptose/genética , Araquidonato 12-Lipoxigenase/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Flavanonas/farmacologia , Humanos , Imuno-Histoquímica , Inibidores de Lipoxigenase/farmacologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína rhoA de Ligação ao GTP/metabolismo
9.
Oncol Rep ; 43(2): 591-600, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894331

RESUMO

Mutation of the p53 tumor suppressor frequently occurs in lung cancer, and can be as high as 75­90% in small­cell lung cancer. Mutant p53 (mtp53) can inhibit the wild­type p53 protein, disrupting its tumor suppressor functions. In addition, mutant p53 often acquires the functions of an oncogene. Post­translational modification of the p53 protein is important for its transcriptional and tumor suppressive functions. We previously revealed that high levels of mutant p53 expression were associated with reduced expression of the deacetylation enzyme sirtuin 3 (SIRT3) in lung cancer tissues. Given this negative correlation between p53 and SIRT3 expression, and given that SIRT3 is a deacetylase, we speculated that SIRT3 participates in the post­translational modification of mutant p53, regulating its stability and function, thereby inhibiting the growth of lung cancer cells. Light microscopy, MTT and flow cytometric assays revealed that SIRT3 overexpression inhibited growth and promoted apoptosis in NCI­H446 human small cell lung cancer cells. SIRT3 overexpression also resulted in necroptosis, and this could be partially reversed following cell treatment with the necroptosis inhibitor necrostatin­1 (Nec­1), which could restore certain cells to survive. Western blotting assays revealed that SIRT3 overexpression resulted in the reduced expression and half­life of mutant p53, indicating that SIRT3 decreases mutant p53 stability. Proteasome inhibitor experiments revealed that the decrease in mutant p53 stability was a result of increased proteasomal degradation of the protein. Immunoprecipitation studies revealed that ubiquitination of mutant p53 was elevated in SIRT3­overexpressing cells, indicating that SIRT3 affected ubiquitination­mediated protein degradation. In the present study, it was therefore revealed that SIRT3 can inhibit the growth of human small­cell lung cancer cells by promoting apoptosis and necroptosis. It was also revealed that SIRT3 expression could regulate the stability of mutant p53 by controlling ubiquitination­mediated proteasomal degradation of the protein. SIRT3 expression may therefore play an important role in the growth of mutant p53­associated lung cancer.


Assuntos
Neoplasias Pulmonares/patologia , Mutação , Sirtuína 3/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína Supressora de Tumor p53/genética , Acetilação , Animais , Apoptose , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Necroptose , Transplante de Neoplasias , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação
10.
Oncogene ; 39(2): 293-307, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31477834

RESUMO

The functional effects of long noncoding RNAs (lncRNAs) in cancer have been widely recognized. However, there is little research on SCLC-related lncRNAs. Here, long intergenic nonprotein coding RNA 173 (Linc00173) was first shown to be involved in chemoresistance and progression of small-cell lung cancer (SCLC). We found that Linc00173 was highly expressed in SCLC chemoresistant cell lines, and promoted SCLC cells chemoresistance, proliferation, and migration-invasion. Animal studies validated that Linc00173 induced tumor chemoresistance and growth of SCLC in vivo. Moreover, Linc00173 upregulated Etk through functioning as a competitive endogenous RNA (ceRNA) by "sponging" miRNA-218 and led to the upregulation of GSKIP and NDRG1, resulting in the translocation of ß-catenin. Importantly, expression analysis revealed that both Linc00173 and Etk were upregulated in SCLC patient samples and exhibiting positive Linc00173/Etk correlation. High expression of Linc00173 closely correlated with chemoresistance, extensive stage, and shorter survival in SCLC patients. Collectively, our study illustrated a Linc00173-mediated process that facilitated chemoresistance and progression in SCLC, which might provide treatment strategy against SCLC.


Assuntos
MicroRNAs/genética , Proteínas Tirosina Quinases/genética , RNA Longo não Codificante/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adulto , Idoso , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Etoposídeo/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , beta Catenina/genética
11.
Cancer Cell ; 37(1): 37-54.e9, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31883968

RESUMO

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Instabilidade Genômica , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Animais , Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Quimiocina CXCL9/metabolismo , Dano ao DNA , Feminino , Humanos , Sistema Imunitário , Inflamação , Interferon gama/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Camundongos , Testes para Micronúcleos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pirazóis/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/imunologia , Fator de Necrose Tumoral alfa/metabolismo
12.
Cancer Sci ; 111(2): 610-620, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31845438

RESUMO

High-grade neuroendocrine lung cancer (HGNEC), which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is a rapidly proliferating, aggressive form of lung cancer. The initial standard chemotherapeutic regimens of platinum doublets are recommended for SCLC and have been frequently used for LCNEC. However, there are currently no molecularly targeted agents with proven clinical benefit for this disease. The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCHL1) is a neuroendocrine cell-specific product that is known as a potential oncogene in several types of cancer, but little is known about the biological function of UCHL1 and its therapeutic potential in HGNEC. In this study, we found that preclinical efficacy evoked by targeting UCHL1 was relevant to prognosis in HGNEC. UCHL1 was found to be expressed in HGNEC, particularly in cell lines and patient samples of SCLC, and the combined use of platinum doublets with selective UCHL1 inhibitors improved its therapeutic response in vitro. Immunohistochemical expression of UCHL1 was significantly associated with postoperative survival in patients with HGNEC and contributed towards distinguishing SCLC from LCNEC. Circulating extracellular vesicles (EV), including exosomes isolated from lung cancer cell lines and serum from early-stage HGNEC, were verified by electron microscopy and nanoparticle tracking analysis. Higher levels of UCHL1 mRNA in EV were found in the samples of patients with early-stage HGNEC than those with early-stage NSCLC and healthy donors' EV. Taken together, UCHL1 may be a potential prognostic marker and a promising druggable target for HGNEC.


Assuntos
Carcinoma Neuroendócrino/patologia , Vesículas Extracelulares/genética , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Células A549 , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Vesículas Extracelulares/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Platina/farmacologia , Platina/uso terapêutico , Prognóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Regulação para Cima
13.
Proc Natl Acad Sci U S A ; 117(1): 513-521, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871154

RESUMO

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, loss of p107 results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130 Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.


Assuntos
Edição de Genes/métodos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Animais , Apoptose/genética , Sistemas CRISPR-Cas/genética , Linhagem Celular , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Estudos de Viabilidade , Humanos , Mutação com Perda de Função , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Estadiamento de Neoplasias , Proteína p107 Retinoblastoma-Like/genética , Proteína p130 Retinoblastoma-Like/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carga Tumoral/genética , Proteína Supressora de Tumor p53/genética
14.
Exp Mol Med ; 51(12): 1-13, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31827074

RESUMO

Small-cell lung cancer (SCLC) remains the deadliest of all the lung cancer types. Its high mortality is largely attributed to the invariable development of resistance to standard chemo/radiotherapies, which have remained unchanged for the past 30 years, underscoring the need for new therapeutic approaches. The discovery of molecular targets for chemoprevention and treatment has been hampered by the poor understanding of SCLC progression. In recent years, comprehensive omics-based analyses have led to the discovery of recurrent alterations in patient tumors, and functional studies using genetically engineered mouse models and patient-derived tumor models have provided information about the alterations critical for SCLC pathogenesis. Defining the somatic alterations scattered throughout the SCLC genome will help to understand the underlying mechanism of this devastating disease and pave the way for the discovery of therapeutic vulnerabilities associated with the genomic alterations.


Assuntos
Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Animais , Epigenômica , Humanos , Mutação/genética
15.
BMC Pulm Med ; 19(1): 246, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842825

RESUMO

Lung adenocarcinoma associated transcript 1 (LUADT1) has been reported as an oncogenic long non-coding RNA (lncRNA) in lung adenocarcinoma, while its roles in small cell lung cancer (SCLC) are unknown. Our RNA interaction bioinformatics prediction showed that LUADT1 could form strong base pairing with miR-15a-3p, which is a tumor-suppressive miRNA that can target Twist1. We found that LUADT1 and Twist1 were upregulated in SCLC, while miR-15a-3p was downregulated in SCLC. However, LUADT1 was posively correlated with Twist1 but was not significnatly correlated with miR-15a-3p. Overexpression experiments showed that and LUADT1 and miR-15a-3p did not significantly affect the expression of each other. Moreover, LUADT1 overexpression mediated the upregualtion of Twist1, and miR-15a-3p overexpression played an oppsoite role. Transwell assays showed that LUADT1 and Twist1 overexpression mediated the increased rate of cell invasion and migration, while miR-15a-3p overexpression mediated the decreased rate of cell invasion and migration. In addition, miR-15a-3p overexpression played an oppsoite role and attenuated the effects of LUADT1 overexpression. Therefore, LUADT1 may sponge miR-15a-3p to upregulate Twist1 in SCLC, thereby promoting cancer cell invasion and migration. TRIAL REGISTRATION: 2017GZH-1-201,746,382, registered at Jan 02,2017.


Assuntos
Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Proteínas Nucleares/metabolismo , RNA Longo não Codificante/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Regiões 3' não Traduzidas , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína 1 Relacionada a Twist/genética
16.
Clin Epigenetics ; 11(1): 175, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791387

RESUMO

BACKGROUND: Lung (LC), prostate (PCa) and colorectal (CRC) cancers are the most incident in males worldwide. Despite recent advances, optimal population-based cancer screening methods remain an unmet need. Due to its early onset, cancer specificity and accessibility in body fluids, aberrant DNA promoter methylation might be a valuable minimally invasive tool for early cancer detection. Herein, we aimed to develop a minimally invasive methylation-based test for simultaneous early detection of LC, PCa and CRC in males, using liquid biopsies. RESULTS: Circulating cell-free DNA was extracted from 102 LC, 121 PCa and 100 CRC patients and 136 asymptomatic donors' plasma samples. Sodium-bisulfite modification and whole-genome amplification was performed. Promoter methylation levels of APCme, FOXA1me, GSTP1me, HOXD3me, RARß2me, RASSF1Ame, SEPT9me and SOX17me were assessed by multiplex quantitative methylation-specific PCR. SEPT9me and SOX17me were the only biomarkers shared by all three cancer types, although they detected CRC with limited sensitivity. A "PanCancer" panel (FOXA1me, RARß2me and RASSF1Ame) detected LC and PCa with 64% sensitivity and 70% specificity, complemented with "CancerType" panel (GSTP1me and SOX17me) which discriminated between LC and PCa with 93% specificity, but with modest sensitivity. Moreover, a HOXD3me and RASSF1Ame panel discriminated small cell lung carcinoma from non-small cell lung carcinoma with 75% sensitivity, 88% specificity, 6.5 LR+ and 0.28 LR-. An APCme and RASSF1Ame panel independently predicted disease-specific mortality in LC patients. CONCLUSIONS: We concluded that a DNA methylation-based test in liquid biopsies might enable minimally invasive screening of LC and PCa, improving patient compliance and reducing healthcare costs. Moreover, it might assist in LC subtyping and prognostication.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Detecção Precoce de Câncer/métodos , Biópsia Líquida/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Neoplasias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Regiões Promotoras Genéticas , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Sensibilidade e Especificidade , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Sequenciamento Completo do Genoma
17.
Respir Res ; 20(1): 248, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699089

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive lung cancer subtype with poor survival and limited treatment options. Sequencing results have revealed gene mutations associated with SCLC, however, the correlation between the genomic alterations and clinical prognosis of SCLC is yet unclear. METHODS: Targeted next-generation sequencing of 62 cancer related genes was performed on 53 SCLC samples. The correlations between clinical outcomes and genomic alterations were analyzed. RESULTS: 38/62 (61.3%) candidate genes harbored some alterations, while all the SCLC samples carried at least 3 gene mutations. The most common nonsynonymous mutations included ERBB2 (95.9%), CREBBP (95.9%), and TP53 (77.6%). The median nonsynonymous tumor mutation burden (TMB) was 21.7 mutations/Mb (rang, 9.3-55.9). High TMB (> 21 mutations/Mb) was good prognostic factor in overall survival (OS) (21.7 vs. 10.4 months, P = 0.012). Multivariate analysis showed that high TMB was an independent prognostic factor. The overall survival (OS) of patients carrying KIAA1211 mutation was significantly longer than those with wild-type KIAA1211 (P < 0.001). CONCLUSIONS: The current study highlights the potential role of genomic alterations for the prognosis of SCLC. Higher TMB was associated with a better prognosis, and KIAA1211 might be a good prognostic factor in SCLC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Pulmonares/genética , Proteínas dos Microfilamentos/genética , Mutação , Carcinoma de Pequenas Células do Pulmão/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Gravidez , Intervalo Livre de Progressão , Medição de Risco , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia
18.
Biomed Res Int ; 2019: 6096350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781628

RESUMO

Purpose: Studies on genetic alterations of the heterogenous small cell lung cancer (SCLC) are rare. We carried out the present study to clarify the genomic alterations and TMB levels of Chinese SCLC patients by whole-exome sequencing. Materials and Methods: Whole-exome sequencing by next-generation sequencing technique was implemented on twenty SCLC samples. Significant somatic mutations and copy number variations were screened, followed by comparison with the data extracted from COSMIC. Besides, altered signaling pathways were examined in order to figure out actionable targets. Results: A total of 8,062 nonsynonymous mutations were defined. The number of mutations for each case ranged from 98 to 864. As for base substitutions, a total of 15,817 substitutions were detected with C > A conversion which was correlated to smoking occupying 25.57%. The TMB values ranged from 2.51/Mb to 22.1/Mb with a median value of 9.95/Mb. RB1 was the most frequently mutated gene altered in 18 (90%) cases, followed by TP53 altered in 17 (85%) cases. Other commonly changed genes were PTEN, and RBL1, with frequencies of 55% and 50%, respectively. SOX2 significantly amplified in 6 (30%) cases and MYCN amplified in 1 (5%) patient. Notch signaling pathway and PI3K/AKT/mTOR signaling pathway were universally and significantly changed. Major genomic alterations were in consistency with data from COSMIC, but frequencies of less common mutations were different. Conclusion: TP53 and RB1 inactivations were universally detected in SCLC. The Notch and PI3K/AKT/mTOR signaling pathways were both significantly altered, implying potential actionable targets.


Assuntos
Neoplasias Pulmonares/genética , Mutação/genética , Carcinoma de Pequenas Células do Pulmão/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Exoma/métodos
19.
Medicine (Baltimore) ; 98(42): e17335, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626089

RESUMO

BACKGROUND: Previous studies have shown that microRNA-32 (miRNA-32) is an exosome microRNA that affects the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells. In this study, our goal was to assess the expression of plasma microRNA-32 and its potential as a biomarker to predict the tumor response and survival of patients with NSCLC undergoing platinum-based chemotherapy. METHODS: Plasma microRNA-32 levels before and after 1 cycle of platinum-based chemotherapy in 43 patients with NSCLC were measured using a quantitative real-time polymerase chain reaction assay (qPCR). In addition, the demographic and survival data of the patients were collected for analysis. RESULTS: A significant correlation was observed between the changes in microRNA-32 levels before and after 1 chemotherapy cycle and the treatment response (P = .035). In addition, Kaplan-Meier analysis showed that the level of microRNA-32 after 1 chemotherapy cycle was significantly correlated with the prognosis of patients. The median progression-free survival (P = .025) and overall survival (P = .015) of patients with high microRNA-32 levels (≥7.73) after 1 chemotherapy cycle was 9 and 21 months, respectively. In contrast, the median survival of patients with low microRNA-32 levels (<7.73) was 5 and 10 months, respectively. CONCLUSIONS: The plasma levels of microRNA-32 correlated with the efficacy of platinum-based chemotherapy and survival, indicating that microRNA-32 may be useful for predicting the effectiveness of platinum-based chemotherapy and prognosis in NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Carcinoma de Pequenas Células do Pulmão/genética , Idoso , Biomarcadores Tumorais/genética , Estudos Controlados Antes e Depois , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Resultado do Tratamento
20.
Med Oncol ; 36(12): 98, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664527

RESUMO

Small cell carcinoma of the bladder (SCCB) is a rare disease associated with high invasiveness and mortality. Histologically, SCCB is difficult to distinguish from small cell lung cancer (SCLC); however, it shares more similar molecular alterations with urothelial carcinoma (UC). As a result, now, the widely accepted theory about the cells of origin is that SCCB and UC probably have a common clone origin. Even the former probably comes from a preexisting UC. At present, given its rarity, early diagnoses, treatments, and follow-ups are not well established, which are vital to patients with SCCB. Inspirationally, in recent years, with the development of molecular diagnostic methods, molecular alterations of SCCB have been understood partially, which are propitious to excavate new potential therapeutic strategies and establish sound follow-ups. Therefore, the future will be light for patients with SCCB.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/terapia , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Carcinoma de Células Pequenas/genética , Diagnóstico Diferencial , Humanos , Prognóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia , Telomerase/genética , Neoplasias da Bexiga Urinária/genética
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