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1.
Sci Rep ; 14(1): 4793, 2024 02 27.
Article in English | MEDLINE | ID: mdl-38413705

ABSTRACT

In the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Non-Small Cell Lung Cancer (NSCLC), tumors exhibiting main bronchial infiltration (MBI) near the carina and those presenting with complete lung obstructive pneumonia/atelectasis (P/ATL) have been reclassified from T3 to T2. Our investigation into the Surveillance, Epidemiology, and End Results (SEER) database, spanning from 2007 to 2015 and adjusted via Propensity Score Matching (PSM) for additional variables, disclosed a notably inferior overall survival (OS) for patients afflicted with these conditions. Specifically, individuals with P/ATL experienced a median OS of 12 months compared to 15 months (p < 0.001). In contrast, MBI patients demonstrated a slightly worse prognosis with a median OS of 22 months versus 23 months (p = 0.037), with both conditions significantly correlated with lymph node metastasis (All p < 0.001). Upon evaluating different treatment approaches for these particular T2 NSCLC variants, while adjusting for other factors, surgery emerged as the optimal therapeutic strategy. We counted those who underwent surgery and found that compared to surgery alone, the MBI/(P/ATL) group experienced a much higher proportion of preoperative induction therapy or postoperative adjuvant therapy than the non-MBI/(P/ATL) group (41.3%/54.7% vs. 36.6%). However, for MBI patients, initial surgery followed by adjuvant treatment or induction therapy succeeded in significantly enhancing prognosis, a benefit that was not replicated for P/ATL patients. Leveraging the XGBoost model for a 5-year survival forecast and treatment determination for P/ATL and MBI patients yielded Area Under the Curve (AUC) scores of 0.853 for P/ATL and 0.814 for MBI, affirming the model's efficacy in prognostication and treatment allocation for these distinct T2 NSCLC categories.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pneumonia , Pulmonary Atelectasis , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Neoplasm Staging , Prognosis , Pulmonary Atelectasis/pathology , Pneumonia/pathology , Bronchi/pathology
2.
BMC Geriatr ; 24(1): 32, 2024 01 08.
Article in English | MEDLINE | ID: mdl-38191289

ABSTRACT

BACKGROUND: Programmed cell death protein 1 (PD-1) checkpoint inhibitors such as pembrolizumab are novel therapeutics used to treat various advanced malignancies. Immune-related adverse events are common, among the most serious of these toxicities is hemophagocytic lymphohistiocytosis (HLH), which is a life-threatening disorder of unbridled immune activation but has not been properly established. METHODS: We have procured the first case of hemophagocytic lymphohistiocytosis as an aftermath of treatment with pembrolizumab from the Sir Run Run Shaw Hospital, Zhejiang University, China. In a pursuit to enhance the understanding of this condition, a comprehensive systematic review was performed encompassing all reported instances of ICI-associated Hemophagocytic lymphohistiocytosis within the realms of PubMed and Embase databases. RESULTS: We detail the recovery of a cervical cancer patient with a history of psoriasis who developed HLH after combined pembrolizumab and bevacizumab treatment. Remarkably, tumor lesions exhibited substantial and sustained regression. From an analysis of 52 identified Immune Checkpoint Inhibitor (ICI)-related HLH cases, we discovered that HLH often occurred within the first two treatment cycles and approximately 20% of these patients had a history of autoimmune-related diseases. Despite a 15% mortality rate, the majority of patients experienced positive outcomes. Notably, in instances of recovery from HLH, 80% showed positive tumor outcomes. Even after discontinuation of ICI treatment, tumor control persisted in some cases. CONCLUSION: We identified the first case of HLH caused by ICI treatment in cervical cancer and summarized the possible occurrence factors of these cases, the treatment outcomes of HLH, and the impact on tumor outcomes.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/drug therapy , Bevacizumab/adverse effects , Lymphohistiocytosis, Hemophagocytic/chemically induced , Lymphohistiocytosis, Hemophagocytic/diagnosis , Antibodies, Monoclonal, Humanized/adverse effects
3.
Autophagy ; 20(2): 242-258, 2024 02.
Article in English | MEDLINE | ID: mdl-37723664

ABSTRACT

ABBREVIATIONS: A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.


Subject(s)
Colitis-Associated Neoplasms , Inflammatory Bowel Diseases , Humans , Autophagy/physiology , Phosphatidylinositol 3-Kinases , Endoribonucleases , Protein Serine-Threonine Kinases , Escherichia coli , DNA Helicases , Nuclear Proteins , Transcription Factors , GTPase-Activating Proteins
4.
Sci Rep ; 12(1): 14624, 2022 08 26.
Article in English | MEDLINE | ID: mdl-36028744

ABSTRACT

Patients with epidermal growth factor receptor (EGFR) exon 21 L858R substitution benefit less from standard EGFR tyrosine kinase inhibitor (TKI) treatment, and whether anti-angiogenic therapy was beneficial to the EGFR L858R subpopulation was inconclusive. A retrospective study was conducted to investigate the survival benefit and the target characteristics of the anti-angiogenic agent in the EGFR L858R patients in our center, comparing those treated with or without anti-angiogenic therapy (cohort A and cohort B). At the median follow-up time of 31.0 months vs 32.7 months (cohort A vs. B) respectively, Cohort A (n = 58) had a significantly prolonged median OS compared to Cohort B (n = 101) (60.0 months vs.37.0 months, HR 0.51, p = 0.016). Anti-angiogenic therapy significantly prolonged the OS in patients with liver metastases (NA vs.26.0 months, HR 0.17, p = 0.023) comparing to patients without liver metastases (60.0 months vs.37.0 months, HR 0.63, p = 0.129). For brain metastatic patients, anti-angiogenic treatment tended to improve median OS with (65.0 months vs.35.0 months, HR 0.29, p = 0.068) or without brain radiotherapy (73.0 months vs.29.0 months, HR 0.24, p = 0.171). The grade 3 or more adverse events were manageable and consistent with previous studies. Patients with EGFR L858R mutation treated with anti-angiogenic therapy in their course of treatment had a significantly prolonged OS compared to those who had never received an anti-angiogenic agent. Patients with liver metastases might benefit more from anti-angiogenic therapy than those without.


Subject(s)
Angiogenesis Inhibitors , Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , ErbB Receptors/genetics , Exons , Humans , Liver Neoplasms/secondary , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors , Retrospective Studies
5.
Sci Rep ; 10(1): 16974, 2020 Oct 07.
Article in English | MEDLINE | ID: mdl-33028954

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Int Immunopharmacol ; 89(Pt A): 107033, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33039958

ABSTRACT

BACKGROUND: The synergistic effects of immunotherapy and antiangiogenic therapy in advanced non-small cell lung cancer (NSCLC) have been reported in both preclinical and clinical trials. Herein, we evaluated the preliminary efficacy and safety of combined immunotherapy and antiangiogenic therapy in patients with previously treated advanced NSCLC in a real-world setting. METHODS: We conducted a 2-center, retrospective study of previously treated advanced NSCLC patients who received any anti-programmed death-1 antibody combined with antiangiogenic agent between May 2018 and March 2020. RESULTS: In total, 57 patients were included in this study, and the objective response rate and disease control rate were 19.3% and 63.2%, respectively. The median progression-free survival (PFS) was 4.2 months (95% confidence interval [CI]: 3.2-5.2 months). Bone metastases (odds ratio [OR] not available; P < .01) and ≥ 3 treatment lines (OR 6.8; 95% CI: 1.6-29.6; P < .05) were independent negative predictors of objective response. Additionally, liver metastases (hazard ratio [HR] 3.7; 95% CI: 1.6-8.5; P < 0.01), poor performance status score (PS) (HR 3.4; 95% CI: 1.6-7.5; P < 0.01) and ≥ 3 treatment lines (HR 3.5; 95% CI: 1.7-7.4; P < 0.01) were found to be negative predictors of PFS. Eighty-nine percent of the patients experienced an adverse event. CONCLUSIONS: Metastatic sites (bone and liver), ≥3 treatment lines and poor PS were potential negative predictors of the efficacy of immunotherapy combined with antiangiogenic therapy for treating NSCLC. Further investigations and randomized controlled trials are needed.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/secondary , China , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Immunotherapy/adverse effects , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Middle Aged , Pilot Projects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Progression-Free Survival , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors
8.
Front Oncol ; 10: 619010, 2020.
Article in English | MEDLINE | ID: mdl-33680942

ABSTRACT

BACKGROUND: Both anlotinib and programmed death 1 (PD-1) monoclonal antibody (mAb) have been approved for the third line treatment of metastatic non-small cell lung cancer (NSCLC). However, the combination of these two standard therapies has not been investigated in third-line or further-line treatment of patients with advanced NSCLC. METHODS: We reviewed 22 patients with NSCLC who received anlotinib combined with PD-1 mAb therapy from July 2018 to October 2019 at Sir Run Run Shaw Hospital. Based on the baseline characteristics, PD-L1 expression and EGFR mutation status, we retrospectively analyzed the efficacy and safety of this combination therapy by RESIST 1.1 and CTCAE 5.0. RESULTS: The combination treatment of anlotinib and PD-1 mAb in 22 NSCLC patients gained a median PFS of 6.8 months and a median OS of 17.3 months. The disease control rate (DCR) was 90.9%, and the objective response rate (ORR) was 36.4%, where 1 (4.6%) patient achieved complete response (CR) and 7 (31.8%) patients achieved partial response (PR). The median time to response was 3.9 months, and the median duration of the response was 6.8 months. The common grades 1-2 adverse events were fatigue 10/22 (45.5%), decreased appetite 9/22 (40.9%), hypertension 10/22 (45.5%); the common grades 3-4 adverse events were hypertension 2/22 (9.1%) and mouth ulceration 2/22 (9.1%). CONCLUSION: Anlotinib combined with PD-1 mAb showed promising efficacy in third-line or further-line treatment of NSCLC, and its adverse effects is tolerable.

9.
Aging (Albany NY) ; 11(19): 8484-8501, 2019 10 04.
Article in English | MEDLINE | ID: mdl-31584877

ABSTRACT

We investigated the role of the competing endogenous RNA (ceRNA) network in the development and progression of pancreatic adenocarcinoma (PAAD). We analyzed the expression profiles of PAAD and normal pancreatic tissues from multiple GEO databases and identified 457 differentially expressed circular RNAs (DEcircRNAs), 19 microRNAs (DEmiRNAs) and 1993 mRNAs (DEmRNAs). We constructed a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs that regulates the NF-kappa B, PI3K-Akt, and Wnt signaling pathways. We then identified and validated five hub genes, CXCR4, HIF1A, ZEB1, SDC1 and TWIST1, which are overexpressed in PAAD tissues. The expression of CXCR4, HIF1A, ZEB1, and SDC1 in PAAD was regulated by circ-UBAP2 and hsa-miR-494. The expression of CXCR4 and ZEB1 correlated with the levels of M2 macrophages, T-regulatory cells (Tregs) and exhausted T cells in the PAAD tissues. The expression of CXCR4 and ZEB1 positively correlated with the expression of CTLA-4 and PD-1. This suggests that CXCR4 and ZEB1 proteins inhibit antigen presentation and promote immune escape mechanisms in PAAD cells. In summary, our data suggest that the circUBAP2-mediated ceRNA network modulates PAAD by regulating the infiltration and function of immune cells.


Subject(s)
Adenocarcinoma , Carcinogenesis/genetics , Carrier Proteins/genetics , Pancreatic Neoplasms , Tumor Microenvironment , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Biomarkers, Tumor , Cell Transformation, Neoplastic , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , RNA, Long Noncoding/genetics , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Pancreatic Neoplasms
10.
Oral Oncol ; 96: 153-160, 2019 09.
Article in English | MEDLINE | ID: mdl-31422208

ABSTRACT

OBJECTIVES: This study aimed to reveal the regulatory roles of microRNAs in head and neck squamous cell carcinoma (HNSCC) through comprehensive ceRNA, miRNA-transcription factor (TF)-hub gene network and survival analysis. MATERIALS AND METHODS: Expression analysis was performed using the 'edgeR' package based on The Cancer Genome Atlas database. The ceRNA network was screened by intersecting prediction results from miRcode, miRTarBase, miRDB and TargetScan. GSE30784, GSE59102 and GSE107591 from the Gene Expression Omnibus repository were chosen for cross-validation. Hub genes were identified using a protein-protein interaction network constructed by Search Tool for the Retrieval of Interacting Genes. The Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TTRUST) was utilized to map the miRNA-TF-Hub gene network. Patient overall survival was analyzed using the 'survival' package in R. Structural and functional analysis of miR-204/211 was based on miRbase and RNAstructure. RESULTS: A ceRNA network of 178 lncRNAs, 19 miRNAs and 55 mRNAs was generated, and a TF regulatory network with 11 miRNAs, 11 TFs and 18 hub genes was constructed from the 52 hub genes identified through the protein-protein interaction (PPI) network. Survival analysis demonstrated that the dysregulated expression of 11 lncRNAs and 14 mRNAs was highly related to overall survival. Furthermore, miR-204 and miR-211 were significantly involved in the network with identical mature structures, indicating them as key miRNAs in HNSCC. CONCLUSION: This study reveals the comprehensive molecular regulatory networks centralized by miRNAs in HNSCC and uncovers the crucial role of miR-204 and miR-211, which may become potential diagnostic and therapeutic targets.


Subject(s)
Head and Neck Neoplasms/genetics , MicroRNAs/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Transcription Factors/genetics , Computational Biology , Gene Regulatory Networks , Head and Neck Neoplasms/metabolism , Humans , MicroRNAs/metabolism , Prognosis , Protein Interaction Mapping , RNA, Messenger/genetics , RNA, Messenger/metabolism , Squamous Cell Carcinoma of Head and Neck/metabolism , Survival Analysis , Survival Rate , Transcription Factors/metabolism , Transcriptome
11.
Cancer Med ; 7(6): 2555-2566, 2018 06.
Article in English | MEDLINE | ID: mdl-29659199

ABSTRACT

This study aimed to identify differentially expressed genes (DEGs) related to the colorectal normal mucosa-adenoma-carcinoma sequence using bioinformatics analysis. Raw data files were downloaded from Gene Expression Omnibus (GEO) and underwent quality assessment and preprocessing. DEGs were analyzed by the limma package in R software (R version 3.3.2). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the DAVID online tool. In a comparison of colorectal adenoma (n = 20) and colorectal cancer (CRC) stage I (n = 31), II (n = 38), III (n = 45), and IV (n = 62) with normal colorectal mucosa (n = 19), we identified 336 common DEGs. Among them, seven DEGs were associated with patient prognosis. Five (HEPACAM2, ITLN1, LGALS2, MUC12, and NXPE1) of the seven genes presented a sequentially descending trend in expression with tumor progression. In contrast, TIMP1 showed a sequentially ascending trend. GCG was constantly downregulated compared with the gene expression level in normal mucosa. The significantly enriched GO terms included extracellular region, extracellular space, protein binding, and carbohydrate binding. The KEGG categories included HIF-1 signaling pathway, insulin secretion, and glucagon signaling pathway. We discovered seven DEGs in the normal colorectal mucosa-adenoma-carcinoma sequence that was associated with CRC patient prognosis. Monitoring changes in these gene expression levels may be a strategy to assess disease progression, evaluate treatment efficacy, and predict prognosis.


Subject(s)
Biomarkers, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Signal Transduction , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Computational Biology/methods , Gene Expression Profiling , Gene Ontology , Humans , Prognosis , Survival Analysis , Transcriptome
12.
Cell Signal ; 35: 223-230, 2017 07.
Article in English | MEDLINE | ID: mdl-28428083

ABSTRACT

The epidermal growth factor receptor (EGFR) is a well-studied receptor-tyrosine kinase that serves vital roles in regulation of organ development and cancer progression. EGFR not only exists on the plasma membrane, but also widely expressed in the nucleus, endosomes, and mitochondria. Most recently, several lines of evidences indicated that autophagy is regulated by EGFR in kinase-active and -independent manners. In this review, we summarized recent advances in our understanding of the functions of different subcellularly located EGFR on autophagy. Specifically, plasma membrane- and cytoplasm-located EGFR (pcEGFR) acts as a tyrosine kinase to regulate autophagy via the PI3K/AKT1/mTOR, RAS/MAPK1/3, and STAT3 signaling pathways. The kinase-independent function of pcEGFR inhibits autophagy by maintaining SLC5A1-regulated intracellular glucose level. Endosome-located EGFR phosphorylates and inhibits Beclin1 to suppress autophagy, while kinase-independent endosome-located EGFR releases Beclin1 from the Rubicon-Beclin1 complex to increase autophagy. Additionally, the nuclear EGFR activates PRKDC/PNPase/MYC signaling to inhibit autophagy. Although the role of mitochondria-located EGFR in autophagy is largely unexplored, the production of ATP and reactive oxygen species mediated by mitochondrial dynamics is most likely to influence autophagy.


Subject(s)
Autophagy/genetics , Cell Membrane/genetics , Endosomes/metabolism , ErbB Receptors/genetics , Autophagy-Related Proteins , Beclin-1/genetics , Cell Membrane/metabolism , Cytoplasm/genetics , Cytoplasm/metabolism , ErbB Receptors/metabolism , Glucose/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mitochondria/genetics , Mitochondria/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Signal Transduction/genetics , Sodium-Glucose Transporter 1/genetics
13.
Cancer Lett ; 379(1): 124-33, 2016 08 28.
Article in English | MEDLINE | ID: mdl-27264264

ABSTRACT

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatically prolonged the overall survival of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, but the presence of primary or acquired resistance eventually leads to therapeutic failure. Thus, how to improve the efficacy and reverse the resistance to EGFR-TKIs remains a significant challenge. In this study, we found that CsA significantly augmented the anti-cancer effect of gefitinib in EGFR-TKI-sensitive and -resistant NSCLC cells. Mechanistically, CsA promoted gefitinib-induced apoptosis through inhibition of the STAT3 pathway. Similar with the function of CsA, siRNAs against STAT3 also enhanced gefitinib-induced apoptosis in multiple lung cancer cells. Xenograft studies further demonstrated that CsA promoted the anti-cancer activity of gefitinib on lung cancer cells through inhibition of STAT3. Moreover, NSCLC patients with high levels of phosphorylated STAT3 (Y705) showed a significantly poorer therapeutic response to EGFR-TKIs. This study provides preclinical evidence that the combination of CsA or a STAT3 inhibitor with EGFR-TKIs is a promising approach to improve the efficacy of EGFR-TKIs for the treatment of patients with advanced NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Cyclosporine/pharmacology , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , A549 Cells , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/metabolism , Female , Gefitinib , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Phosphorylation , RNA Interference , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Time Factors , Transfection , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
14.
J Huazhong Univ Sci Technolog Med Sci ; 35(6): 834-841, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26670433

ABSTRACT

The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have been increasingly recognized to drive the development of malignancies, including non-small cell lung cancer (NSCLC). This study aimed to investigate the effects of IGF-1R and its inhibitor, AG1024, on the progression of lung cancer. Tissue microarray and immunohistochemistry were employed to detect the expressions of IGF-1 and IGF-1R in NSCLC tissues (n=198). Western blotting was used to determine the expressions of IGF-1 and phosphorylated IGF-1R (p-IGF-1R) in A549 human lung carcinoma cells, and MTT assay to measure cell proliferation. Additionally, the expressions of IGF-1, p-IGF-1R and IGF-1R in a mouse model of lung cancer were detected by Western blotting and real-time fluorescence quantitative polymerase chain reaction (FQ-PCR), respectively. The results showed that IGF-1 and IGF-1R were overexpressed in NSCLC tissues. The expression levels of IGF-1 and p-IGF-1R were significantly increased in A549 cells treated with IGF-1 as compared to those treated with IGF-1+AG1024 or untreated cells. In the presence of IGF-1, the proliferation of A549 cells was significantly increased. The progression of lung cancer in mice treated with IGF-1 was significantly increased as compared to the group treated with IGF-1+AG1024 or the control group, with the same trend mirrored in IGF-1/p-IGF-1R/IGF-1R at the protein and/or mRNA levels. It was concluded that IGF-1 and IGF inhibitor AG1024 promotes lung cancer progression.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Disease Models, Animal , Lung Neoplasms/pathology , Receptor, IGF Type 1/physiology , Tyrphostins/pharmacology , Adult , Aged , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Proliferation , Disease Progression , Female , Humans , Insulin-Like Growth Factor I/metabolism , Lung Neoplasms/metabolism , Male , Mice , Middle Aged , Receptor, IGF Type 1/antagonists & inhibitors
15.
Oncotarget ; 6(37): 40268-82, 2015 Nov 24.
Article in English | MEDLINE | ID: mdl-26384345

ABSTRACT

Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinib-mediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.


Subject(s)
Autophagy/drug effects , Lung Neoplasms/drug therapy , Pyrazoles/pharmacology , Pyridines/pharmacology , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Cell Survival/drug effects , Crizotinib , Drug Synergism , Eukaryotic Initiation Factor-2/metabolism , Female , Humans , Hydroxychloroquine/pharmacology , Immunoblotting , Lung Neoplasms/metabolism , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Microtubule-Associated Proteins/metabolism , Phagosomes/drug effects , Phagosomes/metabolism , Phagosomes/ultrastructure , Phosphorylation/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Xenograft Model Antitumor Assays
16.
Autophagy ; 11(5): 729-39, 2015.
Article in English | MEDLINE | ID: mdl-25951043

ABSTRACT

Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field.


Subject(s)
Autophagy , STAT3 Transcription Factor/metabolism , Animals , Humans , Mitochondria/metabolism , Models, Biological , Neoplasms/metabolism , Neoplasms/therapy , STAT3 Transcription Factor/chemistry , Subcellular Fractions/metabolism
17.
Cancer Lett ; 361(2): 174-84, 2015 Jun 01.
Article in English | MEDLINE | ID: mdl-25766658

ABSTRACT

Since nuclear factor of activated T cells (NFAT) was first identified as a transcription factor in T cells, various NFAT isoforms have been discovered and investigated. Accumulating studies have suggested that NFATs are involved in many aspects of cancer, including carcinogenesis, cancer cell proliferation, metastasis, drug resistance and tumor microenvironment. Different NFAT isoforms have distinct functions in different cancers. The exact function of NFAT in cancer or the tumor microenvironment is context dependent. In this review, we summarize our current knowledge of NFAT regulation and function in cancer development and treatment. NFATs have emerged as a potential target for cancer prevention and therapy.


Subject(s)
NFATC Transcription Factors/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Carcinogenesis , Humans , Neoplasm Metastasis , Neoplasms/pathology , Protein Isoforms , T-Lymphocytes/metabolism , Tumor Microenvironment
18.
Sci Rep ; 4: 6683, 2014 Oct 20.
Article in English | MEDLINE | ID: mdl-25327881

ABSTRACT

Autophagy is a critical survival pathway for cancer cells under conditions of stress. Thus, induction of autophagy has emerged as a drug resistance mechanism. This study is to determine whether autophagy is activated by a novel multikinase inhibitor linifanib, thereby impairing the sensitivity of hepatocellular carcinoma (HCC) cells to this targeted therapy. Here, we found that linifanib induced a high level of autophagy in HCC cells, which was accompanied by suppression of phosphorylation of PDGFR-ß and its downstream Akt/mTOR and Mek/Erk signaling pathways. Cell death induced by linifanib was greatly enhanced after autophagy inhibition by the pharmacological inhibitors or siRNAs against autophagy related genes, ATG5 and ATG7, in vitro. Moreover, HCQ, an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-HCC effect of linifanib in a mouse xenograft model. In conclusion, linifanib can induce cytoprotective autophagy by suppression of PDGFR-ß activities in HCC cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of linifanib in the treatment of HCC patients.


Subject(s)
Autophagy/genetics , Carcinoma, Hepatocellular/drug therapy , Indazoles/administration & dosage , Liver Neoplasms/drug therapy , Phenylurea Compounds/administration & dosage , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
19.
Curr Pharm Des ; 20(17): 2912-21, 2014.
Article in English | MEDLINE | ID: mdl-23944361

ABSTRACT

Insulin-like growth factor 1 receptor (IGF-1R) is important in cancer pathogenesis and progression. While its signaling pathway is an interesting therapeutic target, recent clinical trials have exhibited limited effects; however, significant crosstalks between IGF- 1R and other signaling pathways have garnered increasing attention. These complex networks include interactions between IGF-1R and receptor tyrosine kinases (RTKs), including insulin receptor (IR), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), mesenchymal-epithelial transition factor (MET), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Furthermore, IGF-1R also is related to steroid hormones, including estrogen receptors alpha and beta (ER! and ER"), androgen receptor (AR), and progesterone receptor (PR). Cumulatively, actions of crosstalk between IGF-1R, and RTKs/steroid hormones promote tumorigenesis, as demonstrated by the effectiveness of recently proposed therapeutic strategies. These therapeutic strategies, primarily pertaining to crosstalk-cotargeting, exhibited notable advantages in overcoming resistance to conventional chemotherapy and conventional endocrine therapy. Furthermore, these techniques offer benefits beyond the limited effects of single- agent targeting previously reported. Thus, the role of crosstalk between IGF-1R and RTKs/steroid hormones, including strategies to block these pathways in combination with recent development in this field, were reviewed and the potential future cancer therapeutics suggested by this rationale were considered.


Subject(s)
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/metabolism , Receptor Cross-Talk , Receptor, IGF Type 1/metabolism , Signal Transduction , Antineoplastic Agents/pharmacology , Gonadal Steroid Hormones/metabolism , Humans , Models, Biological , Neoplasms/pathology , Receptor Cross-Talk/drug effects , Receptor, IGF Type 1/antagonists & inhibitors , Signal Transduction/drug effects
20.
Curr Pharm Des ; 20(17): 2899-911, 2014.
Article in English | MEDLINE | ID: mdl-23944362

ABSTRACT

Insulin-like growth factors (IGFs), along with their receptors and binding proteins, play key roles in human cell proliferation, differentiation and apoptosis. There is now substantial evidence suggesting that the IGF system is involved in the pathogenesis and progression of various malignancies. Recent studies have shown that targeting of the IGF-1 receptor (IGF-1R) signaling pathway might be a novel approach for the treatment of cancer. Presently numerous agents featuring different mechanisms of IGF targeting methods such as IGF-1R monoclonal antibodies, IGF-1R tyrosine kinase inhibitors and IGF ligand specific antibodies are being investigated in more than 170 clinical trials and appear to have potential therapeutic efficacy. However, advanced trials reiterate the importance of predictive biomarkers to guide the clinical efforts of these agents. As a result, current research strategies are emerging to identify the most suitable subpopulations of patients that might benefit from these treatments. Furthermore, newly presented toxicity and growth hormone response and implication of hybrid receptors in IGF signaling pathway pose unprecedented challenges in the design and application of anti-IGF agents. On the other hand, cross-talk in downstream signaling between IGF-1R and other tumor promoting pathways and the development of multi-target agents might encourage the IGF-1R-targeted therapies further into comprehensive treatments of cancer. With both challenges and prospects ahead, this paper reviewed the progress in this particular field.


Subject(s)
Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy/trends , Neoplasms/drug therapy , Neoplasms/metabolism , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 2/antagonists & inhibitors , Signal Transduction/drug effects , Somatomedins/drug effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/pharmacology , Humans , Insulin-Like Growth Factor Binding Protein 3/therapeutic use , Models, Biological , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Receptor, IGF Type 1/metabolism , Receptor, IGF Type 2/metabolism , Somatomedins/metabolism
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