Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development.
Ontology highlight
ABSTRACT:
SUBMITTER: Furukawa T
PROVIDER: S-EPMC10380948 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
Publications
Approach to Functions of <i>BHLHE41/DEC2</i> in Non-Small Lung Cancer Development.
Furukawa Tatsuhiko T Mimami Kentaro K Nagata Toshiyuki T Yamamoto Masatasu M Sato Masami M Tanimoto Akihide A
International journal of molecular sciences 20230721 14
The circadian rhythm-related genes <i>BHLHE40/DEC1</i> and <i>BHLHE41/DEC2</i> have various functions under different cell and tissue conditions. <i>BHLHE41/DEC2</i> has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of <i>BHLHE41/DEC2</i> on differentiation have been examined using <i>Bhlhe41/Dec2</i> knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro an ...[more]
Similar Datasets
Project description:Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.
| S-EPMC8584041 | biostudies-literature
Project description:Signal Transducer and Activator of Transcription 3 (STAT3) activation is frequently found in non-small cell lung cancer (NSCLC) patient samples/cell lines and STAT3 inhibition in NSCLC cell lines markedly impairs their survival. STAT3 also plays a pivotal role in driving tumor-promoting inflammation and evasion of anti-tumor immunity. Consequently, targeting STAT3 either directly or by inhibition of upstream regulators such as Interleukin-6 (IL-6) or Janus kinase 1/2 (JAK1/2) is considered as a promising treatment strategy for the management of NSCLC. In contrast, some studies also report STAT3 being a tumor suppressor in a variety of solid malignancies, including lung cancer. Here, we provide a concise overview of STAT3's versatile roles in NSCLC and discuss the yins and yangs of STAT3 targeting therapies.
| S-EPMC7281271 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a nuclear receptor involved in regulation of lipid and glucose metabolism, wound healing and inflammation. PPARβ/δ has been associated also with cancer. Here we investigated the expression of PPARβ/δ and components of the prostaglandin biosynthetic pathway in non-small cell lung cancer (NSCLC). We found increased expression of PPARβ/δ, Cox-2, cPLA(2), PGES and VEGF in human NSCLC compared to normal lung. In NSCLC cell lines PPARβ/δ activation increased proliferation and survival, while PPARβ/δ knock-down reduced viability and increased apoptosis. PPARβ/δ agonists induced Cox-2 and VEGF transcription, suggesting the existence of feed-forward loops promoting cell survival, inflammation and angiogenesis. These effects were seen only in high PPARβ/δ expressing cells, while low expressing cells were less or not affected. The effects were also abolished by PPARβ/δ knock-down or incubation with a PPARβ/δ antagonist. Induction of VEGF was due to both binding of PPARβ/δ to the VEGF promoter and PI3K activation through a non-genomic mechanism. We found that PPARβ/δ interacted with the PI3K regulatory subunit p85α leading to PI3K activation and Akt phosphorylation. Collectively, these data indicate that PPARβ/δ might be a central element in lung carcinogenesis controlling multiple pathways and representing a potential target for NSCLC treatment.
| S-EPMC3457940 | biostudies-literature
Project description:Lung cancer is the leading cause of cancer-related deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for about 80% of all cases, which is the major subgroup of lung cancer. G protein-coupled receptor kinase 5 (GRK5) has been demonstrated to play pivotal roles in both development and progression of several pathological conditions including cancer. Here, we found that GRK5 expression was significantly increased in 539 NSCLC cancerous tissues than that in 99 normal non-cancerous tissues by immunohistochemistry analysis; we also showed intensive higher positive staining percentage in female and adenocarcinoma (ADC) NSCLC patients than that in male and squamous cell carcinoma (SCC) patients, respectively. In addition, GRK5 high expression NSCLC patients had a worse overall survival rate than the low expression patients. We provided evidence showing that both the mRNA and protein expression levels of GRK5 were increased in NSCLC cancerous cell lines (GLC-82, SPC-A-1, H520, H838, H358, A549, and H1299) comparing with that in normal human bronchial epithelium cell line (BEAS-2B), and identified many GRK5 mutations in NSCLC cancerous tissues. In addition, we found that depletion of GRK5 inhibited NSCLC cancerous cell proliferation, migration in vitro, and xenograft tumor formation in vivo. Furthermore, GRK5 knockdown promoted cell cycle arrest at G2/M phase and induced cellular apoptosis. In summary, our data reveal an oncogenic role of GRK5 in NSCLC progression, indicating that GRK5 could be used as a new therapeutic target in future.
| S-EPMC5833409 | biostudies-literature
Project description:Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung cancer, either SCLC or NSCLC adenocarcinoma, were retrospectively identified. The post-diagnosis pre-treatment lung CT images were used to segment the lung cancers. Radiomic features were extracted from histogram-based statistics, textural analysis of tumor images and their wavelet transforms. A minimal-redundancy-maximal-relevance method was used for feature selection. The predictive model was constructed with a multilayer artificial neural network. The performance of the SCLC/NSCLC adenocarcinoma classifier was evaluated by the area under the receiver operating characteristic curve (AUC). Our study cohort consisted of 69 primary lung cancer patients with SCLC (n = 35; age mean ± SD = 66.91± 9.75 years), and NSCLC adenocarcinoma (n = 34; age mean ± SD = 58.55 ± 11.94 years). The SCLC group had more male patients and smokers than the NSCLC group (P < 0.05). Our SCLC/NSCLC classifier achieved an overall performance of AUC of 0.93 (95% confidence interval = [0.85, 0.97]), sensitivity = 0.85, and specificity = 0.85). Adding clinical data such as smoking history could improve the performance slightly. The top ranking radiomic features were mostly textural features. Our results showed that CT radiomics could quantitatively represent tumor heterogeneity and therefore could be used to differentiate primary lung cancer subtypes with satisfying results. CT image processing with the wavelet transformation technique enhanced the radiomic features for SCLC/NSCLC classification. Our pilot study should motivate further investigation of radiomics as a non-invasive approach for early diagnosis and treatment of lung cancer.
| S-EPMC7188953 | biostudies-literature
Project description:The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance.
| S-EPMC3927069 | biostudies-literature
Project description:Ivosidenib is an isocitrate dehydrogenase mutant inhibitor that the US Food and Drug Administration recently approved for the treatment of leukemia. Studies suggested that ivosidenib may inhibit the progression of non-small cell lung cancer (NSCLC). In the present study, we explored RNAs and their potential regulatory mechanisms by which ivosidenib treats NSCLC cells. We used MTT assays, Transwell assays, and flow cytometry to measure the anti-tumor effects of ivosidenib in NSCLC cells. We performed whole transcriptome sequencing to determine differentially expressed mRNAs (DE-mRNAs) and non-coding RNAs (ncRNA). We used GO and KEGG pathway enrichment analyses to identify the functions and potential mechanisms. According to miRNA target interactions, we constructed a competing endogenous network. Ivosidenib inhibited the proliferation, invasion, and migration of NSCLC cells and inhibited tumor growth in vivo. We identified 212 DE-mRNAs, four DE-miRNAs, and 206 DE-lncRNAs in ivosidenib-treated NSCLC cells compared to untreated NSCLC cells. DE-mRNAs were significantly enriched in the cancer-associated pathways, including the TGF-β signaling pathway, the PI3K-Akt signaling pathway, the Jak-STAT signaling pathway, the MAPK signaling pathway, the Rap1 signaling pathway, and cell adhesion molecules. Based on the competing endogenous RNA hypothesis, we constructed lncRNA-miRNA-mRNA networks to elucidate the regulatory relationships between mRNA and ncRNA. We found that qRT-PCR results showed corresponding expression trends of differential genes with sequencing data. Our results provide insights into the molecular basis of ivosidenib suppression of NSCLC.
| S-EPMC8042334 | biostudies-literature
Project description:Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive Kras;p53 non-small cell lung cancer mouse model and demonstrated efficacy with a combination of two tumor-suppressive microRNAs (miRNAs). Systemic nanodelivery of miR-34 and let-7 suppressed tumor growth leading to survival advantage. This combinatorial miRNA therapeutic approach engages numerous components of tumor cell-addictive pathways and highlights the ability to deliver multiple miRNAs in a safe and effective manner to target lung tissue.
| S-EPMC4345154 | biostudies-literature
Project description:With the change of the spectrum of disease, the incidence and mortality of non-small cell lung cancer (NSCLC) has been high in global scale, since surgical intervention was applied to treat lung cancer, its status is increasing day by day, at present comprehensive treatment leaded by surgery has become the preferred scheme for NSCLC, there are many different kinds of surgical approaches and operation methods of disease, and the new technologies appear constantly, the paper aim to summarize the research progress of different operationmethods and surgical approach. With the development of software and hardware technology and the concept of minimally invasive thoracoscopic surgery was received by more people, minimally invasive thoracoscopic surgery has brought more benifit than traditional thoracotomy for lung cancer patients, minimally invasive thoracoscopic surgery reserve more lung tissue and improve the survival quality of patients due to better pulmonary function, we believe that minimally invasive thoracoscopic surgery can bring more benefits to people with surgical indications and surgical procedure further standardization.?.
| S-EPMC6137006 | biostudies-literature
Project description:The identification of EGFR mutations and ALK rearrangements in nonsmall cell lung cancer (NSCLC) has led to the rapid development of targeted therapies and significant changes in the treatment paradigm. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and crizotinib are now standard therapies for patients with the appropriate molecular alteration. Current investigations are determining the mechanisms of resistance to targeted therapies and developing novel agents to combat resistance. For patients with KRAS mutant NSCLC, a phase III trial of the MEK inhibitor, selumetinib, has been initiated. For patients without a defined mutation or a mutation without a known targeted therapy, immunotherapy, ganetespib, nintedanib and MET inhibitors in combination with EGFR TKIs are in development. Preliminary results of phase III trials raise doubts about the future development of dacomitinib as a second-line agent.
| S-EPMC4206610 | biostudies-literature