FCN3 functions as a tumor suppressor of lung adenocarcinoma through induction of endoplasmic reticulum stress.
Ontology highlight
ABSTRACT:
SUBMITTER: Jang H
PROVIDER: S-EPMC8050313 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In this study, we report a novel function of FCN3 (Ficolin 3), a secreted lectin capable of activating the complement pathway, as a tumor suppressor of lung adenocarcinoma (LUAD). First, the expression of FCN3 was strongly down-regulated in cancer tissues compared to matched normal lung tissues, and down-regulation of FCN3 was shown to be significantly correlated with increased mortality among LUAD patients. Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells. Rather, we found evidence indicating that activation of the unfolded protein response is induced from ectopic expression of FCN3 which lead to endoplasmic reticulum (ER) stress. Consistently, inhibition of ER stress response led enhanced survival of the LUAD cells. Collectively, our data indicate that FCN3 is a tumor suppressor gene functioning through induction of ER stress.
2021-04-21 | GSE160946 | GEO
Project description:FCN3 functions as a tumor suppressor of lung adenocarcinoma through induction of endoplasmic reticulum stress
| PRJNA674883 | ENA
Project description:Lung cancer is the most common malignancy worldwide, and LUAD is the primary type of lung cancer. Recently, the POU transcription factor family has been associated with the development of multicancer, especially lung cancer. However, the relationship between POU domain class Ⅳ transcription factor Ⅲ (POU4F3) and lung cancer remains unknown. We detected the expression of POU4F3 in human LUAD and adjacent tissues with immunohistochemical staining, and we found that POU4F3 was expressed less in LUAD tissues compared with adjacent tissues. Patients with higher POU4F3 expression have more prolonged overall survival. We then constructed SPCA1 and A549 cells with stable overexpression or inhibition of POU4F3. We found that overexpressed POU4F3 suppressed LUAD cell proliferation in vitro and in vivo, according to CCK-8, colony formation, and xenograft assays. LUAD cell apoptosis was suppressed by POU4F3 overexpression based on Flow cytometry. The downregulation of POU4F3 yielded the opposite patterns. Next, we explored the possible mechanisms through which POU4F3 promoted the apoptosis of LUAD cells. Western blotting suggested that overexpression of POU4F3 significantly increased protein expression levels of the PERK/eIF2α/ATF4/CHOP and IRE1α/XBP1s pathways of ERS, while POU4F3 absence reversed the expressions of the above essential proteins in ERS pathways in SPCA1 and A549 cells. However, we found that PERK inhibitor but not IRE1 inhibitor can reverse the effect of POU4F3 overexpression on apoptosis. This study indicated that POU4F3 may work as a tumor suppressor in LUAD via regulating the PERK/eIF2α/ATF4/CHOP pathway. We made it possible to develop POU4F3 as a diagnostic, therapeutic, and prognostic target of LUAD.
| S-EPMC8771506 | biostudies-literature
Project description:Poorly formed tumor blood vessels lead to regions of microenvironmental stress due to depletion of oxygen and glucose and accumulation of waste products (acidosis). These conditions contribute to tumor progression and correlate with poor patient prognosis. Here we show that the microenvironmental stresses found in the solid tumor are able to inhibit the canonical Wnt/beta-catenin signaling pathway. However, tumor cells harboring common beta-catenin pathway mutations, such as loss of adenomatous polyposis coli, are insensitive to this novel hypoxic effect. The underlying mechanism responsible is hypoxia-induced endoplasmic reticulum (ER) stress that inhibits normal Wnt protein processing and secretion. ER stress causes dissociation between GRP78/BiP and Wnt, an interaction essential for its correct posttranslational processing. Microenvironmental stress can therefore block autocrine and paracrine signaling of the Wnt/beta-catenin pathway and negatively affect tumor growth. This study provides a general paradigm relating oxygen status to ER function and growth factor signaling.
| S-EPMC2593368 | biostudies-literature
Project description:BackgroundThe prognosis and survival of lung adenocarcinoma (LUAD) patients are still not promising despite recent breakthroughs in treatment. Endoplasmic reticulum stress (ERS) is a self-protective mechanism resulting from an imbalance in quality control of unfolded proteins when cells are stressed, which plays an active role in lung cancer development, but the relationship between ERS and the pathological characteristics and clinical prognosis of LUAD patients remains unclear.MethodsLASSO and Cox regression were applied based on sequencing information to construct the model, which was validated to be robust. The risk scores of the patients were calculated using the formula provided by the model, and the patients were divided into high and low-risk groups according to the median cut-off of risk scores. Cox regression analysis identifies independent prognostic factors for these patients, and enrichment analysis of prognosis-related genes was also performed. The relationship between risk scores and tumor mutation burden (TMB), cancer stem cell index, and drug sensitivity was explored.ResultsWe constructed a 13-gene prognostic model for LUAD patients. Patients in the high-risk group had worse overall survival, lower immune score and ESTIMATE score, higher TMB, higher cancer stem cell index, and higher sensitivity to conventional chemotherapeutic agents. In addition, we constructed a nomogram that predicts 5-year survival in LUAD patients, which helps clinicians to foresee the prognosis from a new perspective.ConclusionsOur results highlight the association of ERS with LUAD and the potential use of ERS in guiding treatment.
| S-EPMC10276379 | biostudies-literature
Project description:The role of endoplasmic reticulum (ER) stress in cancer has been studied in detail, and ER stress is known to increase tumor cell apoptosis, and thus, reduce tumor growth. However, in our study, persistent ER stress induced by multiple administrations of low-dose thapsigargin (Tg) accelerated tumor growth in mice. Tg-mediated ER stress increased the generation of Ly6G+CD11b+ myeloid cells, but did not alter anti-tumor effector T cells. 4-Phenylbutyric acid (4-PBA), a chemical chaperone widely used as an ER stress reducer, attenuated Tg-induced myeloid-derived suppressor cell (MDSC) expansion and tumor growth. Tg-mediated ER stress enhanced the immunosuppressive capacity of tumor-infiltrating MDSCs by increasing expression of ARG1, iNOS, and NOX2, although splenic MDSCs were not affected. Consistent with these results, 4-PBA restored the anti-tumor immune response by regulating inflammatory cytokines such as TNF-? and CXCL1/KC, and activated tumor-infiltrating CD8+ T cells that were inhibited by Tg-mediated ER stress. These results suggest that significant ER stress in a tumor-bearing host might induce tumor growth mediated by enhancement of MDSC-mediated suppression. Therefore, ER stress reducers such as 4-PBA could restore anti-tumor immunity by inhibiting suppressive MDSCs that are exacerbated by ER stress.
| S-EPMC4322987 | biostudies-literature
Project description:BackgroundEndoplasmic reticulum stress (ERs) is an important cellular self-defence mechanism, which is closely related to tumorigenesis and development. However, the role of endoplasmic reticulum stress state in the development of lung adenocarcinoma (LUAD) has not been clarified.MethodsThe lncRNAs associated with endoplasmic reticulum stress were identified by co-expression analysis in public databases, and by the least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression modelling, we constructed a prognostic model based on endoplasmic reticulum stress-related lncRNAs (ERs-related lncRNAs), performed immune analysis, TME, TMB and clinical drug prediction for model-related risk scores, and performed correlation validation in public databases and at the human tissue level.ResultsFive ERs-related lncRNAs were used to construct an ERs-related lncRNA signature (ERs-related LncSig), which can predict the prognosis of LUAD. Patients in the high-risk group had worse survival, and differences existed in immune cell infiltration, immune function, immune checkpoint analysis, tumour microenvironment (TME), tumour mutational burden (TMB), immunotherapy efficacy, and sensitivity to some commonly used chemotherapeutic agents between high and low risk groups.ConclusionOur study demonstrated that ERs-related lncRNA signature can be used for the prognostic evaluation of LUAD patients and may provide new insights into clinical decision-making and personalised medicine for LUAD.
| S-EPMC10467521 | biostudies-literature
Project description:BackgroundLung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear.MethodsIn this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort.ResultsWe identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns.ConclusionThis study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.
| S-EPMC10763289 | biostudies-literature
Project description:BackgroundThe transcription factor PR domain containing 16 (PRDM16) is known to play a significant role in the determination and function of brown and beige fat. However, the role of PRDM16 in tumor biology has not been well addressed. Here we investigated the impact of PRDM16 on tumor growth and metastasis in lung cancer.MethodsUALCAN database, immunoblotting and immunohistochemistry analysis were used to assess PRDM16 expression in lung cancer patients. Kaplan-Meier plotter database was used to analyze the overall survival of patients with lung cancer stratified by PRDM16 expression. PRDM16 overexpression and knockdown experiments were conducted to assess the effects of PRDM16 on growth and metastasis in vitro and in vivo, and its molecular mechanism was investigated in lung adenocarcinoma cells by chromatin immunoprecipitation-sequencing (ChIP-Seq), real time-quantitative PCR (RT-qPCR), luciferase assay, xenograft models and rescue experiments.ResultsPRDM16 was downregulated in lung adenocarcinomas, and its expression level correlated with key pathological characteristics and prognoses of lung adenocarcinoma patients. Overexpressing PRDM16 inhibited the epithelial-to-mesenchymal transition (EMT) of cancer cells both in vivo and in vitro by repressing the transcription of Mucin-4 (MUC4), one of the regulators of EMT in lung adenocarcinomas. Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter.ConclusionsOur findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.
| S-EPMC6347838 | biostudies-literature
Project description:BackgroundDERL3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, the correlation of DERL3 expression with the malignant phenotype of lung adenocarcinoma (LUAD) cells is unclear and remains to be elucidated. Herein, we investigated the interaction between the DERL3 and LUAD pathological process.MethodsThe Cancer Genome Atlas (TCGA) database was utilized to determine the genetic alteration of DERL3 in stage I LUAD. Clinical LUAD samples including carcinoma and adjacent tissues were obtained and were further extracted to detect DERL3 mRNA expression via RT-qPCR. Immunohistochemistry was performed to evaluate the protein expression of DERL3 in LUAD tissues. The GEPIA and TIMER website were used to evaluate the correlation between DERL3 and immune cell infiltration. We further used the t-SNE map to visualize the distribution of DERL3 in various clusters at the single-cell level via TISCH database. The potential mechanisms of the biological process mediated by DERL3 in LUAD were conducted via KEGG and GSEA.ResultsIt was indicated that DERL3 was predominantly elevated in carcinoma compared with adjacent tissues in multiple kinds of tumors from the TCGA database, especially in LUAD. Immunohistochemistry validated that DERL3 was also upregulated in LUAD tissues compared with adjacent tissues from individuals. DERL3 was preliminarily found to be associated with immune infiltration via the TIMER database. Further, the t-SNE map revealed that DERL3 was predominantly enriched in plasma cells of the B cell population. It was demonstrated that DERL3 high-expressed patients presented significantly worse response to chemotherapy and immunotherapy. GSEA and KEGG results indicated that DERL3 was positively correlated with B cell activation and unfolded protein response (UPR).ConclusionOur findings indicated that DERL3 might play an essential role in the endoplasmic reticulum-associated degradation (ERAD) process in LUAD. Moreover, DERL3 may act as a promising immune biomarker, which could predict the efficacy of immunotherapy in LUAD.
| S-EPMC9585215 | biostudies-literature