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BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

ABSTRACT: 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.

SUBMITTER: Nagata T

PROVIDER: S-EPMC8584041 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

Nagata Toshiyuki T Minami Kentaro K Yamamoto Masatatsu M Hiraki Tsubasa T Idogawa Masashi M Fujimoto Katsumi K Kageyama Shun S Tabata Kazuhiro K Kawahara Kohichi K Ueda Kazuhiro K Ikeda Ryuji R Kato Yukio Y Komatsu Masaaki M Tanimoto Akihide A Furukawa Tatsuhiko T Sato Masami M

International journal of molecular sciences 20211026 21

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-ex ...[more]

PMID: 34768959

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Project description:Background: Butyrophilin subfamily 3 member A2 (BTN3A2) is an important mediator in immune activation, and it is reported to be linked to many cancer progresses. However, the relation with infiltrating immune and prognosis of BTN3A2 in lung adenocarcinoma are not clear. Methods: In our study, we checked the mRNA expression and protein expression profile of BTN3A2 in lung adenocarcinoma (LUAD) and its relation to clinical outcomes using TIMER and UALCAN databases. In addition, we analyzed the survival of BTN3A2 in LUAD using the Kaplan-Meier Plotter database and PrognoScan database. Moreover, we analyzed gene set enrichment analysis (GSEA) of the BTN3A2. Next, we explored the relation of BTN3A2 expression with the immune infiltration by TIMER. At last, in order to enrich the regulatory mechanism of BTN3A2, we used miRarbase, starbase, and miRDB databases to look for miRNA targets of BTN3A2. Results: The mRNA along with the protein expression of BTN3A2 in the LUAD group was lower than that in the normal group. In addition, high BTN3A2 expression was connected with good first progression (FP) and overall survival (OS) in LUAD. Then, the GSEA analysis demonstrated that T-cell receptor signaling cascade, B-cell receptor signaling cascade, natural killer cell-mediated cytotoxicity, immune receptor activity, immunological synapse, and T-cell activation were enriched differentially in the BTN3A2 high expression phenotype of LUAD. Moreover, BTN3A2 expression is a remarkable positive correlation with invading levels of tumor purity, B cells, neutrophils, CD4+ T cells, dendritic cells, macrophages, and CD8+ T cells in LUAD, and B cells and dendritic cells were linked with a good prognosis of LUAD. To further enrich the possible regulatory mechanisms of BTN3A2, we analyzed the miRNA targets. The results showed that hsa-miR-17-5p may be miRNA targets of BTN3A2. Conclusion: Taking together, we provide evidence of BTN3A2 as possible prognosis biomarkers of LUAD. In addition, high BTN3A2 expression in LUAD may influence the prognosis because of immune invasion. Moreover, our findings provide a potential mechanism that hsa-miR-17-5p may be miRNA targets of BTN3A2.

Project description:BackgroundInositol Polyphosphate-5-Phosphatase B (INPP5B), a inositol 5-phosphatase, plays an important role in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential role of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD.MethodsTCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic role of INPP5B was determined by Kaplan-Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses. The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein-protein interaction (PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. Co-immunoprecipitation assay was used to detect protein-protein interactions. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays.ResultINPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And the low expression of INPP5B was associated with late-stage pathological features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for LUAD patients. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the activity of PI3K/AKT signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B could interact directly with PTEN. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the AKT pathway.ConclusionOur results demonstrated that INPP5B could inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for LUAD patients. Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People's Hospital. The Ethics Committee of Hangzhou First People's Hospital has approved this study. (registration number: IIT-20210907-0031-01; registration date: 2021.09.13).

Project description:BackgroundSerpine Protease Inhibitorclade H1 (SERPINH1) is abnormally expressed in a variety of tumor tissues and is linked to the biological processes of tumorigenesis, migration, invasion, and metastasis. SERPINH1 expression and prognosis in malignant tumors, such as gastric, colorectal, and breast cancers, have previously been studied, but the gene has not yet been investigated in lung adenocarcinoma (LUAD) in terms of prognosis and the potential mechanisms of action.MethodsSERPINH1 was identified as an independent prognostic factor for LUAD in The Cancer Genome Atlas (TCGA) cohort and Affiliated Hospital of Nantong University (NTU) cohort (the LUAD data set) by univariate and multivariate Cox regression analyses. Additionally, we performed immunohistochemical staining to analyze the expression of SERPINH1 in LUAD and normal lung tissue. Based on the TCGA database, we analyzed the correlation of this gene with the tumor mutation burden (TMB), tumor microenvironment, immune infiltration, immune checkpoints, and anti-tumor drugs using the R language-related R package.ResultsSERPINH1 was highly expressed in LUAD tissue. Kaplan-Meier survival curves in both the TCGA cohort and the NTU cohort showed that the SERPINH1 low-expression group had a higher survival rate than the high-expression group. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of the SERPINH1 co-expressed genes revealed that the gene was associated with the extracellular matrix and cell proliferation and migration. The analysis of SERPINH1 and the TMB revealed a superior survival advantage for patients with high TMB and high SERPINH1 expression, and worse survival for those with low TMB and high SERPINH1 expression. The analysis of the tumor microenvironment (TME) and immune infiltration revealed that the high and low expression of SERPINH1 was associated with different immune infiltration characteristics. The analysis of the immune checkpoints and anti-tumor drugs showed that immunotherapy and anti-neoplastic treatment were more efficacious in the high SERPINH1 expression group than the low SERPINH1 expression group.ConclusionsUsing LUAD tissues and clinical samples, we showed that SERPINH1 can be used as a prognostic biomarker for LUAD. Our findings provide a new approach and strategy for the clinical treatment of LUAD patients.

Dataset Information

BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

Publications

BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

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