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The prognostic significance of fibroblast activation protein-? in human lung adenocarcinoma.

ABSTRACT: Background:Fibroblast activation protein (FAP) is a type II cell surface-bound integral serine protease, which is an important biomarker of cancer-associated fibroblasts. FAP-? performs several biological activities, including remolding extracellular matrix and acting as an immunosuppressor in the tumor microenvironment. However, the proliferation role of FAP-? in human lung adenocarcinoma has not been fully elucidated. Methods:The expression of FAP-? in 94-paired human lung adenocarcinoma tissues was identified by immunohistochemistry test. The effect of FAP on cell proliferation was examined by CCK-8 assay. RNA-sequencing and bioinformatics analysis were utilized to investigate the underlying mechanism. Western blot analysis, quantitative polymerase chain reaction (qPCR), and nude mice experiments, were also conducted for further validation. Results:The proliferation rates of human fibroblast strains FAP-HFF and FAP-BJ, and human lung adenocarcinoma cell line FAP-SPC-A-1 were higher than those of controls. The nude mice experiment also showed that FAP could promote the proliferation of SPC-A-1 cell line in vivo. qPCR and Western blot analysis indicated that CCNB1 was upregulated by the overexpression of FAP in the lung adenocarcinoma cell line. The expression of FAP-? was higher in both the cytoplasm and stroma of lung adenocarcinoma than in adjacent normal tissues. Survival analysis indicated that patients with higher expression of FAP-? in tumor stroma had a poor prognosis (P=0.019). The Cancer Genome Atlas Program (TCGA) data also showed that the expression of FAP within tumor tissues was higher (in both cytoplasm and stroma) compared with that in normal tissues (P<0.05). Conclusions:Our study indicates that FAP-? could facilitate the proliferation of lung adenocarcinoma cells and can be a prognostic marker in human lung adenocarcinoma.

SUBMITTER: Shi J

PROVIDER: S-EPMC7154482 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The prognostic significance of fibroblast activation protein-α in human lung adenocarcinoma.

Shi Jianlin J Hou Zongliu Z Yan Jun J Qiu Wanfang W Liang Luxin L Meng Mingyao M Li Lin L Wang Xiaodan X Xie Yanhua Y Jiang Lihong L Wang Wenju W

Annals of translational medicine 20200301 5

<h4>Background</h4>Fibroblast activation protein (FAP) is a type II cell surface-bound integral serine protease, which is an important biomarker of cancer-associated fibroblasts. FAP-α performs several biological activities, including remolding extracellular matrix and acting as an immunosuppressor in the tumor microenvironment. However, the proliferation role of FAP-α in human lung adenocarcinoma has not been fully elucidated.<h4>Methods</h4>The expression of FAP-α in 94-paired human lung adeno ...[more]

PMID: 32309371

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Project description:Background Recent studies have demonstrated that upregulation of heat shock transcription factor 2 binding protein (HSF2BP) may promote genomic instability, thereby leading to the development of tumors and also providing a potential target for biological antitumor therapy. However, the role of HSF2BP has so far remained unclear in lung adenocarcinoma (LUAD). Methods To explore the function of HSF2BP in LUAD, we collected transcriptome data for 551 lung samples from The Cancer Genome Atlas (TCGA) database and methylation data for 461 lung samples from the University of California Santa Cruz (UCSC) genome database, in addition to corresponding clinical information. We used bioinformatic approaches to systematically explore the role of HSF2BP in LUAD, including Gene Set Enrichment Analysis (GSEA), coexpression analysis, the Tumor IMmune Estimation Resource (TIMER) tool, Connectivity Map (CMap) analysis, and a meta-analysis involving three Gene Expression Omnibus (GEO) datasets and one TCGA dataset. Results Our results found that upregulation of HSF2BP in LUAD was an independent risk factor for the prognosis and diagnosis of LUAD. GSEA analysis showed HSF2BP expression was associated with vital signaling pathways, including the cell cycle, P53 signaling pathway, and homologous recombination. Coexpression analysis revealed 10 HSF2BP-associated genes, including oncogenes and tumor suppressor genes. Additionally, we found that HSF2BP expression was negatively correlated with B-cell infiltration and had a potential interaction with CD80 in LUAD, which may play an important role in tumor immune escape. Finally, we identified four small-molecule drugs which show promise for LUAD treatment. Conclusions The present study found that elevated HSF2BP posed a threat to prognosis in LUAD patients. HSF2BP might have been involved in tumorigenesis by influencing genomic stability and contributing to tumor immune evasion in the tumor immune microenvironment of LUAD. These findings suggest that HSF2BP may provide a vulnerable target for improving and enhancing treatment of LUAD.

Project description:BACKGROUND: Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC). METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ? 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ?16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression.

Dataset Information

The prognostic significance of fibroblast activation protein-? in human lung adenocarcinoma.

Publications

The prognostic significance of fibroblast activation protein-α in human lung adenocarcinoma.

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