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CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.

ABSTRACT: The active form of vitamin D, 1?,25-dihydroxyvitamin D(3) (1,25-D(3)), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D(3). The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D(3) in lung AC cells.Tumors and corresponding normal specimens from 86 patients with lung AC (stages I-III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D(3) were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA.CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D(3) compared with SKLU-1 cells (low CYP24A1).CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D(3) in high CYP24A1 expressing lung AC.

SUBMITTER: Chen G

PROVIDER: S-EPMC3058389 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.

Chen Guoan G Kim So Hee SH King Amanda N AN Zhao Lili L Simpson Robert U RU Christensen Paul J PJ Wang Zhuwen Z Thomas Dafydd G DG Giordano Thomas J TJ Lin Lin L Brenner Dean E DE Beer David G DG Ramnath Nithya N

Clinical cancer research : an official journal of the American Association for Cancer Research 20101217 4

<h4>Purpose</h4>The active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D(3). The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D(3) in lung AC cells.<h4>Experimental design</h4>Tumors and corresponding normal specimens from 86 patie ...[more]

PMID: 21169243

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Project description:BackgroundGlucosamine-Phosphate N-Acetyltransferase 1 (GNPNAT1) is a critical enzyme in the biosynthesis of uridine diphosphate-N-acetylglucosamine. It has many important functions, such as protein binding, monosaccharide binding, and embryonic development and growth. However, the role of GNPNAT1 in lung adenocarcinoma (LUAD) remains unclear.MethodsIn this study, we explored the expression pattern and prognostic value of GNPNAT1 in LUAD across TCGA and GEO databases and assessed its independent prognostic value via Cox analysis. LinkedOmics and GEPIA2 were applied to investigate coexpression and functional networks associated with GNPNAT1. The TIMER web tool was deployed to assess the correlation between GNPNAT1 and the main six types of tumor-infiltrating immune cells. Besides, the correlations between GNPNAT1 and the LUAD common genetic mutations, TMB, and immune signatures were examined.ResultsGNPNAT1 was validated upregulated in tumor tissues in TCGA-LUAD and GEO cohorts. Moreover, in both TCGA and GEO cohorts, high GNPNAT1 expression was found to be associated with poor overall survival. Cox analysis showed that high GNPNAT1 expression was an independent risk factor for LUAD. Functional network analysis suggested that GNPNAT1 regulates cell cycle, ribosome, proteasome, RNA transport, and spliceosome signaling through pathways involving multiple cancer-related kinases and E2F family. In addition, GNPNAT1 correlated with infiltrating levels of B cells, CD4+ T cells, and dendritic cells. B cells and dendritic cells could predict the outcome of LUAD, and B cells and CD4+ T cells were significant independent risk factors. The TMB and mutations of KRAS, EGFR, STK11, and TP53 were correlated with GNPNAT1. At last, the correlation analysis showed GNPNAT1 correlated with most of the immune signatures we performed.ConclusionOur findings showed that GNPNAT1 was correlated to the prognosis and immune infiltration of LUAD. In particular, the tight relationship between GNPNAT1 and B cell marker genes may be the epicenter of the immune response and one of the key factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of GNPNAT1 in LUAD.

Project description:BackgroundLung cancer is the leading cause of cancer-related death, and adenocarcinoma is the most common type of lung cancer. Although emerging evidence implicates the role of several aldehyde dehydrogenases in cancer progression, the expression and clinical significance of aldehyde dehydrogenase 3B1 in lung adenocarcinoma has never been studied.MaterialsIn our study, the expression of aldehyde dehydrogenase 3B1 in 250 cases of lung adenocarcinoma was detected with immunohistochemistry, and the patients were further divided into subgroups with different aldehyde dehydrogenase 3B1 expression. Using real-time polymerase chain reaction, we investigated the aldehyde dehydrogenase 3B1 messenger RNA in 20 lung adenocarcinoma and paired normal lung tissues. With the χ2 test, we evaluated the clinical significance of aldehyde dehydrogenase 3B1 by analyzing its correlation with the clinicopathological factors. Propensity score matching was performed to balance the baseline of cohort. With univariate and multivariate analyses, we screened the prognostic factors of lung adenocarcinoma and identified the independent prognostic factors before and after the propensity score matching.ResultsAldehyde dehydrogenase 3B1 expression was significantly associated with the sex and age of patients, tumor size, and histological grade. High expression of aldehyde dehydrogenase 3B1 predicted the poor prognosis (P = .003). Moreover, male patients (P = .020), large tumor size (P = .009), advanced T stage (P = .001), positive lymphatic invasion (P < .001), and advanced tumor-node-metastasis stage (P < .001) were all the prognostic factors for unfavorable outcome. Aldehyde dehydrogenase 3B1 was an independent prognostic biomarker of lung adenocarcinoma, indicating the poor prognosis. In addition, after balancing the baseline characteristics by propensity score matching, we also demonstrated that aldehyde dehydrogenase 3B1 was an independent prognostic biomarker of lung adenocarcinoma (P = .007).ConclusionsAldehyde dehydrogenase 3B1 was an independent prognostic biomarker of lung adenocarcinoma, indicating the unfavorable prognosis. Postoperative detection of aldehyde dehydrogenase 3B1 would help stratify the high-risk patients with lung adenocarcinoma and guide individual treatment.

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CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.

Publications

CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma.

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