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Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.

ABSTRACT: Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. The quantification of immunoreactivity was accomplished by applying an immunohistochemical scoring system (histoscore). Patients with high-level STIP1 expression (histoscore ?169) had a significantly worse survival (high STIP1, mean survival time?=?76 months; low STIP1, mean survival time?=?112 months; P<0.0001). Moreover, STIP1 histoscores were significantly higher in high-grade tumors (grade 3) than in low-grade (grade 1-2) malignancies (P<0.0001), suggesting that STIP1 may be a proxy for tumor aggressiveness. The results of multivariable analysis revealed that high STIP1 histoscores, advanced stages, histologic types, and the presence of residual disease (?2 cm) were independent predictors of poor prognosis. The addition of STIP1 histoscores improved the prediction of overall and progression-free survival rates in the multivariable Cox proportional hazard model. The treatment of ovarian cancer cells with recombinant STIP1 stimulated cell proliferation and migration, but co-treatment with anti-STIP1 antibodies abrogated this effect. Our findings suggest that STIP1 expression may be related to prognosis and that the STIP1 pathway may represent a novel therapeutic target for human ovarian cancer.

SUBMITTER: Chao A

PROVIDER: S-EPMC3584135 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.

Chao Angel A Lai Chyong-Huey CH Tsai Chia-Lung CL Hsueh Swei S Hsueh Chuen C Lin Chiao-Yun CY Chou Hung-Hsueh HH Lin Yu-Jr YJ Chen Hsi-Wen HW Chang Ting-Chang TC Wang Tzu-Hao TH

PloS one 20130227 2

Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation wit ...[more]

PMID: 23468915

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Project description:BackgroundOvarian cancer (OC) is one of the most lethal gynecologic malignancies and a leading cause of death in the world. Thus, this necessitates identification of prognostic biomarkers which will be helpful in its treatment.MethodsThe gene expression profiles from The Cancer Genome Atlas (TCGA) and GSE31245 were selected as the training cohort and validation cohort, respectively. The Kaplan-Meier (KM) survival analysis was used to analyze the difference in overall survival (OS) between high and low RB transcriptional corepressor 1 (RB1) expression groups. To confirm whether RB1 was an independent risk factor for OC, we constructed a multivariate Cox regression model. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were conducted to identify the functions of differentially expressed genes (DEGs). The associations of RB1 with immune infiltration and immune checkpoints were studied by the Tumor Immune Estimation Resource (TIMER 2.0) and the Gene Expression Profiling Interactive Analysis (GEPIA). The immunohistochemistry (IHC) was performed to compare the expression level of RB1 in normal tissues and tumor samples, and to predict the prognosis of OC.ResultsThe KM survival curve of the TCGA indicated that the OS in the high-risk group was lower than that in the low-risk group (HR = 1.61, 95% CI: 1.28-2.02, P = 3×10-5), which was validated in GSE31245 (HR = 4.08, 95% CI: 1.21-13.74, P = 0.01) and IHC. Multivariate Cox regression analysis revealed that RB1 was an independent prognostic biomarker (HR = 1.66, 95% CI: 1.31-2.10, P = 2.02×10-5). Enrichment analysis suggested that the DEGs were mainly involved in cell cycle, DNA replication, and mitochondrial transition. The infiltration levels of fibroblast, neutrophil, monocyte and macrophage were positively correlated with RB1. Furthermore, RB1 was associated with immune checkpoint molecules (CTLA4, LAG3, and CD274). The IHC staining revealed higher expression of RB1 in tumor tissues as compared to that in normal tissues (P = 0.019). Overexpression of RB1 was associated with poor prognosis of OC (P = 0.01).ConclusionThese findings suggest that RB1 was a novel and immune-related prognostic biomarker for OC, which may be a promising target for OC treatment.

Project description:Extracellular, cancer-specific methylated DNA has been shown to be a prognostic marker when detected in serum or plasma. In this study we investigated the effect of treating cancer cells with differentially methylated CpG DNA. When breast cancer cell lines were treated with methylated CpG DNA, a consistent upregulation of CHAC1 mRNA expression was observed. CHAC1 was recently described to be a novel component of the unfolded protein response pathway. To elucidate the role of CHAC1 mRNA expression in cancer in more detail, we analyzed expression of this gene in breast (n=107) and ovarian cancer (n=107) and found a strong correlation with tumor differentiation. Poorly differentiated tumors exhibited higher CHAC1 expression levels (p=0.004 for breast and p=0.031 for ovarian cancer). Additionally, hormone receptor (HR)-negative breast cancers (p<0.001) and advanced stage disease ovarian cancers (p=0.026) also demonstrated high CHAC1 mRNA levels. mRNA expression analysis of the two known CHAC1 isoforms showed a strong association of expression above the median with poor outcome in breast cancer patients in a multivariate analysis (isoform a: relative risk (RR) of death 3.2 (95% CI 1.6-6.5; p<0.01); RR of relapse 3.9 (95% CI 1.6-9.8; p<0.01); isoform b: relative risk (RR) of death 3.5 (95% CI 1.6-7.3; p<0.01); RR of relapse 6.6 (95% CI 2.4-18.5; p<0.01)). Univariate analysis in ovarian cancer showed that CHAC1 mRNA expression above the median was associated with a poor relapse free survival (p=0.03). In younger ovarian cancer patients (age < median age), a high CHAC1 mRNA expression was associated with overall survival (p=0.007) and relapse free survival (p=0.015). Finally, we show that downregulation of CHAC1 by small interfering RNA suppressed breast cancer cell migration and proliferation, whereas overexpression resulted in an observed increase in these cellular behaviours. This is the first report demonstrating that a gene (CHAC1) whose expression is triggered by methylated, but not unmethylated DNA, is involved in tumour biology. Human breast cancer cell lines (BT-20, Hs578T) were treated with methylated and unmethylated DNA oligos, and differentially expressed genes were identified between treatments with methylated and un-methylated oligos.

Dataset Information

Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.

Publications

Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.

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