Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RhSTIP1 induced SAMD1/5 pathway

ABSTRACT: Stress-induced phosphoprotein 1 (STIP1), a co-chaperone that organizes other chaperones- heat shock proteins (HSP), was recently shown to be secreted by human ovarian cancer cells to induce cell proliferation. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular regulated MAP kinase) signaling pathways. However, in this study, we found that STIP1 stimulated cell proliferation of ovarian cancer via a bone morphogenetic protein (BMP) signaling pathway, not through the prion-ERK pathway. The STIP1 binding to a BMP receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate cancer cell proliferation. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3) that promotes cell proliferation. In conclusion, ovarian cancer tissues secrete STIP1 into the local environment and eventually into blood circulation of patients. In an autocrine and/or paracrine fashion, secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Elucidation of the mechanism by which STIP1 stimulates cancer cell proliferation may pave the way for developing novel therapeutic strategies for treatment of ovarian cancer. SKOV3 cell,treated without rhSTIP1 SKOV3 cell,treated with rhSTIP1 SKOV3 cell,treated without rhSTIP1-2 SKOV3 cell,treated with rhSTIP1-2

ORGANISM(S): Homo sapiens

SUBMITTER: Yun-Shien Lee

PROVIDER: E-GEOD-36383 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Epithelial ovarian carcinoma (EOC) is a malignant tumor with high motility in women. Our previous study found that dysregulated NTPCR was associated with the prognosis of ovarian cancer patients, and thus this present study attempted to explore the potential roles of nucleoside-triphosphatase cancer-related (NTPCR) in disease progression. Methods: Expressed level of NTPCR was investigated in ovarian cancer cell lines by RT-qPCR analysis. shRNA targeting NTPCR was generated and transfected into SKOV3 cells to detect the effect of knocking out NTPCR on cell proliferation, cell cycle, cell migration, and invasion. Transcriptomic sequencing and metabolite profiling analysis were performed in shNTPCR groups to identify transcriptome or metabolites alteration that might contribute to ovarian cancer. And finally, we searched the overlapped signaling pathways correlated with differential metabolites and DEGs by integrating analysis. Results: NTPCR was upregulated in EOC cell lines compared with human ovarian epithelium cell IOSE80, especially in SKOV3 and OVCAR-3 (SKOV3 vs IOSE80, P<0.001; OVCAR-3 vs IOSE80, P<0.001). Knocking out NTPCR can induce cell proliferation and S phase arrest, promote migration and invasion in SKOV3 cells. RNA sequencing analysis demonstrated cohorts of differential expressed genes (DEGs) were identified in shNTPCR samples. PPI networks were constructed for DEGs. STAT1 (degree = 43) and OAS2 (degree = 36) were identified as hub genes in network. Several miRNAs together with target genes were predicted to be crucial genes related to disease progression, including hsa-miR-124-3p, hsa-miR-30a-5p, hsa-miR-146a-5, EP300, GATA2, and STAT3. We also screened the differential metabolites from shNTPCR samples, including 22 upregulated and 22 downregulated metabolites. By integrating analysis, eight overlapped pathways were correlated with these DEGs and differential metabolites, such as primary bile acid biosynthesis, protein digestion, and absorption, pentose and glucuronate interconversions. Conclusion: NTPCR might serve as a tumor suppressor in EOC progression. Our results demonstrated that DEGs and differential metabolites were mainly related to several signaling pathways, which might be a crucial role in the progression of ovarian cancer.

Project description:Deregulation of the transforming growth factor-? (TGF?) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGF? signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGF?-induced SMAD4 binding in epithelial ovarian cancer. Following TGF? stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGF?-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells compared to normal epithelial cells. Furthermore, based on gene regulatory network analysis, we determined that the TGF?-induced SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGF?/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer. The results link aberrant TGF?/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers. ChIP-Seq: 1 control lane. 4 unstimulated lanes 4 stimulated lanes Gene expression: 3 technical replicates each of SMAD4 stimulated and SMAD4 unstimulated cells

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RhSTIP1 induced SAMD1/5 pathway

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