PRKCI regulates tumor microenvironment through YAP1 [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57236 | GEO | 2018/01/15
SECONDARY ACCESSION(S): PRJNA246047
REPOSITORIES: GEO
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Project description:A key feature of serous ovarian cancer is frequent amplification in the 3q26 locus, which harbors the PRKCI gene. Here we show that PRKCI is amplified and overexpressed in a 78% of high-grade serous ovarian carcinoma. Our in vivo studies with orthotopic mouse models establish it as an ovarian cancer oncogene. This oncogenic property of PRKCI is mediated by regulation of YAP1 activity. Accordingly YAP1 knockdown partially rescues PRKCI mediated tumorigenesis. Integrated gene expression profiling and YAP1 promoter occupancy analyses reveal that PRKCI and YAP1 cooperate to transcriptionally regulate genes affecting the tumor immune microenvironment. Consistently, CD11b+Gr1+Ly6G+ MDSCs are increased in the tumor microenvironment of PRKCI over-expressing tumors. Importantly, we show that elevated PRKCI expression in high-grade serous ovarian carcinomas strongly correlated with assignment to immunoreactive subtype. In summary, we identify PRKCI and YAP1 as key mediators of a tumor-promoting immunosuppressive microenvironment in ovarian cancers.
2018-01-15 | GSE57257 | GEO
Project description:A key feature of ovarian high-grade serous carcinoma is frequent amplification of the 3q26 locus. Here we show that PRKCI, located on the 3q26 locus is not only amplified and overexpressed in 78% of HGSC patient samples but is also expressed in early fallopian tube lesions, called Serous Tubal Intraepithelial Carcinoma. In vivo studies in a transgenic mouse model establish PRKCI as an ovarian cancer oncogene and identify YAP1 as a downstream regulator. Together, PRKCI and YAP1 regulate TNFα to promote an immune suppressive microenvironment and inhibit cytotoxic T-cell infiltration in tumors. High PRKCI expressing human ovarian tumors show decreased cytotoxic T-cell infiltration. Taken together, we identify PRKCI and YAP1 as key mediators of a tumor-promoting immune microenvironment in ovarian cancer.
2018-06-01 | GSE57262 | GEO
Project description:A key feature of high-grade serous ovarian carcinoma (HGSOC) is frequent amplification of the 3q26 locus harboring PRKC-iota (PRKCI). Here, we show that PRKCI is also expressed in early fallopian tube lesions, called Serous Tubal Intraepithelial Carcinoma. Transgenic mouse studies establish PRKCI as an ovarian cancer specific oncogene and system level and functional analyses identify YAP1 as a downstream effector in tumor progression. Mechanistically, the oncogenic activity of the PRKCI-YAP1 axis relates in part to the upregulation of TNFα to promote an immune suppressive tumor microenvironment characterized by an abundance of myeloid-derived suppressor cells and inhibition of cytotoxic T cell infiltration. In human ovarian cancers, high PRKCI expression also correlates with high expression of YAP1 and low infiltration of cytotoxic T-cell. The PRKCI-YAP1 regulation of the tumor immunity provides a therapeutic strategy for highly lethal ovarian cancer. Robust multi-array average (RMA) method was used with default options (with background correction, quantile normalization, and log transformation) to normalize raw data from batches using R/Bioconductor‘s affy package
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Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas. Total RNA were extracted from microdissected human ovarian surface epithelia (HOSE, n=6), and microdissected serous borderline ovarian tumors (LMP, n=8), low-grade serous ovarian carcinomas (LGOSC, n=13), and 22 high-grade serous ovarian carcinomas (HGOSC, n=22). Gene Expression profiles were then generated with commercial GeneChip Human Genome U133 Plus 2.0 Array. dChip was used to identify significant differentially expressed genes between LMP/LGOSC and HGOSC
2011-03-04 | E-GEOD-27651 | biostudies-arrayexpress
Project description:Ovarian cancer is the fifth most common form of cancer in women in the United States. Among different types of ovarian cancer, epithelial ovarian cancer is the most common and is highly lethal, however, prognostic and predictive markers, which can be used to predict chemoresponse and patient survival, have not been thoroughly explored. One critically important yet often overlooked component to the tumor progression process is the tumor microenvironment. Primarily composed of fibroblasts and extracellular matrix proteins (ECM) as well as endothelial cells and lymphocytic infiltrate, the tumor microenvironment has been shown to directly affect cell growth, migration, and differentiation through secreted proteins, cell-cell interactions and matrix remodeling (Tlsty and Coussens, 2006). The tumor microenvironment has the potential to promote tumor initiation of normal epithelial cells and facilitate progression of malignant cells, thereby, presenting a unique approach to diagnosing, understanding and treating cancer. Using a whole-genome oligonucleotide array platform to perform transcriptome profiling on the fibroblastic stromal component microdissected from a series of advanced stage high-grade serous ovarian adenocarcinomas, we identified a transcriptome signature for the ovarian cancer associated fibroblast (CAF). We further functionally characterized one of the identified genes, MFAP5, and we showed that stromal MFAP5 is a prognostic marker associated with poor patient survival. In addition to that, to investigate the signaling machanism and the effect of MFAP5 treatment on ovarian cancer cells, transcriptome profiling of MFAP5 treated OVCA432 high-grade serous ovarian cancer cells was performed. Further functional studies showed that stromal MFAP5 modulated ovarian cancer cell motility and invasion potential. High grade serous ovarian cancer cell line OVCA432 was used. Total RNA was isolated from control samples and MFAP5 treated cancer cell samples at 48 hours post-treatment. Followed by cDNA synthesis, IVT and biotin labeling, samples were then hybridized onto Affymetrix Human genome U133 plus 2.0 microarrays. For each treatment group, three independent samples were prepared for the microarray experiment.
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Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Gene expression analysis was performed on five serous borderline tumors with BRAF mutation and five serous borderline tumors without BRAF mutation randomly. RNA was extracted from microdissected tumor cells. Expression profiling was carried out with Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays
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Project description:Low-grade serous ovarian carcinoma is believed to arise from serous borderline ovarian tumors, yet the progression from serous borderline tumors to low-grade serous ovarian carcinoma remains poorly understood. The purpose of this study was to identify differentially expressed genes between the two groups. Expression profiles were generated from 6 human ovarian surface epithelia (HOSE), 8 serous borderline ovarian tumors (SBOT), 13 low-grade serous ovarian carcinomas (LG), and 22 high-grade serous ovarian carcinomas (HG). The anterior gradient homolog 3 (AGR3) gene was found to be highly upregulated in serous borderline ovarian tumors; this finding was validated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Anti-AGR3 immunohistochemistry was performed on an additional 56 LG and 103 HG tissues and the results were correlated with clinical data. Expression profiling determined that 1254 genes were differentially expressed (P < 0.005) between SBOT, LG and HG tumors. Serous borderline ovarian tumors exhibited robust positive staining for AGR3, with a lower percentage of tumor cells stained in LG and HG. Immunofluorescence staining indicated that AGR3 expression was limited to ciliated cells. Tumor samples with a high percentage (>10%) of AGR3 positively stained tumor cells were associated with improved longer median survival in both the LG (P = 0.013) and HG (P = 0.008) serous ovarian carcinoma groups. The progression of serous borderline ovarian tumors to low-grade serous ovarian carcinoma may involve the de-differentiation of ciliated cells. AGR3 could serve as a prognostic marker for survival in patients with low-grade and high-grade serous ovarian carcinomas.
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Project description:Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.
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