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Identification of changes in gene expression after knock down of FOXL2 in patient derived immortal fallopian tube cells [CEL-Seq]

ABSTRACT: In order to identify specific events that are causatively involved in the metastatic process, we analyzed matched samples from 3 high grade serous ovarian cancer patients by RNA-seq. For each patient we examined samples representing the three cancer states: 1) primary tumor; 2) omentum metastasis (solid metastasis); 3) effusion metastasis. We identified genes differentially expressed between the various states. One of the genes found to be expressed in the primary tumor but not in the omentum or effusion metastasis is FOXL2, a transcription factor known to play a role in ovarian development and function. This change was successfully validated by RT-PCR in both the patients' samples as well as in a set of 27 independent patient samples representing the three cancer states. Knock-down of FOXL2 in patient-derived immortal fallopian tube cells lead to increased proliferation and survival. RNA-seq of the immortal fallopian tube cells after FOXL2 knock-down revealed a pro-metastatic gene expression signature. Our results suggest that FOXL2 is an important tumor suppressor and an inhibitor of ovarian cancer progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115446 | GEO | 2021/06/01

REPOSITORIES: GEO

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Project description:Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk-reducing salpingo-oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2- mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected in comparison with five mutation-negative control patients undergoing salpingo-oophorectomy for benign indications. Microarray analysis of genome-wide gene expression was performed on ovarian and fallopian tube samples from BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real-time polymerase chain reaction (qRT-PCR) in selected cases of RRSO samples, and also high grade serous carcinoma samples collected from patients with BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when statistically compared to controls pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes were upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies. Both fallopian tube and ovarian samples were collected from each BRCA1/2 mutation carrier resulting in eighteen mutation positive adnexal samples. Both fallopian tube and ovarian control samples were collected from one control patient while either ovarian or fallopian tube sample was available from four control patients, respectively, resulting in 6 adnexal control samples. High quality RNA was available from nine BRCA1/2-mutation positive ovarian and eight BRCA1/2-mutation positive fallopian tube samples and from three control ovarian and three control fallopian tube samples.