ALDH1A2 Is a Candidate Tumor Suppressor Gene in Ovarian Cancer”
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ABSTRACT:
PROVIDER: PRJNA559144 | ENA |
REPOSITORIES: ENA
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Project description:Aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a rate-limiting enzyme involved in cellular retinoic acid synthesis. However, its functional role in ovarian cancer remains elusive. Here, we found that ALDH1A2 was the most prominently downregulated gene among ALDH family members in ovarian cancer cells, according to complementary DNA microarray data. Low ALDH1A2 expression was associated with unfavorable prognosis and shorter disease-free and overall survival for ovarian cancer patients. Notably, hypermethylation of ALDH1A2 was significantly higher in ovarian cancer cell lines when compared to that in immortalized human ovarian surface epithelial cell lines. ALDH1A2 expression was restored in various ovarian cancer cell lines after treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Furthermore, silencing DNA methyltransferase 1 (DNMT1) or 3B (DNMT3B) restored ALDH1A2 expression in ovarian cancer cell lines. Functional studies revealed that forced ALDH1A2 expression significantly impaired the proliferation of ovarian cancer cells and their invasive activity. To the best of our knowledge, this is the first study to show that ALDH1A2 expression is regulated by the epigenetic regulation of DNMTs, and subsequently that it might act as a tumor suppressor in ovarian cancer, further suggesting that enhancing ALDH1A2-linked signaling might provide new opportunities for therapeutic intervention in ovarian cancer.
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Project description:In this study, we identify leucyl-tRNA synthetase (LARS) as a breast tumor suppressor. To identify the mechanism underlying LARS-mediated breast tumor suppression, we conducted TMT-proteomics in PyMT mouse tumors with monoallelic genetic deletion of LARS in the mammary tumor compartment. The analyses implicate LARS as a regulator of leucine-rich protein translation resulting in downregulation of candidate leucine-rich tumor suppressor genes.
2022-01-10 | PXD026609 | Pride
Project description:MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility. In this study we monitored global miRNA expression changes in prostate cancer LNCaP cells treated with the epigenetic compounds 5-Azacytidine (5-AzaC) and/or trichostatin A (TSA). Cells were treated with epigenetic drugs for 36 hours and total RNA was isolated for hybridization to miRNA microarrays. 5 independent experiments were performed (n=4 for combined treatment). The candidate prostate tumor suppressor miRNAs, miR-1, miR-206, and miR-27 were up-regulated in LNCaP cells for Affymetrix microarray analysis. LNCaP cells were transfected with pre-miR oligos and 24 hr post-transfection total RNA was collected for microarray analysis; total of three independent experiments.
2011-12-01 | E-GEOD-31620 | biostudies-arrayexpress
Project description:Dysregulation of miRNA expression is associated with multiple diseases, including cancers where they can have oncogenic or tumor suppressive function. Here we investigated the potential tumor suppressive function of miR-450a, one of the most significantly downregulated miRNAs in ovarian cancer. RNAseq analysis revealed multipe genes involved in the epithelial-to-mesenchymal transition (EMT) were suppressed by miR-450a overexpression ovarian cancer cell line A2780. Consistently, miR-450a overexpression reduced tumor migration, invasion and increased anoikis in A2780 and SKOV-3 cell lines and reduced tumor growth in ovarian xenographic model. Combining AGO-PAR-CLIP and RNAseq analysis, we identified a panel of potential miR-450a targets of which many, including TIMMDC1, MT-ND2, ACO2 and ATP5B, regulate energetic metabolism. miR-450a expression indeed decreased mitochondrial membrane potential but increased glucose uptake and viability after glutamine withdrawal, characteristics of less invasive ovarian cancer cell lines, which are also less dependent on glutamine. In summary, we propose in this work that miR-450a acts as a tumor suppressor in ovarian cancer cells by modulating targets associated with glutaminolysis, which would lead to a decrease in the production of lipids, amino acids and nucleic acids, and also inhibition of signaling pathways associated with EMT
2019-04-30 | GSE129076 | GEO
Project description:In attempt to discover novel aberrantly hypermethylated genes with putative tumor suppressor function in epithelial ovarian cancer (EOC), we applied expression profiling following pharmacologic inhibition of DNA methylation in EOC cell lines. Among the genes identified, one of particular interest was DOK1, or downstream of tyrosine kinase 1, previously recognized as a candidate tumor suppressor gene (TSG) for leukemia and other human malignancies. Using bisulfite sequencing, we determined that a 5'-non-coding DNA region (located at nt -1158 to -850, upstream of the DOK1 translation start codon) was extensively hypermethylated in primary serous EOC tumors compared with normal ovarian specimens; however, this hypermethylation was not associated with DOK1 suppression. On the contrary, DOK1 was found to be strongly overexpressed in serous EOC tumors as compared to normal tissue and importantly, DOK1 overexpression significantly correlated with improved progression-free survival (PFS) values of serous EOC patients. Ectopic modulation of DOK1 expression in EOC cells and consecutive functional analyses pointed toward association of DOK1 expression with increased EOC cell migration and proliferation, and better sensitivity to cisplatin treatment. Gene expression profiling and consecutive network and pathway analyses were also confirmative for DOK1 association with EOC cell migration and proliferation. These analyses were also indicative for DOK1 protective role in EOC tumorigenesis, linked to DOK1-mediated induction of some tumor suppressor factors and its suppression of pro-metastasis genes. Taken together, our findings are suggestive for a possible tumor suppressor role of DOK1 in EOC; however its implication in enhanced EOC cell migration and proliferation restrain us to conclude that DOK1 represents a true TSG in EOC. Further studies are needed to more completely elucidate the functional implications of DOK1 and other members of the DOK gene family in ovarian tumorigenesis.
| S-EPMC5528302 | biostudies-literature
Project description:MicroRNAs (miRs) are small non-coding RNAs that can function as tumor suppressor genes. We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent dataset and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the candidate tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer cells. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair, and actin dynamics. This observation was further corroborated with protein expression analysis and 3’-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters gH2A.X marker expression and affects the cellular organization of F-actin and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.
2011-12-01 | GSE31620 | GEO
Project description:miR-450a acts as a tumor suppressor in ovarian cancer by readjusting energy metabolism
| PRJNA529911 | ENA
Project description:ECRG4 is a promising tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Its expression and prognostic value have never been explored in breast cancer. Using DNA microarray, we examined ECRG4 mRNA expression in 353 invasive breast cancer samples. A meta-analysis was performed on a large public retrospective gene expression dataset (n=1,387) to analyze correlation between ECRG4 expression and histo-clinical features including survival.
2011-12-02 | GSE31448 | GEO
Project description:Recent cancer genome sequencing studies have identified numerous novel candidate driver genes. In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited as a versatile means to validate their pathogenic relevance. In contrast, such functional analyses have been hampered for candidate tumor suppressor genes, e.g. by insufficient knockdown using RNAi-mediated approaches. In order to provide a flexible method for investigating loss-of-function mutations and their potential role in tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo deletion of candidate tumor suppressor genes. We demonstrate the utility of this approach by somatic disruption of the Ptch1 gene in the mouse cerebellum, leading to the formation of medulloblastoma faithfully resembling the SHH-driven subgroup of the disease. This in vivo method for validation of candidate tumor suppressor genes provides a fast and convenient system for the generation of faithful animal models of human cancer.
2014-12-31 | GSE58629 | GEO
Project description:FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome
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