Ras-Association Domain Family 1C Protein Promotes Breast Cancer Cell Migration
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Li xinmin
PROVIDER: S-ECPF-GEOD-24473 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells RASSF1C over-expression enhances T47D cell invasion/migration in vitro Three RASSF1C over-expression samples vs three controls
2010-10-02 | E-GEOD-24473 | biostudies-arrayexpress
Project description:RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells RASSF1C over-expression enhances T47D cell invasion/migration in vitro
2010-10-02 | GSE24473 | GEO
Project description:BACKGROUND: The Ras association domain family 1 (RASSF1) gene is a Ras effector encoding two major mRNA forms, RASSF1A and RASSF1C, derived by alternative promoter selection and alternative mRNA splicing. RASSF1A is a tumor suppressor gene. However, very little is known about the function of RASSF1C both in normal and transformed cells. METHODS: Gene silencing and over-expression techniques were used to modulate RASSF1C expression in human breast cancer cells. Affymetrix-microarray analysis was performed using T47D cells over-expressing RASSF1C to identify RASSF1C target genes. RT-PCR and western blot techniques were used to validate target gene expression. Cell invasion and apoptosis assays were also performed. RESULTS: In this article, we report the effects of altering RASSF1C expression in human breast cancer cells. We found that silencing RASSF1C mRNA in breast cancer cell lines (MDA-MB231 and T47D) caused a small but significant decrease in cell proliferation. Conversely, inducible over-expression of RASSF1C in breast cancer cells (MDA-MB231 and T47D) resulted in a small increase in cell proliferation. We also report on the identification of novel RASSF1C target genes. RASSF1C down-regulates several pro-apoptotic and tumor suppressor genes and up-regulates several growth promoting genes in breast cancer cells. We further show that down-regulation of caspase 3 via overexpression of RASSF1C reduces breast cancer cells' sensitivity to the apoptosis inducing agent, etoposide. Furthermore, we found that RASSF1C over-expression enhances T47D cell invasion/migration in vitro. CONCLUSION: Together, our findings suggest that RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells.
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Project description:Pheochromocytomas (PCCs) are rare neuroendocrine tumors that arise from the medulla of the adrenal gland or the sympathetic ganglia and are characterized by the secretion of catecholamines. In 30-40% of patients, PCCs are genetically determined by susceptibility genes as various as RET, VHL, and NF1. We have analyzed the Ras-association domain family members (RASSFs) in PCCs regarding their inactivating promoter hypermethylation status. Previously, we reported a promoter methylation in PCC for the first family member RASSF1A. Promoter hypermethylation of CpG islands leads to the silencing of the according transcript and is a common mechanism for inactivation of tumor suppressors. In this study, we observed inactivating DNA modifications for the RASSF members RASSF2, RASSF5A, RASSF9, and RASSF10, but not for the members RASSF3, RASSF4, RASSF5C, RASSF6, RASSF7, and RASSF8. The degree of promoter methylation was 19% for RASSF2, 67% for RASSF5A, 18% for RASSF9, and 74% for RASSF10. Interestingly, the degree of hypermethylation for RASSF10 in hereditary PCCs was 89 vs. 60% in sporadic PCCs. A similar but less dramatic effect was observed in RASSF5A and RASSF9. Including all RASSF members, we found that of 25 PCCs, 92% show promoter methylation in at least in one RASSF member. In 75% of the hereditary PCC samples, we found two or more methylated RASSF promoters, whereas in sporadic PCCs only 46% were observed. In summary, we could show that in PCC several RASSF members are strongly hypermethylated in their promoter regions and methylation of more than one RASSF member occurs in the majority of PCCs. This adds the inactivation of genes of the RASSF tumor suppressor family to the already known deregulated genes of PCC.
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Project description:Breast cancer subtypes such as triple-negative that lack the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2), remain poorly clinically managed due to a lack of therapeutic targets. This necessitates identification and validation of novel targets. Suppression of Popeye domain-containing protein 1 (POPDC1) is known to promote tumorigenesis and correlate to poor clinical outcomes in various cancers, and also promotes cardiac and skeletal muscle pathologies. It remains to be established whether POPDC1 is dysregulated in breast cancer, and whether overcoming the dysregulation of POPDC1 could present a potential therapeutic strategy to inhibit breast tumorigenesis. We assessed the potential of POPDC1 as a novel target for inhibiting breast cancer cell migration and proliferation. POPDC1 was significantly suppressed with reduced cell membrane localization in breast cancer cells. Furthermore, functional suppression of POPDC1 promoted breast cancer cell migration and proliferation, which were inhibited by POPDC1 overexpression. Finally, cAMP interacts with POPDC1 and up-regulates its expression in breast cancer cells. These findings suggest that POPDC1 plays a role in breast tumorigenesis and represents a potential therapeutic target or biomarker in breast cancer medicine.
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Project description:Programmed death ligand 1 (PD-L1) is widely known as an immune checkpoint, and immunotherapy through the inhibition of checkpoint molecules has become an important component in the successful treatment of tumours via programmed death 1 (PD-1)/PD-L1 signalling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) are elusive. We previously found that PD-L1 can bind to PD-L1 and cause cell detachment. However, the detailed molecular mechanisms of how PD-L1 binds to PD-L1 and how it transmits signals to the cell remain unclear. In this study, we disclosed that PD-L1 expression was dramatically upregulated in CRC compared to normal tissues. Ectopic expression of PD-L1 inhibits cell adhesive capacity and promotes cell migration in CRC cell lines, while silencing PD-L1 had the opposite effects and suppressed invasion and proliferation. Mechanistically, PD-L1 was found to promote epithelial-mesenchymal transition (EMT) through the ERK signalling molecule pathway and interacted with the 1-86 aa fragment of KRAS to transduce signals. Collectively, our study demonstrated the role of PD-L1 after binding to PD-L1 in CRC, thereby providing a new theoretical basis for further improving immunotherapy with anti-PD-L1 antibodies.
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Project description:Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in approximately 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1-8). RASSF1-6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7-8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours.
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Project description:Psoriasis is a chronic, inflammatory skin disease with a high incidence and recurrence; however, its exact pathogenesis and aetiology remain unclear. This study aimed to analyse the effect of the upstream negative regulator RAS-association domain family 1A (RASSF1A) on Yes-associated protein (YAP) in psoriasis. Skin lesions of 22 patients with psoriasis and 19 healthy controls were used. Human epidermal keratinocytes stimulated by M5 (IL-1α, IL-17, IL-22, TNF-α and oncostatin M) were used to establish a psoriatic cell model. BALB/c mice treated with topical imiquimod were used to establish a psoriatic mouse model. As the methylation level of RASSF1A increased, its expression in psoriatic patients and mice model decreased. Addition of the methylation inhibitor 5-Aza-CdR or RASSF1A-overexpressing lentivirus vector increased RASSF1A and reduced YAP expression; meanwhile improved skin lesions, reduced cell proliferation, induced cell cycle arrest in the G0/G1 phase, increased apoptosis, reduced inflammatory cytokines and activities of ERK, STAT3 and NF-κB signalling pathways. The results indicated that RASSF1A could play a role in the treatment of psoriasis by inhibiting YAP expression. Based on these findings, targeted drugs that can inhibit the methylation or increase the expression of RASSF1A may be useful for treating psoriasis.
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Project description:RAS association domain family protein 1a (RASSF1A) is a putative tumor suppressor gene located on 3p21, has been regarded playing important roles in the regulation of different types of human tumors. Previous reports demonstrated that the frequency of RASSF1A methylation was significantly higher in patients group compared with controls, but the relationship between RASSF1A promoter methylation and pathological features or the tumor grade of bladder cancer remains controversial. Therefore, A meta-analysis of published studies investigating the effects of RASSF1A methylation status in bladder cancer occurrence and association with both pTNM (p, pathologic stage; T, tumor size; N, node status; M, metastatic status) and tumor grade in bladder cancer was performed in the study. A total of 10 eligible studies involving 543 cases and 217 controls were included in the pooled analyses. Under the fixed-effects model, the OR of RASSF1A methylation in bladder cancer patients, compared to non-cancer controls, was 8. 40 with 95%CI=4. 96-14. 23. The pooled OR with the random-effects model of pTNM and tumor grade in RASSF1A methylated patients, compared to unmethylated patients, was 0. 75 (95%CI=0. 28-1. 99) and 0. 39 (95%CI=0. 14-1. 09). This study showed that RASSF1A methylation appears to be an independent prognostic factor for bladder cancer. The present findings also require confirmation through adequately designed prospective studies.
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