S-Phase Cell Cycle Arrest, Apoptosis, and Molecular Mechanisms of Aplasia Ras homolog Member I–Induced Human Ovarian Cancer SKOV3 Cell Lines
| Autor: | Yufei Shen, Jianming Hu, Jinhua Zhou, Huijuan Meng, Qiaoying Zhu, Zhihong Zhu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
STAT3 Transcription Factor
rho GTP-Binding Proteins Blotting Western Green Fluorescent Proteins SKOV3 STAT-signal transduction and activators of transcription Apoptosis Biology ARHI medicine.disease_cause Ovarian neoplasms S Phase STAT3 Basic Science Gene expression medicine Autophagy Tumor Cells Cultured E2F1 Humans IR-inhibitory rate Phosphorylation E2F Extracellular Signal-Regulated MAP Kinases E2F4 P-STAT3-phosphorylated STAT3 Cell Proliferation GAPDH-glyceraldehyde phosphate dehydrogenase ERK-extracellular signal regulated protein kinase Obstetrics and Gynecology Cell Cycle Checkpoints OD-optical density Oncology Tumor progression GFP-green fluorescence protein DIRAS3 Cancer research Female Signal transduction Carcinogenesis ARHI-aplasia Ras homolog member I |
| Zdroj: | International Journal of Gynecological Cancer |
| ISSN: | 1525-1438 1048-891X |
| Popis: | Tumorigenesis is a complex multistep and multifactorial biological process involving the activation of multiple oncogenes and inactivation of tumor suppressor genes; however, studies on the effects and mechanisms of these genes in ovarian cancer are limited and not well connected. Although it is known that changes in the expression of oncogenes and tumor suppressor genes, such as p21, Ras, c-myc, p53, RB, p27, and p16, BRCA1 in human ovarian cancer (HOC), are linked to tumor progression, further studies are required to determine the effect and specific mechanisms on the occurrence and development of HOC. This will include exploring interactions between genes, the clinicopathologic correlation between gene expression products and HOC, and the potential of altering expression of these genes and gene products for treating patients with HOC. The ARHI gene (aplasia Ras homolog member I, also known as DIRAS3 or NOEY2) was first discovered by The University of Texas M. D. Anderson Cancer Center, United States. It is a member of the Ras superfamily and encodes a small GTP-binding protein. ARHI is highly expressed in normal human tissues, including mammary glands and ovaries, and heart, liver, pancreas, and brain. Conversely, it is reported to be down-regulated in tumor tissues including breast, HOC, and prostate cancers.1–3 The possible mechanisms underlying abnormal expression of ARHI in tumors may involve abnormal methylation, loss of heterozygosity, and low expression levels of acetylated histones.4–7 Depletion of histone deacetylases 1, 3, and 11 not only significantly increased the ARHI promoter activity of the transfected reporter but also activated the transcription of the endogenous ARHI gene.8 Some studies by Yu et al9 and Lu et al10 revealed ARHI is down-regulated by transcriptional mechanisms that involve E2F1 and E2F4, as well as by the loss of RNA binding proteins that decrease the half-life of ARHI mRNA. Mutation of the putative E2F binding site in the ARHI promoter reversed this inhibitory effect and significantly increased ARHI promoter activity. Studies have shown that ARHI inhibits cell growth in HOC and that loss of ARHI expression contributes to the formation of HOC.11 When ARHI re-expression was promoted using demethylation factors and histone deacetylase inhibitors in different tissues, tumor growth rates were reduced, and apoptosis increased.12 Furthermore, several studies have found that continuous expression of ARHI in HOC epithelia was associated with expression of cyclin-dependent kinase inhibitor p21 (WAF1/CIP1)1 and extension of tumor-free survival time. Bao et al13 directly injected the ARHI adenovirus vector into human breast tumor in nude mice and found that the tumor volume was significantly reduced. Although these reports demonstrated the possibility of tumor treatment by targeting the ARHI gene, the mechanism remains unclear. To address this, we did some research; according to our preliminary experiment, we found 3 ovarian cancer cell lines show low expression of ARHI in 9 ovarian cancer cell lines including HOSE, ES2, SKOV3, A2780, 3AO, OVCAR3, HO8910, HO8910PM, and CAOV3. They are SKOV3, OVCAR3, and CAOV3. We reconstructed the PIRES2-EGFP-ARHI plasmid and transfected it into HOC SKOV3 cells with low ARHI gene expression levels. We then investigated the effects and molecular mechanisms of ARHI on cell proliferation in HOC SKOV3 cells and changes to the signal transduction pathways of ARHI protein products. This study has provided an experimental basis for new approaches in the development of HOC therapies. |
| Databáze: | OpenAIRE |
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