- Overexpression of ARF1 is associated with cell proliferation and migration through PI3K signal pathway in ovarian cancer. [Journal Article]
- OROncol Rep 2017; 37(3):1511-1520
- ADP-ribosylation factor 1 (ARF1) is a small G protein that regulates many cellular processes such as reorganization of the actin cytoskeleton and is highly expressed in various tumor cells and tissue...
ADP-ribosylation factor 1 (ARF1) is a small G protein that regulates many cellular processes such as reorganization of the actin cytoskeleton and is highly expressed in various tumor cells and tissues. However, the role of ARF1 in ovarian cancer progression remains unknown. In the present study, we explored the expression patterns of ARF1 in clinical ovarian cancer samples and adjacent noncancerous tissues. The results revealed that ARF1 overexpressed in EOC tissues and cell lines, compared with the adjacent non-tumorous tissues and normal ovarian cells. In addition, the immunoreactivity of ARF1 was positively correlated with EOC grade and Ki-67 expression. Knockdown of ARF1 expression notably inhibited cell proliferation and migration rate of EOC cells by the auxiliary of PI3K. Taken together, our findings provide new insights into the functional role of ARF1 on EOC cell growth and migration and it may serve as a diagnostic and therapeutic target.
- Roles of SALL2 in tumorigenesis. [Review]
- APArch Pharm Res 2017; 40(2):146-151
- The proteins p150(Sal2) (product of SALL2) and p53 share growth arrest and pro-apoptotic functions by independently inducing p21(Cip1/Waf1) and BAX, and both proteins are targeted by the human papill...
The proteins p150(Sal2) (product of SALL2) and p53 share growth arrest and pro-apoptotic functions by independently inducing p21(Cip1/Waf1) and BAX, and both proteins are targeted by the human papilloma virus E6 protein, leading to blockage of growth arrest in infected cells. Loss of both p53 and Sall2 in mice causes significantly higher mortality and metastasis rates compared with p53 single mutant mice. Therefore, p150(Sal2) seems to have strong potential as a novel cancer biomarker for early diagnosis and risk prediction. Loss of SALL2 expression is observed in many cases of human serous ovarian carcinoma, whereas normal ovarian epithelial cells maintain high levels of the p150(Sal2) protein, supporting an important tumor suppressive role for p150(Sal2) in the human ovary. In contrast, p150(Sal2) is a transcription factor required to convert differentiated glioblastoma cells into stem-like tumor-propagating cells, suggesting that its functional roles are dependent on tissue types and cellular context. The function of p150(Sal2) in normal and diseased cells and possible therapeutic approaches are discussed in this review.
- Antimicrobial peptide LL-37 promotes YB-1 expression, and the viability, migration and invasion of malignant melanoma cells. [Journal Article]
- MMMol Med Rep 2017; 15(1):240-248
- The cathelicidin antimicrobial peptide, LL-37, is a multifunctional peptide with a broad spectrum of antimicrobial activities, such as chemotaxis and neutralizing endotoxins. Previous studies have de...
The cathelicidin antimicrobial peptide, LL-37, is a multifunctional peptide with a broad spectrum of antimicrobial activities, such as chemotaxis and neutralizing endotoxins. Previous studies have demonstrated that it LL‑37 serves a functional role in the development of numerous types of cancer including ovarian, breast, prostate and lung cancer. However, its role in the development of malignant melanoma (MM) remains unclear. To determine the role of LL‑37 and the potential interaction with Y-box binding protein 1 (YB‑1) in MM, RNA interference, western blot, reverse transcription-quantitative polymerase chain reaction, MTT and Transwell assays were performed. The current study demonstrated that LL‑37 induced YB‑1 expression, and increased tumor cell proliferation, migration and invasion of A375 and A875 MM cell lines. In addition, inhibition of nuclear factor‑κB (NF‑κB) attenuated LL‑37‑induced YB‑1 expression. These results demonstrate that, through the upregulation of YB‑1 expression and the activation of the NF‑κB signaling pathway, LL‑37 may promote the malignant progression of MM cells in vitro.
- A network-pathway based module identification for predicting the prognosis of ovarian cancer patients. [Journal Article]
- JOJ Ovarian Res 2016 Nov 02; 9(1):73
- CONCLUSIONS: The two 7-gene expression signatures may be accurate predictors of clinical outcome in patients with ovarian cancer and has the potential to develop new therapeutic strategies for ovarian cancer patients.
- MicroRNA-127-3p acts as a tumor suppressor in epithelial ovarian cancer by regulating the BAG5 gene. [Journal Article]
- OROncol Rep 2016; 36(5):2563-2570
- In the present study, the tumor-suppressive role of microRNA-127-3p (miR-127-3p) in epithelial ovarian cancer (EOC) was elucidated. Expression of miR-127-3p was examined by quantitative RT-PCR (qRT-P...
In the present study, the tumor-suppressive role of microRNA-127-3p (miR-127-3p) in epithelial ovarian cancer (EOC) was elucidated. Expression of miR-127-3p was examined by quantitative RT-PCR (qRT-PCR) in 9 EOC cell lines and clinical samples from 13 EOC patients. EOC cell lines, OVCAR-3 and Caov-3, were transduced with a lentivirus to overexpress endogenous miR-127-3p. The tumor-suppressive effects of miR-127-3p on EOC proliferation, bufalin sensitivity, invasion and in vivo growth were investigated through proliferation, bufalin sensitivity wound-closure and in vivo tumorigenicity assays, respectively. In addition, luciferase reporter assay and qRT-PCR were conducted to verify whether the Bcl-2-associated athanogene 5 (BAG5) gene was the downstream target of miR-127-3p in EOC. BAG5 was subsequently upregulated in the OVCAR-3 and Caov-3 cells to examine its functional correlation with miR‑127-3p regulation in EOC. The results revealed that in both EOC cell lines and EOC tumor tissues, miR-127-3p was downregulated. Lentiviral-mediated miR-127-3p overexpression exerted tumor-suppressive effects in OVCAR-3 and Caov-3 cells by reducing in vitro proliferation and invasion, increasing bufalin sensitivity, and inhibiting in vivo tumor growth. miR‑127-3p directly regulated the BAG5 gene in EOC. Subsequent BAG5 upregulation ameliorated the tumor-suppressive effects of miR-127-3p overexpression in EOC. In conclusion, miR-127-3p functions as a tumor suppressor in EOC, and its influence on EOC is directly through regulation of BAG5.
- Decreased expression of microRNA-148a predicts poor prognosis in ovarian cancer and associates with tumor growth and metastasis. [Journal Article]
- BPBiomed Pharmacother 2016; 83:58-63
- CONCLUSIONS: MiR-148a may be a potential prognostic factor for ovarian cancer and it can suppress tumor progression.
- Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis. [Journal Article]
- MOMed Oncol 2016; 33(11):130
- Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and m...
Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and microRNA dataset GSE47841 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using GEO2R. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape. Following, overall survival (OS) analysis of hub genes was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Moreover, miRecords was applied to predict the targets of the DEMs. A total of 345 DEGs were obtained, which were mainly enriched in the terms related to cell cycle, mitosis, and ovulation cycle process. A PPI network was constructed, consisting of 141 nodes and 296 edges. Sixteen genes had high degrees in the network. High expression of four genes of the 16 genes was associated with worse OS of patients with ovarian cancer, including CCNB1, CENPF, KIF11, and ZWINT. A significant module was detected from the PPI network. The enriched functions and pathways included cell cycle, nuclear division, and oocyte meiosis. Additionally, a total of 36 DEMs were identified. The expression of KIF11 was negatively correlated with that of has-miR-424 and has-miR-381, and it was also the potential target of two microRNAs. In conclusion, these results identified key genes, which could provide potential targets for ovarian cancer diagnosis and treatment.
- Downregulation of Foxo3 and TRIM31 by miR-551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer. [Journal Article]
- MOMed Oncol 2016; 33(11):126
- Ovarian cancer (OVCa) stem cells are associated with tumor growth, metastasis, and recurrence, which are driving forces behind a majority of the OVCa-related mortality. This subpopulation of cancer c...
Ovarian cancer (OVCa) stem cells are associated with tumor growth, metastasis, and recurrence, which are driving forces behind a majority of the OVCa-related mortality. This subpopulation of cancer cells are characterized by uncontrolled proliferation, high invasiveness, and resistance against the current platinum-based therapy. Thus, targeting OVCa cancer stem cells has been focused in recent therapeutic development. Isolation and purification of cancer stem cells are, however, challenging for the lack of sensitive and specific markers. In this study, we demonstrated that miR-551b was upregulated in OVCa stem cells, by using a quantitative PCR array, correlating with the pathological grades of this malignancy. In vitro experiments indicated that miR-551b promoted the proliferation, invasion, and chemoresistance of OVCa cells and cancer stem cells. Further analysis suggested that miR-551b functioned through the suppression of Foxo3 and TRIM31, two important tumor suppressors. In support of this, our in vivo experiments using mouse xenograft models showed that inhibiting miR-551b significantly increased the susceptibility of OVCa cells to cisplatin and prolonged the survival of the host mice. In conclusion, our study suggested miR-551b as a potential biomarker for OVCa stem cells and explored its functional mechanism, providing a potential therapeutic target for future drug development.
- Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer. [Journal Article]
- IJInt J Mol Sci 2016 Aug 05; 17(8)
- Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of...
Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.
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- Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies. [Journal Article]
- EEBioMedicine 2016; 10:137-49
- Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease a...
Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.