RUNX3 protein is overexpressed in human epithelial ovarian cancer

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Laboratory of Gynecologic Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Gynecologic Oncology (Impact Factor: 3.77). 10/2008; 112(2):325-30. DOI: 10.1016/j.ygyno.2008.09.006
Source: PubMed


RUNX family genes, including RUNX3, are developmental regulators that are important in human cancers. The purpose of this study was to evaluate expression and oncogenic potential of RUNX3 in ovarian carcinoma.
Immunohistochemical staining was performed on 60 malignant, 14 borderline, and 5 normal ovarian specimens. Correlation between RUNX3 expression with tumor histology was performed. RUNX3 expression was evaluated by quantitative real-time polymerase chain reaction (QRT-PCR) in microdissected normal and malignant epithelial ovarian tissues. Cell proliferation and viability studies were performed on cells expressing RUNX3 by lentiviral infection and cells with silenced RUNX3 expression by siRNA.
RUNX3 expression by immunohistochemistry was higher in serous ovarian carcinomas versus normal ovarian epithelium (P<0.001). Immunofluorescent staining confirmed upregulation of cytoplasmic RUNX3 in ovarian cancer cell lines and tissues. QRT-PCR showed higher RUNX3 mRNA expression in microdissected borderline and malignant ovarian tumor tissues compared with the normal ovarian surface epithelial cells (HOSE) (P=0.006 and P=0.023). Forced RUNX3 expression by lentiviral gene delivery in ovarian cancer cells, SKOV3, that initially showed undetectable RUNX3 expression, resulted in increased cell viability (P=0.043). Silencing RUNX3 expression by siRNA transfection into ovarian cancer cells, OVCAR429, initially expressing high levels of endogenous RUNX3 resulted in a decrease in proliferation (P=0.021).
These results suggest that RUNX3 has a role in cell proliferation and viability in ovarian cancer.

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    • "In prostate and ovarian tumors and cell lines, RUNX1 is most often expressed in combination with RUNX2 but the expression of all three RUNX factors is quite common (Fowler et al., 2006; Nevadunsky et al., 2009; Huang et al., 2011). To better understand disease states associated with overexpression or alterations to RUNX family expression, we targeted total CBF activity by silencing the ubiquitous RUNX partner, CBFb. "
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    ABSTRACT: Core Binding Factor (CBF) is a heterodimeric transcription factor containing one of three DNA-binding proteins of the Runt-related transcription factor family (RUNX1-3) and the non-DNA-binding protein, CBFβ. RUNX1 and CBFβ are the most common targets of chromosomal rearrangements in leukemia. CBF has been implicated in other cancer types; for example RUNX1 and RUNX2 are implicated in cancers of epithelial origin, including prostate, breast and ovarian cancers. In these tumors, CBF is involved in maintaining the malignant phenotype and, when highly over-expressed, contributes to metastatic growth in bone. Herein, lentiviral delivery of CBFβ-specific shRNAs was used to achieve a 95% reduction of CBFβ in an ovarian cancer cell line. This drastic reduction in CBFβ expression resulted in growth inhibition that was not associated with a cell cycle block or an increase in apoptosis. However, CBFβ silencing resulted in increased autophagy and production of reactive oxygen species (ROS). Since sphingolipid and ceramide metabolism regulates non-apoptotic cell death, autophagy and ROS production, Fumonsin B1 (FB1), an inhibitor of ceramide synthase, was used to alter ceramide production in the CBFβ-silenced cells. FB1 treatment inhibited the CBFβ-dependent increase in autophagy and provided a modest increase in cell survival. To document alterations to sphingolipids in the CBFβ-silenced cells, ceramide and lactosylceramide levels were directly examined by mass spectrometry. Substantial increases in ceramide species and decreases in lactosylceramides were identified. Altogether, this report provides evidence that CBF transcriptional pathways control cellular survival, at least in part, through sphingolipid metabolism. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 12/2013; 228(12). DOI:10.1002/jcp.24406 · 3.84 Impact Factor
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    • "In addition to the HOX gene network an important transcription factor of embryonic patterning, RUNX3(runt-related transcription factor 3), was found to be differentially expressed within F 7. RUNX3 has been reported to be overexpressed in HSG Ov-Ca cells and tissues, upregulating cells proliferation through downstream interference with TGF-β(transforming growth factor beta) cellular growth inhibition [56]. It is noteworthy that RUNX3 immuno-staining in HSG Ov-Ca subtypes samples correlate with clinical-pathological variables, like overall survival of platinum treated patients [57]. Hence RUNX3 is a key molecule acting as prognostic factor for HSG Ov-Ca characterization, since is involved in platinum resistance mechanisms. "
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    ABSTRACT: Background High-throughput (omic) data have become more widespread in both quantity and frequency of use, thanks to technological advances, lower costs and higher precision. Consequently, computational scientists are confronted by two parallel challenges: on one side, the design of efficient methods to interpret each of these data in their own right (gene expression signatures, protein markers, etc.) and, on the other side, realization of a novel, pressing request from the biological field to design methodologies that allow for these data to be interpreted as a whole, i.e. not only as the union of relevant molecules in each of these layers, but as a complex molecular signature containing proteins, mRNAs and miRNAs, all of which must be directly associated in the results of analyses that are able to capture inter-layers connections and complexity. Results We address the latter of these two challenges by testing an integrated approach on a known cancer benchmark: the NCI-60 cell panel. Here, high-throughput screens for mRNA, miRNA and proteins are jointly analyzed using factor analysis, combined with linear discriminant analysis, to identify the molecular characteristics of cancer. Comparisons with separate (non-joint) analyses show that the proposed integrated approach can uncover deeper and more precise biological information. In particular, the integrated approach gives a more complete picture of the set of miRNAs identified and the Wnt pathway, which represents an important surrogate marker of melanoma progression. We further test the approach on a more challenging patient-dataset, for which we are able to identify clinically relevant markers. Conclusions The integration of multiple layers of omics can bring more information than analysis of single layers alone. Using and expanding the proposed integrated framework to integrate omic data from other molecular levels will allow researchers to uncover further systemic information. The application of this approach to a clinically challenging dataset shows its promising potential.
    BMC Systems Biology 02/2013; 7(1):14. DOI:10.1186/1752-0509-7-14 · 2.44 Impact Factor
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    • "In the present study, our data found that RUNX2 significantly overexpressed in EOC tissues in contrast to normal ovarian tissues. Its expression status in EOC tissues was similar with another RUNX member, RUNX3 [26]. We also showed that the EOC tissues with advanced clinical stage more frequently tend to express high RUNX2. "
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    ABSTRACT: Aim. To investigate clinical significance of runt-related transcription factor (RUNX)-2 in epithelial ovarian cancer (EOC). Methods. RUNX2 protein expression and its subcellular localization were detected by immunohistochemistry in 116 patients with EOC. Results. RUNX2 protein was predominantly expressed in cell nucleus of EOC tissues. The expression level of RUNX2 in EOC tissues was significantly higher than that in normal ovarian tissues (P < 0.001). In addition, the nuclear labeling index (LI) of RUNX2 in tumor cells was significantly associated with the advanced clinical stage of EOC tissues (P = 0.001). Moreover, EOC patients with high RUNX2 LI had significantly shorter overall (P < 0.001) and progression-free (P = 0.002) survival than those with low RUNX2 LI. Especially, subgroup analysis revealed that EOC patients with high clinical stages (III~IV) in high RUNX2 expression group demonstrated a significantly worse clinical outcome than those in low RUNX2 expression group, but patients with low clinical stages (I~II) had no significantly different prognosis between high and low RUNX2 expression groups. Conclusions. Our data suggest for the first time that RUNX2 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients. RUNX2 might be a novel prognostic marker of EOC.
    BioMed Research International 10/2012; 2012(1):456534. DOI:10.1155/2012/456534 · 2.71 Impact Factor
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