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Ovarian tumor AND Ovarian functional and neoplastic tumors [keywords]
- Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Cancer Cell 2013 Feb 11; 23(2):186-99.
Integrated genomic analyses revealed a miRNA-regulatory network that further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141, and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth.
- Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer. [Journal Article, Research Support, Non-U.S. Gov't]
- Proc Natl Acad Sci U S A 2013 Jan 8; 110(2):630-5.
The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.
- Long-range transcriptome sequencing reveals cancer cell growth regulatory chimeric mRNA. [Journal Article, Research Support, Non-U.S. Gov't]
- Neoplasia 2012 Nov; 14(11):1087-96.
mRNA chimeras from chromosomal translocations often play a role as transforming oncogenes. However, cancer transcriptomes also contain mRNA chimeras that may play a role in tumor development, which arise as transcriptional or post-transcriptional events. To identify such chimeras, we developed a deterministic screening strategy for long-range sequence analysis. High-throughput, long-read sequencing was then performed on cDNA libraries from major tumor histotypes and corresponding normal tissues. These analyses led to the identification of 378 chimeras, with an unexpectedly high frequency of expression (≈2 x 10(-5) of all mRNA). Functional assays in breast and ovarian cancer cell lines showed that a large fraction of mRNA chimeras regulates cell replication. Strikingly, chimeras were shown to include both positive and negative regulators of cell growth, which functioned as such in a cell-type-specific manner. Replication-controlling chimeras were found to be expressed by most cancers from breast, ovary, colon, uterus, kidney, lung, and stomach, suggesting a widespread role in tumor development.
- Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- J Biol Chem 2013 Jan 4; 288(1):141-51.
Cells respond to changes in the physical properties of the extracellular matrix with altered behavior and gene expression, highlighting the important role of the microenvironment in the regulation of cell function. In the current study, culture of epithelial ovarian cancer cells on three-dimensional collagen I gels led to a dramatic down-regulation of the Wnt signaling inhibitor dickkopf-1 with a concomitant increase in nuclear β-catenin and enhanced β-catenin/Tcf/Lef transcriptional activity. Increased three-dimensional collagen gel invasion was accompanied by transcriptional up-regulation of the membrane-tethered collagenase membrane type 1 matrix metalloproteinase, and an inverse relationship between dickkopf-1 and membrane type 1 matrix metalloproteinase was observed in human epithelial ovarian cancer specimens. Similar results were obtained in other tissue-invasive cells such as vascular endothelial cells, suggesting a novel mechanism for functional coupling of matrix adhesion with Wnt signaling.
- Associations between gene expression variations and ovarian cancer risk alleles identified from genome wide association studies. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.]
- PLoS One 2012; 7(11):e47962.
Functional genetic variations play important roles in shaping phenotypic differences among individuals through affecting gene expression, and thus, very likely to influence disease susceptibility, such as cancer susceptibility. One critical question in this era of post-genome wide association studies (GWAS) is how to assess the functional significance of the genetic variations identified from GWAS. In the current study, with lymphoblastoid cell lines (LCLs) from 74 non-related women with familial ovarian cancer and 47 unrelated controls matched on gender and race, we explored the associations between seven ovarian cancer risk variants identified from GWAS (rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21, and rs2363956 on 19p13) and whole genome mRNA expression profiles. We observed 95 significant trans-associations at a permutation level of 0.001. Compared to the other risk variants, rs10088218, rs1516982, and rs10098821 on 8q24.21 had the greatest number of significant associations (25, 16, and 38, respectively). Two possible cis-associations were observed between rs10098821 and c-Myc, and rs2072590 and HS.565379 (Permutated P = 0.0198 and 0.0399, respectively). Pathway enrichment analysis showed that several key biological pathways, such as cell cycle (P = 2.59×10(-06)), etc, were significantly overrepresented. Further characterization of significant associations between mRNAs and risk alleles might facilitate understanding the functions of GWAS discovered risk alleles in the genetic etiology of ovarian cancer.
- Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions. [Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Neoplasia 2012 Oct; 14(10):986-93.
AT-rich interactive domain 1A (ARID1A) has emerged as a new tumor suppressor in which frequent somatic mutations have been identified in several types of human cancers. Although most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of protein expression, 5% of ARID1A mutations are in-frame insertions or deletions (indels) that involve only a small stretch of peptides. Naturally occurring in-frame indel mutations provide unique and useful models to explore the biology and regulatory role of ARID1A. In this study, we analyzed indel mutations identified in gynecological cancers to determine how these mutations affect the tumor suppressor function of ARID1A. Our results demonstrate that all in-frame mutants analyzed lost their ability to inhibit cellular proliferation or activate transcription of CDKN1A, which encodes p21, a downstream effector of ARID1A. We also showed that ARID1A is a nucleocytoplasmic protein whose stability depends on its subcellular localization. Nuclear ARID1A is less stable than cytoplasmic ARID1A because ARID1A is rapidly degraded by the ubiquitin-proteasome system in the nucleus. In-frame deletions affecting the consensus nuclear export signal reduce steady-state protein levels of ARID1A. This defect in nuclear exportation leads to nuclear retention and subsequent degradation. Our findings delineate a mechanism underlying the regulation of ARID1A subcellular distribution and protein stability and suggest that targeting the nuclear ubiquitin-proteasome system can increase the amount of the ARID1A protein in the nucleus and restore its tumor suppressor functions.
- 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.]
- J Biol Chem 2012 Nov 30; 287(49):41297-309.
Telomerase is an essential enzyme that counteracts the telomere attrition accompanying DNA replication during cell division. Regulation of the promoter activity of the gene encoding its catalytic subunit, the telomerase reverse transcriptase, is established as the dominant mechanism conferring the high telomerase activity in proliferating cells, such as embryonic stem and cancer cells. This study reveals a new mechanism of telomerase regulation through non-coding small RNA by showing that microRNA-498 (miR-498) induced by 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) decreases the mRNA expression of the human telomerase reverse transcriptase. MiR-498 was first identified in a microarray analysis as the most induced microRNA by 1,25(OH)(2)D(3) in ovarian cancer cells and subsequently validated by quantitative polymerase chain reaction assays in multiple human cancer types. A functional vitamin D response element was defined in the 5-prime regulatory region of the miR-498 genome, which is occupied by the vitamin D receptor and its coactivators. Further studies showed that miR-498 targeted the 3-prime untranslated region of human telomerase reverse transcriptase mRNA and decreased its expression. The levels of miR-498 expression were decreased in malignant human ovarian tumors as well as human ovarian cancer cell lines. The ability of 1,25(OH)(2)D(3) to decrease human telomerase reverse transcriptase mRNA and to suppress ovarian cancer growth was compromised when miR-498 was depleted using the sponges in cell lines and mouse tumor models. Taken together, our studies define a novel mechanism of telomerase regulation by small non-coding RNAs and identify miR-498 as an important mediator for the anti-tumor activity of 1,25(OH)(2)D(3).
- The transcriptional targets of mutant FOXL2 in granulosa cell tumours. [Journal Article, Research Support, Non-U.S. Gov't]
- PLoS One 2012; 7(9):e46270.
Despite their distinct biology, granulosa cell tumours (GCTs) are treated the same as other ovarian tumours. Intriguingly, a recurring somatic mutation in the transcription factor Forkhead Box L2 (FOXL2) 402C>G has been found in nearly all GCTs examined. This investigation aims to identify the pathogenicity of mutant FOXL2 by studying its altered transcriptional targets.The expression of mutant FOXL2 was reduced in the GCT cell line KGN, and wildtype and mutant FOXL2 were overexpressed in the GCT cell line COV434. Total RNA was hybridised to Affymetrix U133 Plus 2 microarrays. Comparisons were made between the transcriptomes of control cells and cells altered by FOXL2 knockdown and overexpression, to detect potential transcriptional targets of mutant FOXL2.The overexpression of wildtype and mutant FOXL2 in COV434, and the silencing of mutant FOXL2 expression in KGN, has shown that mutant FOXL2 is able to differentially regulate the expression of many genes, including two well known FOXL2 targets, StAR and CYP19A. We have shown that many of the genes regulated by mutant FOXL2 are clustered into functional annotations of cell death, proliferation, and tumourigenesis. Furthermore, TGF-β signalling was found to be enriched when using the gene annotation tools GATHER and GeneSetDB. This enrichment was still significant after performing a robust permutation analysis.Given that many of the transcriptional targets of mutant FOXL2 are known TGF-β signalling genes, we suggest that deregulation of this key antiproliferative pathway is one way mutant FOXL2 contributes to the pathogenesis of adult-type GCTs. We believe this pathway should be a target for future therapeutic interventions, if outcomes for women with GCTs are to improve.
- Epigenetic silencing of DKK2 and Wnt signal pathway components in human ovarian carcinoma. [Journal Article, Research Support, Non-U.S. Gov't]
- Carcinogenesis 2012 Dec; 33(12):2334-43.
Wnt/β-Catenin signaling dysregulation is involved in tumorigenesis. Furthermore, epigenetic modification of the Dickkopf (DKK) family (DKK1-DKK4) has been shown to be important in Wnt signaling regulation. In this study, the role of DKK2, a Wnt antagonist, in epithelial ovarian cancer (EOC) was evaluated by examining the expression and methylation of DKK2 in SKOV3 and ES-2 ovarian cancer cell lines and 78 tissues collected from patients (50 ovarian carcinoma, 20 benign tumor and 8 normal ovarian tissues). DKK2 is highly downregulated in EOCs; however, DKK2 expression levels are higher in both normal tissues and benign tumors. In most cases of ovarian carcinoma, DKK2 is methylated, compared with the more common unmethylated form present in benign tumors and normal ovarian tissues. Additionally, DKK2 may be epigenetically silenced by methylation in higher grades and stages of EOC. Functional analysis revealed that overexpression of DKK2 suppressed malignant cell growth and invasion in SKOV3 and ES-2 cell lines. The expression of the downstream genes of Wnt signaling, including β-catenin, c-Myc and cyclin D1, was decreased in DKK2-transfected cells compared with mock cells. The expression of matrix metalloproteinase-2 and focal adhesion kinase were also decreased in DKK2 transfectants, supporting findings indicating inhibition of cell migration and invasion. This report provides novel indications that DKK2 is a unique hypermethylated target gene in EOC and that DKK2 may contribute to tumorigenesis in EOC through the Wnt/β-catenin signaling mechanisms.
- Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. [Journal Article, Research Support, Non-U.S. Gov't]
- Gynecol Oncol 2012 Dec; 127(3):569-78.
Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression.Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed.Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126.This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.