[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer is a highly invasive cancer with poor prognosis. Previous studies have revealed lots of connections between the invasiveness and epithelial-mesenchymal transition (EMT), which is common during the progression of ovarian cancer. MDC1, a mediator of DNA damage checkpoint, has recently been implicated as a potential oncogene. Here, in this article, we studied the role of MDC1 in ovarian cancer metastasis. First, in tissue samples, we found that high expression level of MDC1 was correlated with poor prognosis. Furthermore, MDC1 overexpression in ovarian cancer cells significantly increased migration and invasion. In contrast, silencing MDC1 reversed these processes. Consistently, nude mice xenograft confirmed that silencing MDC1 suppressed tumor metastasis in vivo. We further demonstrated that MDC1 induced EMT through modulation EMT markers such as E-cadherin, N-cadherin, and vimentin. Taken together, our findings suggest that MDC1 promotes ovarian cancer metastasis through the induction of EMT.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 01/2015;
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer causes more deaths than any other malignant tumor of the female reproductive system. This is because the condition usually goes undetected until the late stages. The purpose of the present study is to identify alterations in the serum proteome profile during the development of ovarian cancer and to provide an experimental basis for discovering new and valuable serum biomarkers for the early detection of ovarian carcinoma. Surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF-MS) was used to profile changes in the serum proteome of Fischer 344 rats with ovarian cancer during the progress of tumor development. Sera were collected from the rats on day A (1 week before injection of tumor cells), day B (4 weeks after injection), and day C (6 weeks after injection). Each sample was subjected to SELDI-TOF-MS testing. Peak detection and alignment and selection of peaks with the highest discriminatory power were performed using proteinchip biomarker software. Decision tree analyses were performed using biomarker pattern software. Finally, 3 peaks were found to be the most valuable ones (3759, 4659 and 9318 Da). The expression frequency of m/z 3759-Da peaks was downregulated and another two frequencies (4659 and 9318 Da) were upregulated, and the levels of expression of these three proteins showed the same tendency as the expression frequency during the development of ovarian cancer. The total accuracy rate of diagnosis at 4 and 6 weeks post-injection was 94.7 and 97.3%, respectively. Profiling the serum proteome changes during the process of the cancer development using SELDI-TOF-MS may provide useful information regarding carcinogenesis and facilitate discovery of novel serum biomarkers for early detection.
International Journal of Oncology 12/2014; 45(6):2495-501. · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.
[Show abstract][Hide abstract] ABSTRACT: Pharmacokinetics and bio-distribution are crucial factors affecting the performance of an intravenous drug. In this study, we explore the combined use of glucose and polyethylene glycol (PEG) ligands to further improve gold nanoparticle (GNP) pharmacokinetics and bio-distribution, with the aim of using the drug for in-vivo radiotherapy. The inclusion of PEG was found to significantly prolong the half-life period, where PEG-Glu-GNPs achieved 6.17 +/- 3.71 h, compared to 1.23 +/- 0.14 h for Glu-GNPs and 1.07 +/- 0.22 h for uncoated GNPs. Our data indicates that nanoparticle size impacts cell uptake performance, with 20 nm being the optimal diameter for cancer treatment applications. Although PEG-Glu-GNPs mainly distributed in the spleen, liver, lung, and kidneys, the concentration of PEG-Glu-GNPs in tumour tissue was 20 times higher than healthy cells in the uterus and ovaries, reaching 9.22 +/- 2.41 microg/g cancer tissue at 48 h after injection. This difference in uptake holds promise for selective tumor targeting which can in turn lead to more effective radiotherapy through the interaction of X-rays and GNPs. Specifically tumor size after 47 days of treatment had reduced to (769 +/- 92) mm3 compared to (1432 +/- 269) mm3 using X-rays alone and (3514 +/- 1818) mm3 without any treatment. Moreover, the mice remained healthy without statistically significant weight loss. Results of our pharmacokinetic and bio-distribution study as well as therapeutic data for PEG-Glu-GNPs in our tumor bearing animal model demonstrate that PEG-Glu-GNPs provide excellent in-vivo stability, tumor targeting function, and radiotherapeutic enhancement effects, providing useful insights for further clinical studies.
Journal of Biomedical Nanotechnology 07/2014; 10(7):1205-16. · 7.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uterine smooth muscle tumors (USMTs) constitute a group of histologic, genetic, and clinical heterogeneous tumors that include at least 6 major histologically defined tumor types: leiomyoma (ULM), mitotically active leiomyoma (MALM), cellular leiomyoma (CLM), atypical leiomyoma (ALM), uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). Apart from ULM and LMS, the nature of these variants is not well defined.
[Show abstract][Hide abstract] ABSTRACT: Serous endometrial intraepithelial carcinoma is often associated with extrauterine disease. It is currently unclear where does the extrauterine disease come from. This study addressed this issue. A total of 135 samples from 21 serous endometrial intraepithelial carcinoma patients were studied. Cellular lineage relationships between intrauterine and extrauterine serous carcinomas were determined by TP53-mutation analysis and correlated to the clinicopathologic features. There were three conditions contributing the extrauterine disease: metastasis from serous endometrial intraepithelial carcinoma (n=10) showed identical TP53 mutation between intrauterine lesions and extrauterine disease, cases of adnexal origin (n=5) had discordant TP53 mutations, and the mixed cellular origin cases (n=6) with both identical and discordant mutation status. Patients with extrauterine disease from serous endometrial intraepithelial carcinoma metastasis typically had small tumor masses (<2 cm) in extrauterine sites and without finding of serous tubal intraepithelial carcinoma, while extrauterine disease with adnexal or tubal origin commonly had larger tumor masses in extrauterine sites including ovary and omentum and serous tubal intraepithelial carcinoma. The majority of extrauterine diseases associated with serous endometrial intraepithelial carcinoma are metastasized from the endometrium. Serous endometrial intraepithelial carcinoma is frequently associated with serous cancers of adnexal or tubal origin, indicating that endometrial and adnexal or tubal serous cancers may share similar etiologies. TP53-mutation analysis provides a strong linkage for cellular lineage analysis. Tumor size in extrauterine disease and presence of serous tubal intraepithelial carcinoma or not are useful clinicopathologic features to determine primary cancer site, which helps in clinical management.Modern Pathology advance online publication, 13 June 2014; doi:10.1038/modpathol.2014.76.
[Show abstract][Hide abstract] ABSTRACT: High-grade serous ovarian carcinoma (HGSOC) is a fatal disease, and its grave outcome is largely due to widespread metastasis at the time of diagnosis. Current chemotherapies reduce tumor burden, but they do not provide long term benefits for cancer patients. The aggressive tumor growth and metastatic behavior characteristic of these tumors demand novel treatment options such as anti-microRNA treatment which is emerging as a potential modality for cancer therapy. MicroRNA-182 (miR-182) overexpression contributes to aggressive ovarian cancer, largely by its negative regulation of multiple tumor suppressor genes involved in tumor growth, invasion, metastasis, and DNA instability. In this study, we examined the therapeutic potential of anti-miR-182 utilizing the animal orthotopic model to mimic human ovarian cancer using ovarian cancer cells SKOV3 (intrabursal xenografts) and OVCAR3 (IP injection). These models provide a valuable model system for the investigation of ovarian cancer therapy in vivo. Through a combination of imaging, histological, and molecular analyses, we found that anti-miR-182 treatment can significantly reduce tumor burden (size), local invasion, and distant metastasis compared to its control in both models. The bases of anti-miR-182 treatment are mainly through the restoration of miR-182 target expression, including but not limited to BRCA1, FOXO3a, HMGA2 and MTSS1. Overall, our results strongly suggest that anti-miR-182 can potentially be used as a therapeutic modality in treating HGSOC.
Molecular Cancer Therapeutics 05/2014; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The over-expression of leptin is a crucial feature for the maintenance of pregnancy. The effects of leptin on trophoblasts invasion are important to its reproductive function, but the underlying mechanisms remain poorly understood. MMP14 is a member of matrix metalloproteinase (MMP) family that is closely involved in the invasion process. Here, we characterized the importance of MMP14 in the pro-invasion effect of leptin on EVT cells and elucidated its molecular mechanisms. Transwell assay revealed that leptin promoted invasion of the immortalized EVT cell line HTR-8/SVneo in a dose- and time-related fashion. Further studies suggested that leptin enhanced HTR-8/SVneo cells invasion by up-regulating MMP14 expression, and knockdown of MMP14 by small interference RNA (siRNA) blocked the pro-invasion effect of leptin. Notably, leptin promoted the expression of Notch1 receptor and activated its signaling in HTR-8/SVneo cells, and blocking this pathway by siRNA inhibited both leptin-enhanced MMP14 expression and invasiveness of HTR-8/SVneo cells. Such effects of Notch1 signaling were related with the activation of PI3K/Akt pathway, which was significantly activated after leptin stimulation and was interfered by Notch1 signaling perturbation. Taken together, our observations suggest that leptin is an effective regulator of MMP14 expression, which consequently plays critical roles in invasion of EVT cells. The promoting effects of leptin on MMP14 require the crosstalk between Notch1 and PI3K/Akt signaling pathway.
Biology of Reproduction 02/2014; · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer, particularly high-grade serous ovarian carcinoma (HG-SOC), is still the main cause of death among gynecological malignancies. However, the molecular mechanisms related to its malignant biological behavior are still unclear. Recent studies indicate that microRNAs (miRNAs) play an important role in tumor metastasis. Here, we report that miR-1236-3p expression was downregulated in HG-SOC when compared to that in normal fallopian tube tissue. Manipulation of miR-1236-3p significantly influenced the morphology, migration and invasion of ovarian cancer cell lines (A2780 and SKOV3). With dual-luciferase reporter assay, we demonstrated that miR‑1236-3p binds to the 3'UTR of zinc-finger E-box binding homeobox 1 (ZEB1) mRNA, and functions as a negative regulator of ZEB1. Furthermore, we revealed that manipulation of miR-1236-3p modulates ZEB1 expression and influences expression of its downstream genes E-cadherin and N-cadherin at both the mRNA and protein levels. We also found an inverse relationship between miR‑1236-3p and ZEB1 expression in the HG-SOC tissue samples. Taken together, our results indicate that miR-1236-3p regulates ovarian cancer metastasis by directly targeting ZEB1, and it may play an important role in the diagnosis and treatment of ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated.
The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining.
Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues.
This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis.
PLoS ONE 02/2014; 9(2):e86812. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This meta-analysis was designed to assess the overall performance of GnRHa in preserving the ovarian function in young women undergoing chemotherapy. Electronic literature databases including Pubmed, MEDLINE, Cochrane library, Embase, CNKI and Wanfang were searched for articles published till November, 2013. The articles written in both Chinese and English were considered. Only randomized controlled trials (RCTs) were selected. Main Outcome Measure was evaluated by assessing the post‑chemotherapy ovarian function. A random-effects model was used to calculate the risk ratio (RR) and associated 95% confidence intervals (95% CI). Out of the eight RCTs including 621 patients, 321 women were treated with GnRHa during chemotherapy, 9.66% of whom suffered premature ovarian failure (POF). On the other hand, 26.67% of the remaining 300 women suffered POF. More women treated without GnRHa experienced post-chemotherapy POF, yielding an RR of 0.45 [chemotherapy plus GnRHa vs. chemotherapy alone, 95% confidence interval (CI) (0.22, 0.92)]. Based on the available studies, GnRHa plays an important role in the prevention of post-chemotherapy POF, but does not exhibit its protective effects in fertility.
International Journal of Oncology 02/2014; · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to characterize the clinical significance of GMFG, a novel ADF/cofilin superfamily protein, and investigate its role in cell migration and invasion in epithelial ovarian cancer (EOC).
The expression of GMFG in EOC tissues and ovarian cancer cell lines was evaluated by immunohistochemistry and immunoblotting respectively. The data were statistically analyzed for the associations of GMFG expression with clinicopathologic parameters and survival. In vitro cell migration and invasion assays were performed to determine the role of GMFG in cell migratory behaviors. The effect of GMFG on reorganization of actin cytoskeleton was investigated by immunostaining.
GMFG was overexpressed in EOC. Up-regulated GMFG expression was closely correlated with advanced FIGO stage and chemoresistance of the disease. EOC patients with higher GMFG expression showed poorer progression-free survival (PFS) and overall survival (OS). In vitro cellular assays revealed that GMFG promoted cell migration and invasion. GMFG expression altered actin cytoskeleton organization probably by interacting with Arp2/3 complex.
GMFG expression independently predicts poorer prognosis in patients with EOC. Ectopic overexpression of GMFG contributes to the malignant biological behavior of ovarian cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Uterine leiomyomas (fibroids) are a major public health problem. Current medical treatments with GnRH analogues do not provide long term benefit. Thus, permanent shrinkage or inhibition of fibroid growth via medical means remains a challenge. The AKT pathway is a major growth and survival pathway for fibroids. We propose that AKT inhibition results in a transient regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In this study, we investigated specific mechanisms of AKT inhibition that resulted in senescence. We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species (ROS), upregulated the microRNA miR-182, and several senescence associated genes (including p16, p53, p21, and β-galactosidase), and drove leiomyoma cells into stress induced premature senescence (SIPS). Moreover, induction of SIPS was mediated by HMGA2 which co-localized to senescence-associated heterochromatin foci (SAHF). This study provides a conceivable molecular mechanism of SIPS by AKT inhibition in fibroids.
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is a puzzling and debilitating disease that affects millions of women around the world. Ovary is the most common organ site involved by endometriosis. Despite various hypotheses about its cell of origin, uncertainty remains. On the basis of our clinicopathologic observations, we hypothesize that fallopian tube may contribute the histogenesis of ovarian endometriosis. To examine if the hypothesis, tubal origin of ovarian endometriosis, has scientific supporting evidence, we identified a set of novel genes, which are either highly expressed in the normal fallopian tube or in the endometrium through a gene differential array study. Among many differentially expressed genes, FMO3 and DMBT1 were selected as the initial biomarkers to test the hypothesis. These biomarkers were then validated in ovarian sections with foci of endometriosis by comparing their expression levels in the fallopian tube and the endometrium within the same patients with real-time PCR, western blot and immunohistochemistry analysis. FMO3 was highly expressed in the tubal epithelia while low in the paired endometrium. In contrast, DMBT1 was high in the endometrium but low in the fallopian tube. In 32 ovarian endometriosis cases analyzed by real-time PCR, 18 (56%) showed a high level of FMO3 and a low level of DMBT1 expression. However, 14 (44%) endometriosis cases showed a reversed expression pattern with these two markers. Results were similarly seen in the methods of western blot and immunohistochemistry. The findings suggest that approximately 60% of the ovarian endometriosis we studied may be derived from the fallopian tube, whereas about 40% of the cases may be of endometrial origin. The fallopian tube epithelia may represent one of the tissue sources contributing to ovarian endometriosis. Such novel findings, which require confirmation, may have a significant clinical impact in searching for alternative ways of prevention and treatment of endometriosis.Modern Pathology advance online publication, 3 January 2014; doi:10.1038/modpathol.2013.245.
[Show abstract][Hide abstract] ABSTRACT: Recent identification of somatic MED12 mutations in most uterine leiomyomas brings a new venue for the study of the tumorigenesis of leiomyomas. We are particularly interested in the correlation of MED12 and HMGA2 gene products in leiomyomas and leiomyosarcomas with and without MED12 mutations. To address these issues, in this study we examined MED12 mutations in a large cohort of usual type leiomyomas (178 cases) and uterine leiomyosarcomas (32 cases). We found that 74.7% (133/178) of leiomyomas had MED12 mutations, which was consistent with several independent studies. In contrast, only 9.7% (3/32) of leiomyosarcomas harbored MED12 mutations. Expression analysis by western blot and immunohistochemistry revealed that those leiomyomas with complex MED12 mutations had significantly lower protein products than the matched myometrium. Interestingly, most leiomyosarcomas without MED12 mutations also had very low levels of MED12 expression in comparison to the matched myometrium. These findings suggest a potential functional role of MED12 in both benign and malignant uterine smooth muscle tumors. When we further examined HMGA2 expression in all leiomyomas and leiomyosarcomas, we found that HMGA2 overexpression was exclusively present in those leiomyomas with no MED12 mutation, accounting for 10.1% (18/178) of total leiomyomas and 40% (18/45) of non-MED12 mutant leiomyomas. Twenty-five percent (8/32) of leiomyosarcomas had HMGA2 overexpression, and no MED12 mutations were found in HMGA2 positive leiomyosarcoma. These findings strongly suggest that MED12 mutations and HMGA2 overexpression are independent genetic events that occur in leiomyomas, and they may act differently in the tumorigenesis of uterine leiomyomas.Modern Pathology advance online publication, 3 January 2014; doi:10.1038/modpathol.2013.243.
[Show abstract][Hide abstract] ABSTRACT: T helper 17 (Th17), T cytotoxic 17 (Tc17) and regulatory T (Treg) cells are important factors in the pathogenesis of inflammatory and autoimmune diseases. However, information concerning the roles of these cells in antitumor immunity or endometrial tumorigenesis remains limited.
We assessed the expression of interleukin (IL)-17 and Foxp3 in the peripheral blood of endometrial carcinoma patients and healthy controls by flow cytometry to determine the relative numbers of Th17, Tc17 and Treg cells. Th17 cells and Tc17 cells were counted as percentages of the total number of CD3(+) T cells; Treg cells were counted as a percentage of the total number of CD4(+) T cells. We also evaluated Th17 and Tc17 cells in tumor tissue by immunohistochemical staining. IL-17 and IL-10, dominant products of these three cell types, were detected by using enzyme-linked immunosorbent assays.
The frequencies of Th17, Tc17 and Treg cells, as well as the serum level of IL-10, were significantly elevated in endometrial carcinoma patients compared to healthy controls. The Th17/Tc17 and Th17/Treg ratios were also observed to change significantly. However, there was no significant difference on the IL-17 levels in the serum. Additionally, immunohistochemistry performed on tumor tissues indicated that the amounts of Th17 and Tc17 increased in the cancer patients.
Our data suggests a probable involvement of Th17, Tc17 and Treg cells in the pathogenesis of endometrial carcinoma. Restoring the balance of these cells may help in the research and development of immunotherapies for endometrial carcinoma.
[Show abstract][Hide abstract] ABSTRACT: Cervical cancer encompasses several histological types, including neuroendocrine tumors (NETs). Small-cell carcinoma of the uterine cervix (SCCC) is the most common and aggressive subtype of cervical NET. The objective of this case report was to investigate SCCC using a retrospective clinicopathological approach. Four cases of large (≥4 cm) SCCCs are presented in this case study. The patients were diagnosed with SCCC through a sequential hierarchy of physical examinations, laboratory reports, radiological reports, immunohistochemical and pathological tests. The diagnosis for each case was made at various stages (Ib1, Ib2, IIa2 and IIb, according to the FIGO staging system, 2000) and each of the patients received different multimodality therapeutic regimens. All the patients underwent radical hysterectomy and pelvic lymphadenectomy, followed by adjuvant chemotherapy. Neoadjuvant chemotherapy was administered prior to surgery in two of the patients. The clinical and pathological analyses were assessed using a retrospective measure, maintaining timely follow-ups. SCCC is a rare but serious gynecological malignancy. This condition has a poor prognosis due to its high aggressiveness, high rate of metastases and mortality. Furthermore, the rarity of this disease represents a hindrance to adequate research and development of novel, efficient therapeutic regimens.
Molecular and Clinical Oncology 01/2014; 2(1):71-75.
[Show abstract][Hide abstract] ABSTRACT: This meta-analysis aims to examine whether the XRCC3 polymorphisms are associated with ovarian cancer risk. Eligible case-control studies were identified through search in PubMed. Pooled odds ratios (ORs) were appropriately derived from fixed effects models. We therefore performed a meta-analysis of 5,302 ovarian cancer cases and 8,075 controls from 4 published articles and 8 case-control studies for 3 SNPs of XRCC3. No statistically significant associations between XRCC3 rs861539 polymorphisms and ovarian cancer risk were observed in any genetic models. For XRCC3 rs1799794 polymorphisms, we observed a statistically significant correlation with ovarian cancer risk using the homozygote comparison (T2T2 versus T1T1: OR = 0.70, 95% CI = 0.54-0.90, P = 0.005), heterozygote comparison (T1T2 versus T1T1: OR = 1.10, 95% CI = 1.00-1.21, P = 0.04), and the recessive genetic model (T2T2 versus T1T1+T1T2: OR = 0.67, 95% CI = 0.52-0.87, P = 0.002). For XRCC3 rs1799796 polymorphisms, we also observed a statistically significant correlation with ovarian cancer risk using the heterozygote comparison (T1T2 versus T1T1: OR = 0.91, 95% CI = 0.83-0.99, P = 0.04). In conclusion, this meta-analysis shows that the XRCC3 were associated with ovarian cancer risk overall for Caucasians. Asian and African populations should be further studied.
BioMed Research International 01/2014; 2014:648137. · 2.71 Impact Factor