Xiang Tao

Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways

Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in β-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.

Knockdown of RAB25 promotes autophagy and inhibits cell growth in ovarian cancer cells

RAB25 belongs to the Rab family of small GTPases and is implicated in the development of various types of human cancer. To evaluate the role of RAB25 in ovarian cancer, RAB25 was knocked down by siRNA in HEY and ES‑2 human ovarian cancer cells. Autophagy, cell growth and cell apoptosis were evaluated. The results showed that knockdown of RAB25 increased acidic vesicle organelles and GFP-microtubule-associated protein 1 light chain 3 punctate fluorescence in ovarian cancer cells. Autophagy that promoted by knockdown of RAB25 was not observed in cells where the ERK1/2 signaling pathway had been inhibited by U0126. Knockdown of RAB25 reduced cell cycle progression and cell growth. Apoptosis of ovarian cancer cells could be induced by knockdown of RAB25. These results support the tumorigenic role of RAB25 in ovarian cancer cells.

Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway.

Gankyrin is a regulatory subunit of the 26kD proteasome complex. As a novel oncoprotein, gankyrin is expressed aberrantly in cancers from several different sites and has been shown to contribute to oncogenesis in endometrial and cervical carcinomas. Neither gankyrin’s contribution to the development of epithelial ovarian cancer nor its interaction with follicle-stimulating hormone (FSH)-driven proliferation in ovarian cancer has been studied. Here we have found that gankyrin is overexpressed in ovarian cancers compared with benign ovarian cystadenomas and that gankyrin regulates FSH upregulation of cyclin D1. Importantly, gankyrin regulates PI3K/AKT signaling by downregulating PTEN. Prolonged AKT activation by FSH stimulation of the FSH receptor (FSHR) promotes gankyrin expression, which, in turn, enhances AKT activation by inhibiting PTEN. Overexpression of gankyrin decreases hypoxia inducible factor-1α (HIF-1α) protein levels, but has little effect on HIF-1α mRNA levels, which could be attributed to gankyrin mediating HIF-1α protein stability via the ubiquitin–proteasome pathway. Reduction in HIF-1α protein stability led to attenuation of the binding with cyclin D1 promoter, resulted in abolishment of the negative regulation of cyclin D1 by HIF-1α, which promotes proliferation of ovarian cancer cells. Our results document that gankyrin regulates HIF-1α protein stability and cyclin D1 expression, ultimately mediating FSH-driven ovarian cancer cell proliferation.

Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma

Endometrial carcinoma is the second most common gynecological malignancy of the female genital tract worldwide. Enhancer of zeste homolog 2 (EZH2), a critical component of the polycomb repressive complex 2, has been found to be involved in multiple biological processes and is overexpressed in several types of cancer. Previous studies have demonstrated that EZH2 is associated with endometrial carcinoma. The present study showed that EZH2 was overexpressed in complex hyperplasia, atypical hyperplasia and endometrial cancer, but not in simple hyperplasia and normal endometrium. Additionally, by analyzing the correlation between EZH2 expression and clinicopathological characteristics, the expression of EZH2 was found to be associated with myometrial invasion and lymph-vascular space invasion of endometrial cancer. Furthermore, small interfering RNA was utilized to investigate the role of EZH2 in endometrial carcinoma cell proliferation, and the results showed that EZH2 knockdown suppressed the proliferation of endometrial carcinoma cells in vitro. Therefore, these findings indicate that EZH2 expression may predict a more aggressive biological behavior in endometrial carcinoma and it may provide potential therapeutic targets for treatment of endometrial carcinoma.

FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3

Recent studies have suggested that FSH plays an important role in ovarian epithelial carcinogenesis. We demonstrated that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis and facilitates neovascularisation. Our previous work has shown that transient receptor potential channel C3 (TRPC3) contributes to the progression of human ovarian cancer. In this study, we further investigated the interaction between FSH and TRPC3. We found that FSH stimulation enhanced the expression of TRPC3 at both the mRNA and protein levels. siRNA-mediated silencing of TRPC3 expression inhibited the ability of FSH to stimulate proliferation and blocked apoptosis in ovarian cancer cell lines. FSH stimulation was associated with the up-regulation of TRPC3, while also facilitating the influx of Ca(2)(+) after treatment with a TRPC-specific agonist. Knockdown of TRPC3 abrogated FSH-stimulated Akt/PKB phosphorylation, leading to decreased expression of downstream effectors including survivin, HIF1-α and VEGF. Ovarian cancer specimens were analysed for TRPC3 expression; higher TRPC3 expression levels correlated with early relapse and worse prognosis. Association with poor disease-free survival and overall survival remained after adjusting for clinical stage and grade. In conclusion, TRPC3 plays a significant role in the stimulating activity of FSH and could be a potential therapeutic target for the treatment of ovarian cancer, particularly in postmenopausal women with elevated FSH levels.

Luteinizing hormone upregulates survivin and inhibits apoptosis in ovarian epithelial tumors.

OBJECTIVE Luteinizing hormone (LH) plays an important role in the development of ovarian cancer, and has been shown to inhibit apoptosis in ovarian cancer cells. Similarly, survivin is a molecule that has been shown to inhibit apoptosis in other types of cancer. Therefore, the aim of this study was to determine whether survivin can be induced by LH in ovarian cancer, and whether this induction influences the sensitivity of ovarian cancers to chemotherapy. STUDY DESIGN Survivin expression was monitored using western blot assays, and flow cytometry was used to detect the effects of cisplatin on the induction of apoptosis by LH. MTT assays were also used to analyze rates of cell proliferation. RESULTS Administration of LH in vitro induced survivin expression in a dose-dependent manner. Moreover, this signaling was dependent on the ERK1/2 signaling pathway. LH also blocked apoptosis induced by cisplatin. CONCLUSION These results suggest that LH influences the sensitivity of ovarian cancer cells to chemotherapy via signaling to inhibit apoptosis that also upregulates survivin.

Uterine carcinosarcoma and high-risk endometrial carcinomas: a clinicopathological comparison.

Objective This retrospective study aimed to evaluate the clinicopathological characteristics of carcinosarcoma, grade 3 endometrial endometrioid carcinoma (G3EEC), uterine serous carcinoma (USC), and uterine clear cell adenocarcinoma (CC) to determine whether carcinosarcoma exhibited the same characteristics and outcomes as the other 3 high-risk endometrial cancers. Methods A total of 358 patients recruited from the Obstetrics and Gynecology Hospital of Fudan University were included in this study; the cases included 44 carcinosarcomas, 118 G3EECs, 118 USCs, and 78 CCs. Kaplan-Meier and Cox proportional hazards models were used to analyze outcomes and prognostic factors. Results Uterine carcinosarcomas had significantly worse outcomes (overall survival, disease-specific survival, and recurrence-free survival) compared with G3EEC, USC, and CC (P < 0.001), whereas the other 3 shared similar outcomes. Carcinosarcoma type was an independent factor, even stratified by stage. Eighty-three percent of recurred carcinosarcoma patients occurred within 1 year. Compared with USC and CC, patients with carcinosarcoma had a greater incidence of deep myometrial invasion (55.8%, P < 0.05) and cervical stromal involvement (P = 0.046). The carcinomatous regions of carcinosarcomas demonstrated a similar ER/P53 expression pattern as did USC and CC. However, all features were similar in carcinosarcoma and G3EEC patients, although the P53-positive rate was higher in carcinosarcoma patients compared with G3EEC patients (59.0% vs 38.5%, P = 0.037). For carcinosarcomas, a multivariate analysis showed that advanced stage (P = 0.006) was an independent prognostic factor for disease-specific survival. With regard to endometrioid-or-not epithelial and heterologous-or-homologous sarcomatous components, none of these components demonstrated apparent relationship with prognosis. Conclusions Carcinosarcomas exhibited significantly poorer outcomes than did G3EECs, USCs, and CCs. Therefore, it seems reasonable to regard carcinosarcomas as a particular type among high-risk epithelial endometrial carcinomas.

DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer

This work investigated the role of paired box 2 (PAX2) in endometrial cancer and its epigenetic regulation mechanism. Endometrial cancer tissues and cell lines exhibited increased PAX2 expression compared with hyperplasia, normal endometrium and endometrial epithelial cells. Knock-down of PAX2 resulted in reduced cell viability, invasion and migration, and PAX2 overexpression caused the opposite effects. Increased methylation of the PAX2 promoter was observed in both cancer tissues and cell lines and was positively correlated with PAX2 expression. After 5-Aza-CdR treatment, PAX2 mRNA and protein were down-regulated, and PAX2 methylation was decreased. Deletion analysis confirmed that a repressive transcriptional regulatory region of the PAX2 promoter coincided with the hypermethylated region identified in MassARRAY analysis. Binding sites of myeloid zinc finger 1 (MZF1) are predicted in the defined region. Knock-down of MZF1 up-regulated the transcriptional activity and protein level of PAX2 after 5-Aza-CdR treatment, which indicated that MZF1 may act as a repressive transcription factor when the PAX2 promoter is unmethylated. In conclusion, PAX2 is involved in the carcinogenesis of endometrial cancer by stimulating cell growth and promoting cell motility. The overexpression of PAX2 in endometrial cancer is regulated by promoter hypermethylation and the transcription factor MZF1.

A gestational choriocarcinoma of the ovary diagnosed by DNA polymorphic analysis: a case report and systematic review of the literature

BackgroundChoriocarcinoma of the ovary is rare. This tumor can arise from gestational tissue or pure germ cells of the ovary, the former results in gestational choriocarcinoma. The clinical characteristics and histology of both tumor types are identical, differentiation of these tumors is necessary for effective treatment. One strategy for the differentiation of these tumors types is to identify the presence of paternal DNA by DNA polymorphic analysis.Case presentationIn the present case, a 27-year-old patient with a history of amenorrhea, lower abdominal pain and vaginal bleeding received a laparoscopic dissection of cystic mass of the right ovary according to an initial diagnosis of ectopic pregnancy. Primary choriocarcinoma of the ovary was diagnosed by pathology, but its origin was uncertain. DNA polymorphic analysis was then performed and a gestational origin was confirmed. The patient subsequently exhibited an excellent response to chemotherapy, achieved complete remission and gave birth to a healthy baby.ConclusionDifferentiation between two etiologies of primary choriocarcinoma can be achieved with DNA polymorphic analysis and it is necessary to distinguish between them to approach to an appropriate treatment of a patient.

Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism

Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.