Search

The aberrant expression of miR107‑5p is closely related to the development of several types of human cancers. However, the role of miR‑107‑5p in endometrial carcinoma (EC) has not been fully confirmed. In the present study, we aimed to explore the function of miR‑107‑5p in EC carcinogenesis. EC samples and normal endometrial tissues were obtained by laser capture microdissection. It was determined that the expression of miR‑107‑5p in EC was significantly higher than that in normal endometrium, and higher miR‑107‑5p expression was related to advanced FIGO stages, lymph node metastasis and myometrial invasion in EC patients. Blocking miR‑107‑5p significantly inhibited cell proliferation, migration and invasion of EC cells in vitro and in vivo. The results of bioinformatic algorithms and luciferase reporter assays revealed that estrogen receptor α (ERα) was a direct target of miR‑107‑5p. miR‑107‑5p downregulated the expression of ERα mRNA and protein. In conclusion, our results highlighted that miR‑107‑5p is a novel prognostic factor that targets ERα to promote tumor proliferation and invasion of EC.

Extensive exposure to estrogen is generally acknowledged as a risk factor for endometrial cancer. Given that the accumulation of adipocytes also contributes to the increased production of estrogen, in the present study, we evaluated the expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored the mechanism of how estrogen facilitates FTO nuclear localization and promotes endometrial cancer cell proliferation. Immunohistochemical (IHC) staining assay was used to detect the FTO expression in endometrial tumor samples. Western blotting was performed to investigate the mechanism of estrogen-induced FTO nuclear localization. siRNA was used to knock down ERα and further explore its role in FTO nuclear localization. MTT assay was carried out to determine cell proliferation. We found that FTO was overexpressed in endometrial carcinoma tissues and served as a poor prognostic marker. Additionally, estrogen induced FTO nuclear accumulation via the mTOR signaling pathway and the nuclear localization was ERα-dependent, which contributed to enhanced proliferative activity. Therefore, the present study provides new insight into the mechanisms of estrogen-induced proliferation, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.

Aim: Metformin plays an important role in the inhibition of cancer cell growth and prolongs remission durations. It reverses progestin-resistance in endometrial cancer cells by downregulating glyoxalase I (GloI) expression. This study aimed to investigate the effect of metformin on endometrial cancer cell chemotherapeutic sensitivity and explore the underlying molecular mechanisms., Material and Methods: MTT assay was performed to determine the rate of cell death after cisplatin and paclitaxel with or without metformin. Western blot was carried out to analyze GloI expression. SiRNA-targeting of GloI was used to knockdown GloI expression before further treatment with chemotherapeutic agents to examine the effect of GloI downregulation on chemotherapy-induced cell killing. In addition, plasmid transfection was used to overexpress GloI and determine whether high GloI levels blocked metformin-enhanced cell sensitivity to chemotherapy. PCR was used to analyze the efficiency of RNA interference and plasmid transfection., Results: The addition of metformin enhanced the sensitivity of endometrial cells to cisplatin and paclitaxel, which was associated with reduced levels of GloI expression. Moreover, low-dose chemotherapeutic drugs alone could not significantly reduce GloI expression, whereas the addition of metformin potently downregulated GloI protein levels. Cisplatin and paclitaxel markedly inhibited the proliferative ability of GloI-depleted endometrial cancer cells. However, the overexpression of GloI abolished the effect of metformin-enhanced cell sensitivity to chemotherapeutic drugs., Conclusion: Metformin enhances the rate of cell-killing induced by chemotherapeutic agents by repressing GloI expression., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

To elucidate the mechanisms of nuclear estrogen receptor (ER)-mediated and G protein-coupled receptor 30 (GPR30)-mediated signaling in the regulation of proliferation in ER-positive and ER-negative endometrial cancer cells, two human endometrial carcinoma cell lines, Ishikawa (ER-positive) and KLE (ER-negative), were used. PCR and Western blot analyses were used to determine the effects of estrogen stimulation on the activation of Notch and GPR30-PI3K/AKT signaling. Cell growth was investigated using MTT assays. Overexpression of ER in ER-negative cells was achieved by plasmid transfection and was used to investigate the effects on cellular growth and Notch signaling. GPR30-mediated signaling was evaluated using siRNA interference. Estrogen stimulated cell proliferation in both cell lines, it activated Notch signaling in ER-positive Ishikawa cells, but not in ER-negative KLE cells. Blockade of this signaling by a Notch inhibitor resulted in partial arrest of estrogen-induced cell proliferation in Ishikawa cells. Overexpression of ER in KLE cells restored estrogen-enhanced Notch signaling and further promoted cell growth. GPR30, as a new G-protein-coupled estrogen receptor, was detected in both cell lines, but was stronger in ER-negative KLE cells. Depletion of GPR30 in KLE cells abolished estrogen-induced PI3K/AKT signaling activation and resulted in inhibition of cell proliferation. Conclusively, regulation of proliferation in nuclear ER-positive endometrial cancer cells is mediated by both ER-Notch signaling and GPR30-PI3K/AKT signaling, whereas only the latter pathway is involved in the regulation of growth in nuclear ER-negative endometrial cancer cells.

Introduction: A long-term treatment with progestin commonly results in progestin resistance in endometrial cancer. So, the aim of this study was to investigate the role of glyoxalase I (GloI), a mediator of chemotherapy resistance, in metformin reversal of progestin resistance in endometrial carcinoma., Methods: The proliferation variety of endometrial cancer cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium (MTT) assay after exposure to medroxyprogesterone acetate, metformin, or both reagents; apoptosis rates were assessed by flow cytometry. Real-time polymerase chain reaction was used to evaluate the effect of small interfering RNA sequence on target gene expression. Western immunoblotting was performed to determine the expression of GloI and the molecules of the mammalian target of rapamycin (mTOR) pathway., Result: Knocking down GloI sensitized progestin-resistant Ishikawa cells to progestin. Metformin downregulated GloI expression, reversed progestin resistance, enhanced progestin-induced cell proliferation inhibition, and induced apoptosis in progestin-resistant Ishikawa cells. In addition, medroxyprogesterone acetate-induced mTOR phosphorylation was blocked by metformin. Metformin abolishes mTOR phosphorylation and inhibits GloI expression, attenuating proliferation and inducing apoptosis in progestin-resistant Ishikawa cells., Conclusions: Dysregulation of GloI expression in endometrial cancer may be part of the molecular mechanisms for progestin resistance.