Epigenetic mechanisms in endometrial cancer.
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Purpose: Endometrial cancer is a very common type of cancer in females worldwide. Advances in diagnosis and treatment have not decreased the incidence of endometrial cancer. Lately, research has been focused on revealing the molecular and genetic characteristics of endometrial cancer in order to provide new insights in the biology of this entity, leading hopefully to innovating therapies. Research has revealed that epigenetic modifications govern endometrial carcinogenesis. In this review, the epigenetic mechanisms that are involved in endometrial cancer as well as the differences between the different types of endometrial cancer are discussed. The review also refers to the putative therapeutic benefits that hopefully can arise.Cite
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MiRNAs play important roles in tumorigenesis. This study focused on exploring the effects and regulation mechanism of miRNA-137 on the biological behaviors of gastric cancer. Total RNA was extracted from tissues of 100 patients with gastric cancer and from four gastric cancer cell lines. Expression of miR-137 was detected by real-time PCR from 100 patients. The effects of miR-137 overexpression on gastric cancer cells' proliferation, apoptosis, migration and invasion ability were investigated in vitro and in vivo. The target gene of miR-137 was predicted by Targetscan on line software, screened by dual luciferase reporter gene assay and demonstrated by western blot. As a result, the expression of miR-137 was significant reduced in gastric cancer cell line HGC-27, HGC-803, SGC-7901 and MKN-45 as well as in gastric cancer tissues compared with GES-1 cell or matched adjacent non-neoplastic tissues (p<0.001). The re-introduction of miR-137 into gastric cancer cells was able to inhibit cell proliferation, migration and invasion. The in vivo experiments demonstrated that the miR-137 overexpression can reduce the gastric cancer cell proliferation and metastasis. Bioinformatic and western blot analysis indicated that the miR-137 acted as tumor suppressor roles on gastric cancer cells through targeting AKT2 and further affecting the Bad and GSK-3β. In conclusion, the miR-137 which is frequently down-regulated in gastric cancer is potentially involved in gastric cancer tumorigenesis and metastasis by regulating AKT2 related signal pathways.
AKT2
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MicroRNA-1292-5p inhibits cell growth, migration and invasion of gastric carcinoma by targeting DEK.
Gastric cancer ranks as the third most lethal cancer worldwide. Although many efforts have been made to identify novel markers for early diagnosis and effective drugs for the treatment of gastric cancer, the outcome is still poor due to delayed diagnosis and lack of therapeutic options. MicroRNAs (miRNAs) play crucial roles during tumorigenesis, and several miRNAs were found to be critical for gastric cancer development, offering promise as therapeutic targets. The results of this study indicate that a novel miRNA, miR-1292-5p, is downregulated both in gastric carcinoma in vivo and in gastric cancer cell lines in vitro. In addition, we showed that attenuation of miR-1292-5p inhibited the growth, migration and invasion of the AGS and SGC-7901 gastric cancer cell lines. Importantly, our results demonstrate that the proto-oncogenic protein DEK is a direct target of miR-1292-5p in gastric carcinoma. Our results therefore demonstrate a tumor suppressor role of miR-1292-5p in gastric carcinoma and hint at the diagnostic and therapeutic potential of the miR-1292-5p/DEK pathway in gastric cancer.
Gastric carcinoma
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Endometrial cancer is the most commonly diagnosed gynecological cancer and its incidence is increasing worldwide. The number of patients with this disease is likely to continue to grow, including younger patients. It is a complex disease driven by abnormal genetic and epigenetic alterations, as well as environmental factors. Many endometrial cancers show estrogen-dependent proliferation. The carcinogenic mechanisms are unknown or not completely explained beyond mutations of single oncogenes and tumor suppressor genes. Possible carcinogenic mechanisms include imbalance between endometrial proliferation by unopposed estrogen and the mismatch repair (MMR) system; rmethylation changes and mutation of genes. Epigenetic changes resulting in aberrant gene expression are dynamic and modifiable features of many cancer types. A significant epigenetic change is aberrant DNA methylation. In this review, we review evidence on the role of different changes in relation to endometrial carcinogenesis. Carcinogenic mechanisms of endometrial cancer involve both genetic and epigenetic changes. Determination of the detailed carcinogenic mechanisms will be useful for prevention and diagnosis of endometrial cancer, risk assessment, and development of new treatment strategies targeting genes.
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Abstract Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.
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Multiple genetic and epigenetic changes have been studied in ovarian cancer,endometrial cancer and cervical cancer,however,such changes are selected for during tumorigenesis and tumor aggression is not yet clear.The epigenetic changes of oncogenes,tumor suppressor genes and abnormal signaling pathways cause tumorigenesis.Aberrations epigenetic regulation in cell proliferation,apoptosis,autophagy and changes in cell adhesion and motility all contribute to disease development and metastasis.In contrast to genetic mutations,epigenetic events lead to changes in gene expression other than by means of DNA sequence alteration including DNA methylation,histone modifications and microRNA dysregulation.From what is presently known,epigenetics are more and more important in the development and progression of ovarian cancer,endometrial cancer and cervical cancer.
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Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.
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