Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in microRNAs expression have been proposed to play role in endometrial cancer pathogenesis. Dicer and Drosha are main regulators of microRNA biogenesis and deregulation of their expression has been indicated as a possible cause of microRNAs alterations observed in various cancers. The objective of this study was to investigate Dicer and Drosha genes expression in endometrial cancer and to analyze the impact of clinicopathological characteristics on their expression. Fresh tissue samples were collected from 44 patients (26 endometroid endometrial carcinoma and 18 controls). Clinical and pathological data were acquired from medical documentation. Dicer and Drosha genes expressions were assessed by qRT-PCR using validated reference genes. Dicer and Drosha expression levels were significantly lower in endometrial cancer samples comparing to controls. Dicer was down-regulated by the factor of 1.54 (p=0.009) and Drosha gene mean expression value was 1.4 times lower in endometrial cancer group versus control group (p=0.008). Down-regulation of Dicer significantly correlated with decreased expression of Drosha (coefficient value 0.75). Decreased expression of Drosha correlated with higher histological grade and was influenced by BMI. Lower Dicer expression was found in nulli- and uniparous females comparing to multiparous individuals (p=0.002). Neither the FIGO stage nor the menstrual status had significant influence on the expression of studied genes. This study revealed for the first time that expression alterations of main regulators of microRNAs biogenesis are present in endometrial cancer tissue and could be potentially responsible for altered microRNAs profiles observed in this malignancy.
 ...
PMID:Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. 2155 80

Mutations in the tumor suppressor TP53 occur in almost all advanced ovarian cancers and in many advanced serous endometrial cancers. Mutations in TP53 can alter the function of the p53 protein, and some mutations result in a mutated protein with oncogenic activity. Previously referred to as gain of function (GOF) p53 proteins, we now term these "oncomorphic" mutations to better describe their function as oncogenes. We reviewed the data from The Cancer Genome Atlas (TCGA) and demonstrate that of the patients diagnosed with endometrial cancer that harbor TP53 mutations, approximately 30% of these mutations are oncomorphic. In ovarian cancer, approximately 20% are oncomorphic. The wild type (WT) p53 protein transactivates genes and micro- RNAs (miRNAs) necessary in the response to cellular stress, which turn off growth and induce apoptosis. In addition to direct transcriptional activation, WT p53 also acts through protein:protein interactions with Drosha and the miRNA processing complex to mediate rapid, enhanced processing of a subset of anti-growth miRNAs. We validated the interaction of WT p53 with the Drosha complex in the cell line UCI-107. We observed that miRNAs that inhibit the expression of oncogenes were induced. Specifically, some miRNAs were induced very rapidly over minutes, consistent with enhanced processing, while others required hours, consistent with transcriptional activation. In contrast, the most common oncomorphic TP53 mutations failed to interact with the Drosha complex and lost the ability to rapidly induce the miRNAs which inhibit oncogene expression. These studies highlight one mechanism underlying the oncomorphic properties of specific TP53 mutations: loss of the enhanced processing of anti-proliferative miRNAs.
 ...
PMID:Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex. 2533 94

The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial-mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in endometrial carcinoma (EC) by disrupting p68-Drosha complex assembly. Overexpression of mutp53 has the opposite effect of wild-type p53 (WTp53), repressing miR-26a expression by reducing pri-miR-26a-1 processing in p53-null EC cells. Re-expression of miR-26a in mutp53 EC cells decreases cell invasion and promotes mesenchymal-epithelial transition (MET). Rescuing miR-26a expression also inhibits EZH2, N-cadherin, Vimentin, and Snail expression and induces E-cadherin expression both in vitro and in vivo. Moreover, patients with higher serum miR-26a levels have a better survival rate. These results suggest that p53 gain-of-function mutations accelerate EC tumor progression and metastasis by interfering with Drosha and p68 binding and pri-miR-26a-1 processing, resulting in reduced miR-26a expression and EZH2 overexpression.
...
PMID:Mutant p53 induces EZH2 expression and promotes epithelial-mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing. 2658 74