KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1.

Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27kip1. Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity.

Twist induces epithelial-mesenchymal transition in cervical carcinogenesis by regulating the TGF-ß/Smad3 signaling pathway.

Epithelial-mesenchymal transition (EMT) is associated with the metastasis and poor prognosis of cervical cancer. However, the underlying mechanisms are poorly defined. In the present study, we investigated whether Twist plays a direct role in human cervical cancer using immunohistochemical and western blot analyses. Immunohistochemical analysis revealed that Twist is highly expressed in cervical cancer, which correlates with poor tumor pathological differentiation or lymph node metastasis (P<0.05). Depletion of Twist by stable shRNA-mediated knockdown decreased the migratory ability of cancer cell lines in vitro. Suppression or overexpression of Twist also resulted in an altered expression of the molecular mediators of EMT. Furthermore, exogenous TGF-ß promoted EMT by upregulating the expression of Twist through the TGF-ß/Smad3 pathway, and this effect was eliminated by Twist depletion in cancer cells as demonstrated in the in vitro study. The use of in vivo models revealed a decreased tumor proliferation potential in Twist-depleted cancer cells. The results suggested a novel function for Twist in the promotion of EMT via TGF-ß/Smad3 signaling pathway. Thus, Twist constitutes a potential therapeutic target in human cervical cancer.

A TrkB-STAT3-miR-204-5p regulatory circuitry controls proliferation and invasion of endometrial carcinoma cells.

BACKGROUND: We previously identified TrkB as an oncogene involved in promoting metastasis in endometrial carcinoma (EC). Here, we sought to delineate the effect of changes in TrkB expression on the global profile of microRNAs (miRNAs) in EC cells and further investigated the correlation between the expression of certain miRNA and TrkB in the clinicopathologic characteristics of EC patients. METHODS AND RESULTS: Using quantitative reverse transcription-PCR (qRT-PCR), we found that expression of TrkB mRNA has no significant difference in transcript levels between normal endometrium and EC cells captured by laser capture microdissection, while immunohistochemistry results demonstrated a markedly higher expression of TrkB protein in EC tissues. The microRNA array showed that ectopic overexpression and knockdown of TrkB expression caused global changes in miRNA expression in EC cells. qRT-PCR results showed that elevated TrkB repressed miR-204-5p expression in EC cells. Furthermore, immunoblotting assays revealed that TrkB overexpression in IshikawaTrkB cells noticeably increased JAK2 and STAT3 phosphorylation, which, however, was aborted by TrkB knockdown in HEC-1BshTrkB cells. Moreover, ChIP assays showed that phospho-STAT3 could directly bind to STAT3-binding sites near the TRPM3 promoter region upstream of miR-204-5p. Interestingly, using bioinformatics analysis and luciferase assays, we identified TrkB was a novel target of miR-204-5p. Functionally, the MTT assays, clonogenic and Transwell assays showed that miR-204-5p significantly suppressed the clonogenic growth, migration and invasion of EC cells. Furthermore, miR-204-5p also inhibited the growth of tumor xenografts bearing human EC cells. Importantly, we found lower miR-204-5p expression was associated with advanced FIGO stages, lymph node metastasis and probably a lower chance for survival in EC patients. CONCLUSIONS: This study uncovers a new regulatory loop involving TrkB/miR-204-5p that is critical to the tumorigenesis of EC and proposes that reestablishment of miR-204-5p expression could be explored as a potential new therapeutic target for this disease.