TRAF4 knockdown triggers synergistic lethality with simultaneous PARP1 inhibition in endometrial cancer.

Endometrial cancer (EC) is one of the most common cancers among females worldwide. Advanced stage patients of EC have poor prognosis. Inevitable side effects and treatment tolerance of chemotherapy for EC remain to be addressed. Our results in this study showed that EC cells with higher tumor necrosis factor receptor-associated factor 4 (TRAF4) expression have lower sensitivity to poly ADP-ribose polymerase 1 (PARP1) inhibitors. Upon TRAF4 knockdown, the colony numbers of EC cells were markedly down-regulated, and the markers of DNA double-strand breakage were significantly up-regulated after the treatment of olaparib, a PARP1 inhibitor. TRAF4 knockdown reduced the phosphorylation of protein kinase B (Akt), promoted DNA double-strand breakage, and decreased levels of DNA repair related proteins, including phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). In addition, TRAF4's effect on the sensitivity of EC cells to olaparib was further found to be mainly mediated by Akt phosphorylation. Moreover, in vivo results showed that TRAF4 knockdown enhanced the sensitivity of EC to PARP1 inhibitors using a mouse xenograft model. Collectively, our data suggest that combined application of TRAF4 knockdown and PARP1 inhibition can be used as a promising strategy for synthetic lethality in EC treatment.

ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

Partial Hydatidiform Mole and Coexistent Live Fetus: A Case Report and Review of the Literature.

Twin pregnancy of a hydatidiform mole with a coexistent live fetus is very rare, and complete molar pregnancy is involved in most cases. A partial molar pregnancy almost always ends in miscarriage due to a triploid fetus. Here, we report a case of a 32-year-old Chinese woman with ultrasound diagnosis of a partial molar pregnancy. Amniocentesis suggested mosaicism, but the fetus was morphologically normal. The woman chose to continue the pregnancy after fully understanding the risk. The infant was delivered prematurely, and the presence of a large single placenta with molar changes. The baby's peripheral blood chromosomes were diploid, and the pregnant woman had no serious complications. The diagnosis, management, and monitoring of this condition will remain challenging because of its rarity. Partial hydatidiform mole combined with pregnancy can result in delivering of a normal fetus and live birth under proper management.