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Pseudogenes have long been considered as nonfunctional genomic sequences. Recent studies have shown that they can potentially regulate the expression of protein-coding genes and are dysregulated in diseases including cancer. However, the potential roles of pseudogenes in ovarian cancer have not been well studied. Here we characterized the pseudogene expression profile in HGSOC (high-grade serous ovarian carcinoma) by microarray. We identified 577 dysregulated pseudogenes and most of them were up-regulated (538 of 577). HMGA1P6 (High mobility group AT-hook 1 pseudogene 6) was one of the overexpressed pseudogenes and its expression was inversely correlated with patient survival. Mechanistically, HMGA1P6 promoted ovarian cancer cell malignancy by acting as a ceRNA (competitive endogenous RNA) that led to enhanced HMGA1 and HMGA2 expression. Importantly, HMGA1P6 was transcriptionally activated by oncogene MYC in ovarian cancer. Our findings reveal that MYC may contribute to oncogenesis through transcriptional regulation of pseudogene HMGA1P6 in ovarian cancer.

The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.

Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3’UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells. miR-130a could also attenuate rapamycin/starvation-induced autophagy. Ectopic TSC1 expression could block the effects of miR-130a on cell proliferation, migration and autophagy. Finally, we found that miR-130a expression could be upregulated by inflammatory factors and was transactivated by NF-κB. Therefore, our findings establish a crosstalk between inflammation and mTOR signaling that is mediated by miR-130a, which might have a pivotal role in the initiation and progression of HGSOC.

Ovarian cancer is the most lethal gynecological malignancy. Patients usually have poor prognosis because of late diagnosis, relapse, and chemoresistance. It is pressing to seek novel agent for the treatment of ovarian cancer. Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus (Nelumbo nucifera). In this study, we investigated the antitumor effect of neferine on ovarian cancer cells. We found that neferine exhibited growth-inhibitory effect on human ovarian cancer cells, whereas showing less cytotoxic to non-malignant fallopian tube epithelial cells. Furthermore, we demonstrated that neferine induced autophagy and inactivated the mTOR pathway. Finally, we found that both p38 MAPK and JNK signaling pathways were activated by neferine treatment and contributed to the induction of autophagy in ovarian cancer cells. In conclusion, our findings showed that neferine induced autophagy of human ovarian cancer cells via p38 MAPK/JNK activation. Neferine may be explored as a promising antitumoral agent in ovarian cancer.

The synthesis of high purity intermetallic FeAl nanoparticles using the flow-levitation (FL) method was reported. Iron and aluminium droplets were levitated stably at about 2 230 °C. The morphology, crystal structure and chemical composition of FeAl nanoparticles were investigated by transmission electron microscopy (TEM), high-resolution TEM, X-ray diffraction and energy dispersive spectrometry. The results show that the average particle size of these nanoparticles is about 34.5 nm. Measurements of the d-spacing from X-ray diffraction and electron diffraction studies confirm that the intermetallic nanoparticles have the same crystal structure (B2) as the bulk FeAl. A thin oxidation coating is formed around the particles when being exposed to air. Based on the XPS measurements, the surface coating of the FeAl nanoparticles is composed of Fe2O3 and FeAl2O4. Besides, hysteresis curve reveals that saturation magnetization (M s) of FeAl is 1.66 A/m2, and the coercivity is about 1.214×103 A/m.

Many cancer drugs exert their therapeutic effect by inducing oxidative stress in the cancer cells. Oxidative stress compromises cell survival by inflicting lesions in macromolecules like DNA. Cancer cells rely on enhanced antioxidant metabolism and increased DNA repair function to survive oxidative assault. PARP1, a protein that senses DNA-strand breaks and orchestrates their repair, has an important role in the repair of oxidative DNA damage. Berberine, an alkaloid compound present in many herbal plants, is capable of inducing oxidative DNA damage and downregulating homologous recombination repair (HRR) in cancer cells. In this study, we demonstrated that berberine and PARP inhibitor niraparib have a synthetic lethal effect on ovarian cancer cells. Oxidative DNA damage was greatly induced by berberine in ovarian cancer cells. In addition, the level of RAD51 and the capacity of HRR were also reduced by berberine. Correspondingly, PARP became hyperactivated in response to berberine treatment. Cancer cells treated with berberine and niraparib in combination exhibited greatly increased apoptosis and remarkably reduced tumor growth in vivo. Together, the results indicate that by inducing oxidative DNA damage and downregulating HRR in cancer cells berberine is able to further sensitize cancer cells to PARP inhibition. Our findings demonstrate a potential therapeutic value of combined application of berberine and PARP inhibitors in ovarian cancer treatment.

Adopting prospective, multi-center, random, single-blind and equal rank-control methods, 226 patients with rheumatoid arthritis (RA) were divided into two groups. The 114 patients of the test group were treated with oral sustained release tablets of Tripterygium Wilfordii (TW-SR), 2 tablets twice a day for 4 weeks, 112 patients of the control group received tablets of Tripterygium Wilfordii (TW) orally 2 tablets 3 times per day for 4 weeks. Testing results showed the total effective rates of the two groups were 92.11 % and 90.65 %, respectively (P>0.05). The adverse reaction rate of TW-SR was 20.18%, which was lower than that of TW group of 70.54% (P

We previously reported that marchantin M (Mar) is an active agent to induce apoptosis in human prostate cancer (PCa), but the molecular mechanisms of action remain largely unknown. Here, we demonstrate that Mar potently inhibited chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing activities of 20S proteasome both in in vitro and intracellular systems and significantly induced the accumulation of polyubiquitinated proteins in PCa cells. The computational modeling analysis suggested that Mar non-covalently bound to active sites of proteasome β5 and β1 subunits, resulting in a non-competitive inhibition. Proteasome inhibition by Mar subsequently resulted in endoplasmic reticulum (ER) stress, as evidenced by elevated glucose-regulated protein 78 and CHOP, increased phospho-eukaryotic translation initiation factor 2α (eIF(2α)), splicing of X-box-binding protein-1 and dilation of the ER. However, Mar-mediated cell death was not completely impaired by a pan inhibitor of caspases. Further studies revealed that the Mar-induced cell death was greatly associated with the activation of autophagy, as indicated by the significant induction of microtubule-associated protein-1 light chain-3 beta (LC3B) expression and conversion. Electron microscopic and green fluorescent protein-tagged LC3B analyses further demonstrated the ability of autophagy induction by Mar. Time kinetic studies revealed that Mar induced a rapid and highly sustained processing of LC3B in treated cells and simultaneously decreased the expression of p62/SQSTM1. Pharmacological blockade or knockdown of LC3B and Atg5 attenuated Mar-mediated cell death. The autophagic response triggered by Mar required the activation of RNA-dependent protein kinase-like ER kinase/eIF(2α) and suppression of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin axis via preventing activation and expression of Akt. Our results identified a novel mechanism for the cytotoxic effect of Mar, which strengthens it as a potential agent in cancer chemotherapy.