Mechanisms of Chemoresistance in Human Ovarian Cancer at a Glance

published_or_final_versio

Supernatants derived from chemotherapy-treated cancer cell lines can modify angiogenesis

BACKGROUND: There is evidence that tumours produce substances such as cytokines and microvesicular bodies bearing bioactive molecules, which support the carcinogenic process. Furthermore, chemotherapy has also been shown to modify these exudates and in doing so, neutralise their tumourigenic influence. METHODS: In the current study, we have investigated the effect of chemotherapy agents on modifying the cytokine profile and microvesicular cargo of supernatants derived from cancer cell lines. In addition, we have explored the effect of these tumour-derived supernatants on angiogenesis, and how chemotherapy can alter the supernatants rendering them less pro-angiogenic. RESULTS: Herein, we show that supernatants contain a rich cocktail of cytokines, a number of which are potent modulators of angiogenesis. They also contain microvesicular bodies containing RNA transcripts that code for proteins involved in transcription, immune modulation and angiogenesis. These supernatants altered intracellular signalling molecules in endothelial cells and significantly enhanced their tubulogenic character; however, this was severely compromised when supernatants from tumours treated with chemotherapy was used instead. CONCLUSION: This study suggests tumour exudates and bioactive material from tumours can influence cellular functions, and that treatment with some chemotherapy can serve to negate these pro-tumourigenic processes

PITX2 transcription factor is overexpressed and involved in the tumorigenicity of ovarian cancer

Free Paper Session - Biomedicine: abstract no. A2

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer.

Epithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNATM microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.published_or_final_versio

Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade

published_or_final_versio

In situ loading and delivery of short single- And double-stranded dna by supramolecular organic frameworks

Short DNA represents an important class of biomacromolecules that are widely applied in gene therapy, editing, and modulation. However, the development of simple and reliable methods for their intracellular delivery remains a challenge. Herein, we describe that seven water-soluble, homogeneous supramolecular organic frameworks (SOFs) with a well-defined pore size and high stability in water that can accomplish in situ inclusion of single-stranded (ss) and double-stranded (ds) DNA (21, 23, and 58 nt) and effective intracellular delivery (including two noncancerous and six cancerous cell lines). Fluorescence quenching experiments for single and double endlabeled ss- and ds-DNA support that the DNA sequences can be completely enveloped by the SOFs. Confocal laser scanning microscopy and flow cytometry reveal that five of the SOFs exhibit excellent delivery efficiencies that, in most of the studied cases, outperform the commercial standard Lipo2000, even at low SOF-nucleic acid ratios. In addition to high delivery efficiencies, the watersoluble, self-assembled SOF carriers have a variety of advantages, including convenient preparation, high stability, and in situ DNA inclusion, which are all critical for practical applications in nucleic acid delivery

Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer

AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism. Our previous study revealed that the subunits of the heterotimeric AMPK enzyme are diversely expressed during ovarian cancer progression. However, the impact of the variable expression of these AMPK subunits in ovarian cancer oncogenesis remains obscure. Here, we provide evidence to show that reduced expression of the AMPK-beta1 subunit during tumor progression is associated with the increased oncogenic capacity of advanced ovarian cancer cells. Immunohistochemical analysis revealed that AMPK-beta1 levels were reduced in advanced-stage (P = 0.008), high-grade (P = 0.013) and metastatic ovarian cancers (P = 0.008). Intriguingly, down-regulation of AMPK-beta1 was progressively reduced from tumor stages 1 to 3 of ovarian cancer. Functionally, enforced expression of AMPK-beta1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion. Conversely, depletion of AMPK-beta1 by siRNA enhanced the oncogenic capacities of ovarian cancer cells, suggesting that the loss of AMPK-beta1 favors the aggressiveness of ovarian cancer. Mechanistically, enforced expression of AMPK-beta1 increased AMPK activity, which, in turn, induced cell-cycle arrest via inhibition of AKT/ERK signaling activity as well as impaired cell migration/invasion through the suppression of JNK signaling in ovarian cancer cells. Taken together, these findings suggest that the reduced expression of AMPK-beta1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.published_or_final_versio

A pore-expanded supramolecular organic framework and its enrichment of photosensitizers and catalysts for visible-light-induced hydrogen production

A pore-expanded three-dimensional supramolecular organic framework SOF-bpb, with a previously unattained aperture size of 3.6 nm, has been constructed in water from the co-Assembly of cucurbit[8]uril (CB[8]) and a tetraphenylmethane-cored 1,4-bis(pyridin-4-yl)-benzene-Appended building block M1. The periodicity of SOF-bpb in water and in the solid state has been confirmed using synchrotron X-ray scattering and diffraction experiments. SOF-bpb can adsorb anionic and neutral Ru complex photosensitizers and anionic Wells-Dawson-Type and Keggin-Type polyoxometalates (POMs). The adsorption leads to an important enrichment effect, which remarkably increases the catalytic efficiency of the Ru complex-POM systems for visible light-induced reduction of protons to produce H . The expanded aperture of SOF-bpb also facilitates light absorption of the adsorbed Ru complex photosensitizers and electron transfer between excited complexes and the POM catalysts, leading to enhanced photocatalytic activities as compared with the prototypical SOF that has an aperture size of 2.1 nm. 2+ 2+ 2+

The role of haptic communication in dyadic collaborative object manipulation tasks

Intuitive and efficient physical human-robot collaboration relies on the mutual observability of the human and the robot, i.e. the two entities being able to interpret each other's intentions and actions. This is remedied by a myriad of methods involving human sensing or intention decoding, as well as human-robot turn-taking and sequential task planning. However, the physical interaction establishes a rich channel of communication through forces, torques and haptics in general, which is often overlooked in industrial implementations of human-robot interaction. In this work, we investigate the role of haptics in human collaborative physical tasks, to identify how to integrate physical communication in human-robot teams. We present a task to balance a ball at a target position on a board either bimanually by one participant, or dyadically by two participants, with and without haptic information. The task requires that the two sides coordinate with each other, in real-time, to balance the ball at the target. We found that with training the completion time and number of velocity peaks of the ball decreased, and that participants gradually became consistent in their braking strategy. Moreover we found that the presence of haptic information improved the performance (decreased completion time) and led to an increase in overall cooperative movements. Overall, our results show that humans can better coordinate with one another when haptic feedback is available. These results also highlight the likely importance of haptic communication in human-robot physical interaction, both as a tool to infer human intentions and to make the robot behaviour interpretable to humans