Bile acids destabilise HIF-1a and promote anti-tumour phenotypes in cancer cell models.

BACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1a subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1a is known to be active under hypoxic conditions. HIF-1a status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1a was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1a in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression

Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells

<p>Abstract</p> <p>Background</p> <p>The Akt/PKB family of kinases is frequently activated in human cancers, including oral squamous cell carcinoma (OSCC). Akt-induced epithelial-to-mesenchymal transition (EMT) involves downregulation of E-cadherin, which appears to result from upregulation of the transcription repressor Snail. Recently, it was proposed that carcinoma cells, especially in metastatic sites, could acquire the mesenchymal-to-epithelial reverting transition (MErT) in order to adapt the microenvironments and re-expression of E-cadherin be a critical indicator of MErT. However, the precise mechanism and biologic or clinical importance of the MErT in cancers have been little known. This study aimed to investigate whether Akt inhibition would restore the expression of E-cadherin and β-catenin, reduce that of Vimentin, and induce the MErT in OSCC cells with low or negative expression of E-cadherin. We also investigate whether inhibition of Akt activity would affect the E-cadherin repressors and signaling molecules like NF-κB, ERK, and p38.</p> <p>Methods</p> <p>We screened several OSCC cell lines in order to select suitable cell line models for inducing MErT, using immunoblotting and methylation specific-PCR. We examined whether Akt inhibitor phosphatidylinositol ether lipid analogues (PIA) treatment would restore the expression of E-cadherin and β-catenin, reduce that of Vimentin, and induce the MErT in KB and KOSCC-25B cells using RT-PCR, immunoblotting, immunofluorescence analysis, and <it>in vitro </it>migration assay. We also investigated whether inhibition of Akt activity would affect the E-cadherin repressors, including Snail, Twist, and SIP-1/ZEB-2 and signaling molecules like NF-κB, ERK, JNK, and p38 using RT-PCR, immunoblotting, and immunofluorescence analysis.</p> <p>Results</p> <p>Of the 7 OSCC cell lines, KB and KOSCC-25B showed constitutively activated phosphorylated Akt and low or negative expression of E-cadherin. Inhibition of Akt activity by PIA decreased NF-κB signaling, but did not affect phosphorylation of ERK, JNK, and p38 in KB and KOSCC-25B cells. Akt inhibition led to downregulation of Snail and Twist expression. In contrast, inhibition of Akt activity by PIA did not induce any changes in SIP-1/ZEB-2 expression. PIA treatment induced the expression of E-cadherin and β-catenin, reduce that of Vimentin, restored their epithelial morphology of a polygonal shape, and reduced tumor cell migration in KB and KOSCC-25B cells, which was the corresponding feature of MErT.</p> <p>Conclusion</p> <p>All of these findings suggest that Akt inhibition could induce the MErT through decreased NF-κB signaling and downregulation of Snail and Twist in OSCC cells. A strategy involving Akt inhibition might be a useful therapeutic tool in controlling cancer dissemination and metastasis in oral cancer patients.</p

High-contrast Polarimetry Observation of the T Tau Circumstellar Environment

We conducted high-contrast polarimetry observations of T Tau in the H-band, using the HiCIAO instrument mounted on the Subaru Telescope, revealing structures as near as 0.\arcsec1 from the stars T Tau N and T Tau S. The whole T Tau system is found to be surrounded by nebula-like envelopes, and several outflow-related structures are detected in these envelopes. We analyzed the detailed polarization patterns of the circumstellar structures near each component of this triple young star system and determined constraints on the circumstellar disks and outflow structures. We suggest that the nearly face-on circumstellar disk of T Tau N is no larger than 0.\arcsec8, or 117 AU, in the northwest, based on the existence of a hole in this direction, and no larger than 0.\arcsec27, or 40 AU, in the south. A new structure "N5" extends to about 0.\arcsec42, or 59 AU, on the southwest of the star, believed to be part of the disk. We suggest that T Tau S is surrounded by a highly inclined circumbinary disk with a radius of about 0.\arcsec3, or 44 AU, with a position angle of about 30$^\circ$, that is misaligned with the orbit of the T Tau S binary. After analyzing the positions and polarization vector patterns of the outflow-related structures, we suggest that T Tau S should trigger the well-known E-W outflow, and is also likely to be responsible for a southwest precessing outflow "coil" and a possible south outflow

JCMT BISTRO Observations: Magnetic Field Morphology of Bubbles Associated with NGC 6334

We study the Hii regions associated with the NGC 6334 molecular cloud observed in the submillimeter and taken as part of the B-fields In STar-forming Region Observations Survey. In particular, we investigate the polarization patterns and magnetic field morphologies associated with these Hii regions. Through polarization pattern and pressure calculation analyses, several of these bubbles indicate that the gas and magnetic field lines have been pushed away from the bubble, toward an almost tangential (to the bubble) magnetic field morphology. In the densest part of NGC 6334, where the magnetic field morphology is similar to an hourglass, the polarization observations do not exhibit observable impact from Hii regions. We detect two nested radial polarization patterns in a bubble to the south of NGC 6334 that correspond to the previously observed bipolar structure in this bubble. Finally, using the results of this study, we present steps (incorporating computer vision; circular Hough transform) that can be used in future studies to identify bubbles that have physically impacted magnetic field lines

The JCMT BISTRO Survey: Magnetic Fields Associated with a Network of Filaments in NGC 1333

We present new observations of the active star formation region NGC 1333 in the Perseus molecular cloud complex from the James Clerk Maxwell Telescope B-Fields In Star-forming Region Observations (BISTRO) survey with the POL-2 instrument. The BISTRO data cover the entire NGC 1333 complex (~1.5 pc × 2 pc) at 0.02 pc resolution and spatially resolve the polarized emission from individual filamentary structures for the first time. The inferred magnetic field structure is complex as a whole, with each individual filament aligned at different position angles relative to the local field orientation. We combine the BISTRO data with low- and high- resolution data derived from Planck and interferometers to study the multiscale magnetic field structure in this region. The magnetic field morphology drastically changes below a scale of ~1 pc and remains continuous from the scales of filaments (~0.1 pc) to that of protostellar envelopes (~0.005 pc or ~1000 au). Finally, we construct simple models in which we assume that the magnetic field is always perpendicular to the long axis of the filaments. We demonstrate that the observed variation of the relative orientation between the filament axes and the magnetic field angles are well reproduced by this model, taking into account the projection effects of the magnetic field and filaments relative to the plane of the sky. These projection effects may explain the apparent complexity of the magnetic field structure observed at the resolution of BISTRO data toward the filament network

First Results from BISTRO: A SCUBA-2 Polarimeter Survey of the Gould Belt

We present the first results from the B-fields In STar-forming Region Observations (BISTRO) survey, using the Sub-millimetre Common-User Bolometer Array 2 camera, with its associated polarimeter (POL-2), on the James Clerk Maxwell Telescope in Hawaii. We discuss the survey's aims and objectives. We describe the rationale behind the survey, and the questions that the survey will aim to answer. The most important of these is the role of magnetic fields in the star formation process on the scale of individual filaments and cores in dense regions. We describe the data acquisition and reduction processes for POL-2, demonstrating both repeatability and consistency with previous data. We present a first-look analysis of the first results from the BISTRO survey in the OMC 1 region. We see that the magnetic field lies approximately perpendicular to the famous "integral filament" in the densest regions of that filament. Furthermore, we see an "hourglass" magnetic field morphology extending beyond the densest region of the integral filament into the less-dense surrounding material, and discuss possible causes for this. We also discuss the more complex morphology seen along the Orion Bar region. We examine the morphology of the field along the lower-density northeastern filament. We find consistency with previous theoretical models that predict magnetic fields lying parallel to low-density, non-self-gravitating filaments, and perpendicular to higher-density, self-gravitating filaments.Includes Horizon 2020 and STFC

The JCMT BISTRO Survey: The Magnetic Field in the Starless Core ρ Ophiuchus C

We report 850 μm dust polarization observations of a low-mass (~12 M ⊙) starless core in the ρ Ophiuchus cloud, Ophiuchus C, made with the POL-2 instrument on the James Clerk Maxwell Telescope (JCMT) as part of the JCMT B-fields In STar-forming Region Observations survey. We detect an ordered magnetic field projected on the plane of the sky in the starless core. The magnetic field across the ~0.1 pc core shows a predominant northeast–southwest orientation centering between ~40° and ~100°, indicating that the field in the core is well aligned with the magnetic field in lower-density regions of the cloud probed by near-infrared observations and also the cloud-scale magnetic field traced by Planck observations. The polarization percentage (P) decreases with increasing total intensity (I), with a power-law index of −1.03 ± 0.05. We estimate the plane-of-sky field strength (B pos) using modified Davis–Chandrasekhar–Fermi methods based on structure function (SF), autocorrelation function (ACF), and unsharp masking (UM) analyses. We find that the estimates from the SF, ACF, and UM methods yield strengths of 103 ± 46 μG, 136 ± 69 μG, and 213 ± 115 μG, respectively. Our calculations suggest that the Ophiuchus C core is near magnetically critical or slightly magnetically supercritical (i.e., unstable to collapse). The total magnetic energy calculated from the SF method is comparable to the turbulent energy in Ophiuchus C, while the ACF method and the UM method only set upper limits for the total magnetic energy because of large uncertainties