The long noncoding RNA HOTAIR plays significant roles in promoting cancer metastasis. However, how it conveys an invasive advantage in cancer cells is not clear. Here we identify the chondroitin ...sulfotransferase CHST15 (GalNAc4S‐6ST) as a novel HOX transcript antisense intergenic RNA (HOTAIR) target gene using RNA profiling and show that CHST15 is required for HOTAIR‐mediated invasiveness in breast cancer cells. CHST15 catalyzes sulfation of the C6 hydroxyl group of the N‐acetyl galactosamine 4‐sulfate moiety in chondroitin sulfate to form the 4,6‐disulfated chondroitin sulfate variant known as the CS‐E isoform. We show that HOTAIR is necessary and sufficient for CHST15 transcript expression. Inhibition of CHST15 by RNA interference abolished cell invasion promoted by HOTAIR but not on HOTAIR‐mediated migratory activity. Conversely, reconstitution of CHST15 expression rescued the invasive activity of HOTAIR‐depleted cells. In corroboration with this mechanism, blocking cell surface chondroitin sulfate using a pan‐CS antibody or an antibody specifically recognizes the CS‐E isoform significantly suppressed HOTAIR‐induced invasion. Inhibition of CHST15 compromised tumorigenesis and metastasis in orthotopic breast cancer xenograft models. Furthermore, the expression of HOTAIR closely correlated with the level of CHST15 protein in primary as well as metastatic tumor lesions. Our results demonstrate a novel mechanism underlying the function of HOTAIR in tumor progression through programming the context of cell surface glycosaminoglycans. Our results further establish that the invasive and migratory activities downstream of HOTAIR are distinctly regulated, whereby CHST15 preferentially controls the arm of invasiveness. Thus, the HOTAIR‐CHST15 axis may provide a new avenue toward novel therapeutic strategies and prognosis biomarkers for advanced breast cancer.
What's new?
The long noncoding RNA HOTAIR is known to influence cancer growth, and now researchers have identified a molecule that mediates the effect. Using both loss‐of‐function and gain‐of‐function experiments, these authors identified chondroitin sulfotransferase (CHST15) as a downstream target of HOTAIR required for invasive activity of breast cancer cells. Antibodies against cell surface chondroitin sulfate suppressed HOTAIR‐induced invasion in xenograft models. Further, HOTAIR expression correlates with CHST15 protein both in primary tumors and metastases. The identification of HOTAIR‐CHST15 regulation of cell surface moieties could lead to new therapeutic targets or diagnostic biomarkers for breast cancer.
Early detection of bladder cancer remains challenging because patients with early-stage bladder cancer usually have no incentive to take cytology or cystoscopy tests if they are asymptomatic. Our ...goal is to find non-invasive marker candidates that may help us gain insight into the metabolism of early-stage bladder cancer and be examined in routine health checks. We acquired urine samples from 124 patients diagnosed with early-stage bladder cancer or hernia (63 cancer patients and 61 controls). In which 100 samples were included in our marker discovery cohort, and the remaining 24 samples were included in our independent test cohort. We obtained metabolic profiles of 922 compounds of the samples by gas chromatography-mass spectrometry. Based on the metabolic profiles of the marker discovery cohort, we selected marker candidates using Wilcoxon rank-sum test with Bonferroni correction and leave-one-out cross-validation; we further excluded compounds detected in less than 60% of the bladder cancer samples. We finally selected eight putative markers. The abundance of all the eight markers in bladder cancer samples was high but extremely low in hernia samples. Moreover, the up-regulation of these markers might be in association with sugars and polyols metabolism. In the present study, comparative urine metabolomics selected putative metabolite markers for the detection of early-stage bladder cancer. The suggested relations between early-stage bladder cancer and sugars and polyols metabolism may create opportunities for improving the detection of bladder cancer.
Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancers. This cancer lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor ...receptor 2. The current therapeutic strategy for patients with this subtype is the use of cytotoxic chemotherapy and surgery. Luteolin is a natural herbal flavonoid and a potential therapeutic candidate for multiple diseases. The use of a treatment that combines Chinese herbal medicine and western medicine is rising in Asia.
The present study evaluates the effects and molecular mechanisms involved with luteolin treatment and evaluates whether this herb affects androgen receptor-positive breast cancer cell proliferation or metastasis.
In vitro evaluation of the effect of luteolin on androgen receptor-positive TNBC cell proliferation and metastasis
Cell viability analysis was used for the cytotoxicity test. Colony formation and Bromodeoxyuridine (BrdU) staining-based proliferation experiments were used for cell proliferation. Wound healing and transwell assays were used for in vitro migration/invasion. The RT-qPCR analysis was used for gene expression. Furthermore, ChIP-qPCR analysis was used for epigenetic modification of gene promoters.
Luteolin significantly inhibited the proliferation and metastasis of androgen receptor-positive TNBC. Furthermore, luteolin inactivated the AKT/mTOR signaling pathway and reversed the epithelial-mesenchymal transition (EMT). The combination of luteolin and inhibitors of AKT/mTOR synergistically repressed an androgen receptor-positive TNBC cell proliferation and metastasis. Luteolin also downregulated MMP9 expression by decreasing the levels of the AKT/mTOR promoting H3K27Ac and H3K56A on the MMP9 promoter region.
Our findings indicate that luteolin inhibited the proliferation and metastasis of androgen receptor-positive TNBC by regulating MMP9 expression through a reduction in the levels of AKT/mTOR-inducing H3K27Ac and H3K56Ac.
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Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem ...cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5
basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy.
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There has been no long-term clinical follow-up data of survivors or victims of sudden cardiac death (SCD). The Taiwan multi-center sudden arrhythmia death syndrome follow-up and clinical study ...(TFS-SADS) is a collaborative multi-center study with median follow-up time 43 months. In this cohort, the clinical characteristics of these SADS patients were compared with those with ischemic heart disease (IHD). In this SCD cohort, around half (42%) were patients with IHD, which was different from Caucasian SCD cohorts. Among those with normal heart, most had Brugada syndrome (BrS). Compared to those with SADS, patients with IHD were older, more males and more comorbidities, more arrhythmic death, and lower left ventricular ejection fraction. In the long-term follow-up, patients with SADS had a better survival than those with IHD (p < 0.001). In the Cox regression analysis to identify the independent predictors of mortality, older age, lower LVEF, prior myocardial infarction and history of out-of-hospital cardiac arrest were associated with higher mortality and beta blocker use and idiopathic ventricular fibrillation or tachycardia (IVF/IVT) with a better survival during follow-up. History of prior MI was associated with more arrhythmic death. Several distinct features of SCD were found in the Asia-Pacific region, such as higher proportion of SADS, poorer prognosis of LQTS and better prognosis of IVF/IVT. Patients with SADS had a better survival than those with IHD. For those with SADS, patients with channelopathy had a better survival than those with cardiomyopathy.
Tuning the Fermi level (
E
F
) in Bi
2
Te
3
topological-insulator (TI) films is demonstrated on controlling the temperature of growth with molecular-beam epitaxy (MBE). Angle-resolved photoemission ...spectra (ARPES) reveal that
E
F
of Bi
2
Te
3
thin films shifts systematically with the growth temperature (
T
g
). The key role that a Bi-on-Te(1) (Bi
Te1
) antisite defect plays in the electronic structure is identified through extended X-ray-absorption fine-structure (EXAFS) spectra at the Bi L
3
-edge. Calculations of electronic structure support the results of fitting the EXAFS, indicating that the variation of
E
F
is due to the formation and suppression of Bi
Te1
that is tunable with the growth temperature. Our findings provide not only insight into the correlation between the defect structure and electronic properties but also a simple route to control the intrinsic topological surface states, which could be useful for applications in TI-based advanced electronic and spintronic devices.
Tuning the Fermi level (
E
F
) in Bi
2
Te
3
topological-insulator (TI) films is demonstrated on controlling the temperature of growth with molecular-beam epitaxy (MBE).
Cytidine triphosphate synthase (CTPS) and inosine monophosphate dehydrogenase (IMPDH) (both of which have two isoforms) can form fiber-like subcellular structures termed 'cytoophidia' under certain ...circumstances in mammalian cells. Although it has been shown that filamentation of CTPS downregulates its activity by disturbing conformational changes, the activity of IMPDH within cytoophidia is still unclear. Most previous IMPDH cytoophidium studies were performed under conditions involving inhibitors that impair GTP synthesis. Here, we show that IMPDH forms cytoophidia without inhibition of GTP synthesis. First, we find that an elevated intracellular CTP concentration or treatment with 3'-deazauridine, a CTPS inhibitor, promotes IMPDH cytoophidium formation and increases the intracellular GTP pool size. Moreover, restriction of cell growth triggers the disassembly of IMPDH cytoophidia, implying that their presence is correlated with active cell metabolism. Finally, we show that the presence of IMPDH cytoophidia in mouse pancreatic islet cells might correlate with nutrient uptake in the animal. Collectively, our findings reveal that formation of IMPDH cytoophidia reflects upregulation of purine nucleotide synthesis, suggesting that the IMPDH cytoophidium plays a role distinct from that of the CTPS cytoophidium in controlling intracellular nucleotide homeostasis.
Internet ethics is an issue that has garnered the attention of civic education. Integrating the foundation of social cognitive theory with the perspectives of the ethical decision making (EDM) model, ...we investigated whether a mediation effect is present between high school student's internet self-efficacy (IESE), internet ethical judgment (IEJ), and internet ethical behavioral intention (IEBI) under two scenarios: piracy and internet plagiarism. Using high school students in the Taiwan region as our research subjects, a total of 331 valid samples were collected. Partial least square structural equation modeling (PLS-SEM) was used to verify the hypothesis. The results of the study show that IEJ has an indirect-only mediation effect between IESE and IEBE in the piracy scenario, but a complementary mediator effect in the internet plagiarism scenario. In other words, IEJ exerts different mediation effects under different internet ethical scenarios. These results provide social cognitive theory a new insight on individual ethical judgment in different contexts. The present study provides important theoretical and practical implications for internet ethics education.
•Explore ethical cognition process in piracy, online plagiarism scenarios.•Integrate the insights of social cognitive theory and ethical decision model.•Judgment mediates between self-efficacy and behavior intention in both scenarios.•Discuss why the type of mediation is different in two scenarios.
A wirelessly powered electrochemical sensing chip with high-efficiency adaptive power management for a wide RF-powering range and a low-noise chopper-stabilization potentiostat for high-resolution ...electrochemical current detection is presented. The chip is fabricated using a 0.18-μm CMOS process. A novel, power-aware, multiple-path, RF-energy harvesting front end extends the high-efficiency (>20%) RF-powering range to 8.5 dB. In the sensor-readout interface, a chopper-stabilization potentiostat with an oscillator-based current readout achieves a 3.3-pA current resolution in the current range of 800nA and an R 2 linearity of 0.9987 while consuming only 4.4μW. The power efficiency of the electrochemical readout interface is 0.18, and the dynamic detection range is 107 dB.
Melanoma is the least common but most fatal form of skin cancer. Previous studies have indicated that an aqueous extract of Hibiscus sabdariffa leaves possess hypoglycemic, hypolipidemic, and ...antioxidant effects. In this study, we want to investigate the anticancer activity of Hibiscus leaf polyphenolic (HLP) extract in melanoma cells. First, HLP was exhibited to be rich in epicatechin gallate (ECG) and other polyphenols. Apoptotic and autophagic activities of HLP and ECG were further evaluated by DAPI stain, cell‐cycle analysis, and acidic vascular organelle (AVO) stain. Our results revealed that both HLP and ECG induced the caspases cleavages, Bcl‐2 family proteins regulation, and Fas/FasL activation in A375 cells. In addition, we also revealed that the cells presented AVO‐positive after HLP treatments. HLP could increase the expressions of autophagy‐related proteins autophagy‐related gene 5 (ATG5), Beclin1, and light chain 3‐II (LC3‐II), and induce autophagic cell death in A375 cells. These data indicated that the anticancer effect of HLP, partly contributed by ECG, in A375 cells. HLP potentially could be developed as an antimelanoma agent.
Practical Application
This research showed that HLP induced human melanoma cell death through dual regulation of apoptosis and autophagy pathways. These data demonstrated that HLP may be a good agent for antimelanoma, and developed a novel strategy on human skin cancer treatment in the future.
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