LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α.

Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods: A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes. Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions: These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.

Nutrient Stress-Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression.

Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was downregulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis.Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.large.jpg.See related commentary by Mafra and Dias, p. 1302.

Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription.

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.

A novel metastable state magnetic phase of monolayer FeSe.

We found a novel metastable magnetic phase by systematically calculating total energy of monolayer FeSe in various antiferromagnetic (AFM) orders using first-principles method. The new metastable magnetic phase named as QAFM is a magnetic state with short-range magnetic structure which can be regarded as a transitional state between checkerboard-like AFM state and collinear AFM state. Both magnetic moments with important fluctuation and charge density difference with a 2 × 4 reconstruction of orbitals breaks C 4 symmetry and possibly commonly corresponds to the nematic phase in recent transmission electron microscopy and neutron scattering experiment observations. Its electronic band displays a Dirac-like band structure along Γ-X in the folding Brillouin zone of the supercell. The QAFM phase of FeSe holds metallic feature with d xz , d yz and [Formula: see text] band crossing Fermi level even including spin-orbit coupling. Additionally, the weight of 3d orbitals varies as the applied expansion strain which may be directly correlated with the emerging nematic phase and superconducting state of strained monolayer FeSe. The finding of novel magnetic order may provide important clues to elucidate the relationship of antiferromagnetism and superconductivity for unconventional Fe-based superconductor.

MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.

Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.

Therapeutic effect of carotid artery stenting versus endarterectomy for patients with high-risk carotid stenosis.

OBJECTIVE: To investigate therapeutic effect of carotid artery stenting versus endarterectomy for patients with high-risk carotid stenosis. METHODS: A total of 130 carotid stenosis patients at high-risk of stroke were randomly divided into stenting group and endarterectomy group, including 65 patients in each group. The patients in the endarterectomy group underwent endarterectomy and those in the stenting group received carotid artery stenting for treatment. RESULTS: After operation, carotid intima-media thickness (IMT), plague areas and carotid artery resistance indexes in both groups decreased significantly, and the carotid artery peak blood flow velocities increased significantly and had significant differences with that before operation (P < 0.05). After operation, total cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL) values in two groups all significantly decreased, and intragroup and intergroup differences were statistically significant (P < 0.05). Postoperative three months of followed-up found that the mortality rate in stenting group was 1.5% and that in the endarterectomy group was 9.2%; the mortality rate in the stenting group was significantly lower than the endarterectomy group (P < 0.05). CONCLUSION: Compared with carotid endarterectomy, application of carotid artery stenting can effectively promote patency of blood flow in the carotid artery, and exertion of its effect is related to lowering lipid and lowering inflammatory factor expression.

[Geographic distribution and gene sequencing of Paragonimus westermani in some areas of Guangdong Province].

OBJECTIVE: To investigate the current distribution of Paragonimus westermani in Guangdong Province. METHOD: Snails and crabs collected from mountain streams in regional survey sites were dissected to detect cercarial and metacercarial infections of P. westermani. Domestic cats and dogs artificially infected with the collected metacercariae were also dissected to detect adult worms of P. westermani. The COI and ITS2 gene sequences of those adult worms were compared with those of known Paragonimus specimen deposited in the GenBank. RESULTS: All of the first intermediate hosts in five survey sites of Liangkou, Nankun, Mountain, Dadong, Muxi, Guowu, were identified as Semisulcospira libertina, whose cercariae infection rates were 0.33%, 0.15%, 0.058%, 0.10%, and 0.05%, respectively; the second intermediate hosts in above five sites were all identified as Sinopotamon denticulatum, whose metacercariae infection rates were 100%, 100%, 38.09%, 55.36%, and 65.26%, respectively. The numbers of metacercariae in the five sites were 79.4, 105.66, 9.16, 16.18, and 15.6 per positive crab, respectively, and 11.12, 7.87, 0.58, 0.69, and 0.85 per gram of crab, respectively. All the metacercariae were identical to those of P. westermani. Adult worms and eggs of P. westermani were found in both reservoir hosts of domestic cats and dogs infected artificially. By comparing the COI genes of five representative samples from each survey site with that of Paragonimus #AF219379.21, AF540958.1 from GenBank, we found out the homology to be 99%, 99%, 99%, 98%, and 99%, respectively. In addition, a comparison of the ITS2 gene sequences between the above five samples and Paragonimus #DQ836243.1, DQ351845.1, AB354217.1 from GenBank revealed 98%, 99%, 98%, 98%, and 98% gene homology, respectively. CONCLUSION: Two ultra-high and three high endemic areas of P. westermani are discovered in Guangdong Province. No obvious differences were found among the types of P. westermani in the above five endemic areas.

Modified morphology of graphene sheets by Argon-atom bombardment: molecular dynamics simulations.

By a molecular dynamics method, we simulated the process of Argon-atom bombardment on a graphene sheet with 2720 carbon atoms. The results show that, the damage of the bombardment on the graphene sheet depends not only on the incident energy but also on the particle flux density of Argon atoms. To compare and analyze the effect of the incident energy and the particle flux density in the Argon-atom bombardment, we defined the impact factor on graphene sheet by calculating the broken-hole area. The results indicate that, there is an exponential accumulated-damage for the impact of both the incident energy and the particle flux density and there is a critical incident energy ranging from 20-30 eV/atom in Argon-atom bombardment. Different configurations, such as sieve-like and circle-like graphene can be formed by controlling of different particle flux density as the incident energy is more than the critical value. Our results supply a feasible method on fabrication of porous graphene-based materials for gas-storages and molecular sieves, and it also helps to understand the damage mechanism of graphene-based electronic devices under high particle radiation.