MiR-301a transcriptionally activated by HIF-2αpromotes hypoxiainduced epithelial-mesenchymal transition by targeting TP63 in pancreatic cancer

BACKGROUND Pancreatic cancer(PC)is one of the deadliest cancers worldwide.PC metastasis involves a complex set of events,including epithelial-mesenchymal transition(EMT),that increase tumor cell invasiveness.Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis;however,the mechanisms remain elusive.AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells.METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions.Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression.Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout.Luciferase assay was used to detect the miR-301a promoter and the 3’untranslated region activity of TP63.Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo.In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples(adjacent paratumor and paired tumor tissues).RESULTS Hypoxic environment could directly promote the EMT of PC cells.The expression level of miR-301a was increased in a HIF2αdependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells.Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells,while knocking out miR-301a result in the suppression of hypoxia-induced EMT.TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells.Furthermore,miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo.Additionally,miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis.CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.

Genome-wide CRISPR-Cas9 screening identifies that hypoxiainducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis

BACKGROUND Pancreatic cancer(PC)is one of the most lethal malignancies worldwide.It is known that the proliferation of PC cells is a critical process in the disease.Previous studies have failed to identify the key genes associated with PC cell proliferation,using bioinformatic analysis,genome-wide association studies,and candidate gene testing.AIM To investigate the function of the chromobox 8(CBX8)/receptor substrate 1(IRS1)/AKT axis in PC.METHODS A genome-wide CRISPR-Cas9 screening was performed to select genes that could facilitate PC cell proliferation.Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of CBX8 in PC tissues and cells.The regulatory roles of CBX8 in cell proliferation,migration,and invasion were verified by in vivo and in vitro functional assays.RESULTS CBX8 was upregulated in PC tissues and shown to drive PC cell proliferation.Higher expression of CBX8 was correlated with worse outcomes of PC patients from two independent cohorts comprising a total of 116 cases.CBX8 was also proved to serve as a promising therapeutic target for a PC xenograft model.We demonstrated that hypoxia-inducible factor(HIF)-1a induced CBX8 transcription by binding to the promoter of CBX8.CBX8 efficiently activated the PI3K/AKT signaling by upregulating insulin IRS1.CONCLUSION CBX8 is a key gene regulated by HIF-1α,and activates the IRS1/AKT pathway,which suggests that targeting CBX8 may be a promising therapeutic strategy for PC.

Magnetar giant flare originating from GRB 200415A:transient GeV emission, time-resolved E_(p)-L_(iso) correlation and implications

Giant flares(GFs)are unusual bursts from soft gamma-ray repeaters(SGRs)that release an enormous amount of energy in a fraction of a second.The afterglow emission of these SGR-GFs or GF candidates is a highly beneficial means of discerning their composition,relativistic speed and emission mechanisms.GRB 200415A is a recent GF candidate observed in a direction coincident with the nearby Sculptor galaxy at 3.5 Mpc.In this work,we searched for transient gamma-ray emission in past observations by Fermi-LAT in the direction of GRB 200415A.These observations confirm that GRB 200415A is observed as a transient GeV source only once.A pure pair-plasma fireball cannot provide the required energy for the interpretation of GeV afterglow emission and a baryonic poor outflow is additionally needed to explain the afterglow emission.A baryonic rich outflow is also viable,as it can explain the variability and observed quasi-thermal spectrum of the prompt emission if dissipation is happening below the photosphere via internal shocks.Using the peak energy(Ep)of the time-resolved prompt emission spectra and their fluxes(Fp),we found a correlation between Ep and Fp or isotropic luminosity Liso for GRB 200415A.This supports the intrinsic nature of Ep-Liso correlation found in SGRs-GFs,hence favoring a baryonic poor outflow.Our results also indicate a different mechanism at work during the initial spike,and that the evolution of the prompt emission spectral properties in this outflow would be intrinsically due to the injection process.

Correction to“Genome-wide CRISPR-Cas9 screening identifies that hypoxia-inducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis”

Correction to“Genome-wide CRISPR-Cas9 screening identifies that hypoxiainducible factor-1a-induced CBX8 transcription promotes pancreatic cancer progression via IRS1/AKT axis”(PMID:34853645 PMCID:PMC8603463 DOI:10.4251/wjgo.v13.i11.1709).In this article,the picture of Figure 6C was misused due to our carelessness while typesetting.We corrected this mistake,and replaced the incorrect image with the correct one.

自扩散过程中聚二甲基硅氧烷印章微结构表面力学性能研究

为了探究微接触印刷时,有机溶剂在聚二甲基硅氧烷(PDMS)内部微纳孔隙中自扩散对PDMS印章表面微结构的影响,制备了一系列具有不同高宽比微结构、不同墨水含量以及不同交联剂比例的PDMS印章,并进一步揭示了高宽比、墨水自扩散程度以及交联剂比例对印章表面微结构的模量、黏附力和几何尺寸的影响.该结果可用于作为制备具有较高结构稳定性和印刷精度的PDMS弹性印章的参考基础.

Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice

Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have supported a protective role of ketamine against stress-induced depressive behavior.However,the effect of ketamine on fear generalization remains unclear.In this study,we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model.The mice were given a single sub-anesthetic dose of ketamine(30 mg/kg,i.p.)1 h before,1 week before,immediately after,or 22 h after fear conditioning.The behavioral measure of fear(indicated by freezing level)and synaptic protein expression in the basolateral amygdala(BLA)and inferior-limbic pre-frontal cortex(IL-PFC)of mice were examined.We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization,and the effect was dose-dependent and lasted for at least 2 weeks.The fear-generalized mice showed a lower level of brainderived neurotrophic factor(BDNF)and a higher level of GluN2B protein in the BLA and IL-PFC,and this was reversed by a single administration of ketamine.Moreover,the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC,but had no effect when infused into the BLA.Infusion of ANA-12(an antagonist of the BDNF receptor TrkB)into the BLA or ILPFC blocked the effect of ketamine on fear generalization.These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.