长非编码RNA PVT1与消化系统肿瘤

长非编码RNA（long non-coding RNAs, lncRNAs）在肿瘤发生、发展进程中承担重要角色,是近年来的研究热点之一。大量研究表明,浆细胞瘤变异易位基因1（plasmacytoma variant translocation 1, PVT1）可通过多种分子机制参与调控消化系统肿瘤的增殖凋亡、迁移侵袭、细胞自噬、血管生成、多药耐药及肿瘤代谢等过程,从而发挥致癌作用。本文主要就PVT1在消化系统肿瘤中的表达水平变化,及其与临床病理特征和预后的关系,以及PVT1对消化系统肿瘤的致癌作用机制和多药耐药机制等研究进展作一综述。     

Long noncoding RNA PVT1: A highly dysregulated gene in malignancy

Recent studies have verified the contribution of several long noncoding RNAs (lncRNAs) in the carcinogenesis. Among the highly acknowledged lncRNAs is the human homolog of the plasmacytoma variant translocation gene, which is called PVT1. PVT1 resides near Myc oncogene and regulates the oncogenic process through modulation of several signaling pathways, such as TGF-β, Wnt/ β-catenin, PI3K/AKT, and mTOR pathways. This lncRNA has a circular form as well. Expression analyses and functional studies have appraised the oncogenic roles of PVT1 and circPVT1. Experiments in several cancer cell lines have shown that PVT1 silencing suppresses cancer cell proliferation, whereas its overexpression has the opposite effect. Its silencing has led to the accumulation of cells in the G0/G1 phase and diminished the number of cells in the S phase. Moreover, genome-wide association studies have signified the role of single nucleotide polymorphisms of this lncRNA in conferring risk of lymphoma in different populations. In the current study, we have summarized recent data about the role of PVT1 and circPVT1 in the carcinogenesis process.     

PVT1 (rs13281615) and miR-146a (rs2910164) polymorphisms affect the prognosis of colon cancer by regulating COX2 expression and cell apoptosis

In this study, we aimed to investigate the potential correlation between rs13281615/rs2910164 polymorphisms and the prognosis of colon cancer (CC). Taqman was utilized to genotype the rs13281615/rs2910164 polymorphisms in recruited subjects. Kaplan–Meier survival curves were calculated to study the prognostic values of different genotypes of rs13281615/rs2910164 polymorphisms. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays were conducted to establish a potential signaling pathway underlying the role of rs13281615/rs2910164 polymorphisms, whereas bioinformatics analysis and luciferase reporter assays were performed to identify plasmacytoma variant translocation 1 (PVT1) and cyclooxygenase-2 (COX2) as targets of microRNA-146a (miR-146a). No significant difference was observed in respect to clinical characteristics among subjects with different genotypes. However, patients genotyped as GG/CC + GC showed the lowest chance of survival, whereas patients of GA + AA/GG genotype showed the highest chance of survival. Moreover, the relative expressions of PVT1, prostaglandin E2 (PGE2), and COX2 were the lowest and the relative expression of miR-146a was the highest in GA + AA/GG subjects, validating the roles of PVT1, miR-146a, and COX2 in CC. In addition, both PVT1 and COX2 were identified as virtual targets of miR-146a, and the luciferase activities of cells cotransfected with wild-type PVT1/COX2 and miR-146a mimics were significantly reduced. Moreover, the presence of PVT1 decreased the level of miR-146a whereas increasing the messenger RNA and protein levels of COX2, thus establishing a PVT1/miR-146a/COX2 signaling pathway underlying the pathogenesis of CC. The presence of rs13281615 G > A polymorphism on PVT1 and the rs2910164 C > G polymorphism on miR-146a contributes to a favorable prognosis in CC patients via modulating the activity of the PVT1/miR-146a/COX2 signaling pathway.     

Long noncoding RNA PVT1 facilitates high glucose-induced cardiomyocyte death through the miR-23a-3p/CASP10 axis

Dilated cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetic patients. Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) has been shown to be related to the pathogenesis of DCM. However, the mechanism by which PVT1 regulates DCM pathogenesis is unclear. High glucose level was employed to construct a DCM cell model in vitro. Cell viability was determined via cell counting kit-8 assay. The level of lactate dehydrogenase (LDH) was measured with the corresponding kit. Expression levels of PVT1, miR-23a-3p, and caspase-10 (CASP10) messenger RNA were evaluated with a quantitative real-time polymerase chain reaction. Cell apoptosis was assessed by flow cytometry assay. Protein levels of B-cell lymphoma 2-associated X (Bax), cleaved-caspase-3 (cleaved-casp-3), and CASP10 were examined via western blot analysis. The relationship between PVT1 or CASP10 and miR-23a-3p was verified with dual-luciferase reporter assay. We observed that PVT1 and CASP10 were upregulated while miR-23a-3p was downregulated in high glucose-induced cardiomyocytes. High glucose levels repressed cardiomyocyte activity and induced cardiomyocyte apoptosis, but this influence was antagonized by PVT1 knockdown or miR-23a-3p overexpression. Furthermore, PVT1 acted as a sponge for miR-23a-3p, and miR-23a-3p inhibition counterbalanced the influence of PVT1 silencing on viability and apoptosis of cardiomyocytes under high glucose level treatment. PVT1 could increase CASP10 expression via sponging miR-23a-3p. In conclusion, PVT1 acted as a deleterious lncRNA in DCM. PVT1 facilitated cardiomyocyte death by regulating the miR-23a-3p/CASP10, which offered a new mechanism to comprehend the pathogenesis of DCM.     

Circadian adaptation of airline pilots during extended duration operations between the USA and Asia

This study tracked circadian adaptation among airline pilots before, during, and after trips where they flew from Seattle (SEA) or Los Angeles (LAX) to Asia (7--9 time zones westward), spent 7--12?d in Asia, and then flew back to the USA. In Asia, pilots' exposures to local time cues and sleep opportunities were constrained by duty (short-haul flights crossing ≤1 time zone/24?h). Fourteen captains and 16 first officers participated (median age?=?56 versus 48 yrs, p.U)?<?0.001). Their sleep was monitored (actigraphy, duty/sleep diaries) from 3?d pre-trip to 5?d post-trip. For every flight, Karolinska Sleepiness and Samn-Perelli Fatigue scales and 5-min psychomotor vigilance task (PVT) tests were completed pre-flight and at top of descent (TOD). Participants had ≥3 d free of duty prior to outbound flight(s). From 72--24?h prior to departure (baseline sleep), mean total sleep/24?h (TST)?=?7.00?h (SD?=?1.18?h) and mean sleep efficiency?=?87% (SD?=?4.9%). Most pilots (23/30) flew direct to and from Asia, but 7 LAX-based pilots flew via a 1-d layover in Honolulu (HNL). On flights with ≥2 pilots, mean total in-flight sleep varied from 0.40 to 2.09?h outbound and from 0.74 to 1.88?h inbound. Duty patterns in Asia were variable, with ≤2 flights/d (mean flight duration?=?3.53?h, SD?=?0.53?h). TST on days 17 in Asia did not differ from baseline (p.F)?=?0.2031). However, mean sleep efficiency was significantly lower than baseline on days 5--7 (p.F)?=?0.0041). More pilots were on duty between 20:00 and 24:00?h on days 57 (mean?=?21%) than on days 24 (mean?=?14%). Sleep propensity distribution phase markers and chi-square periodogram analyses suggest that adaptation to local time was complete by day 4 in Asia. On pre-flight PVT tests in Asia, the slowest 10% of responses improved for flights departing 14:00--19:59?h (p.F)?=?0.0484). At TOD, the slowest 10% of responses improved across days for flights arriving 14:00--19:59?h (p.F)?=?0.0349) and 20:00--01:59?h (p.F)?=?0.0379). Sleepiness and fatigue ratings pre-flight and at TOD did not change across days in Asia. TST on post-trip day 1 was longer than baseline (estimated mean extension?=?1.68?h; adjusted p(t)?<?0.0001). On all post-trip days, sleep efficiency was comparable to baseline. Sleep propensity distribution phase markers and chi-square periodogram analyses suggest complete readaptation in 12?d. Two opposing influences appeared to affect sleep and PVT performance across days in Asia: progressive circadian adaptation to local time and increasing duty during local night, which displaced sleep from the optimal physiological time. Cumulative sleep restriction across the return flight may explain the large rebound in TST on day 1 post-trip. Thereafter TST, sleep efficiency, and sleep timing suggest that readaptation was complete. Rapid post-trip readaptation may be facilitated by pilots having unconstrained nocturnal sleep opportunities, coupled with stronger patterns of family and social cues than in Asia.     

Thermal expansion of ZnSe by molecular dynamics simulation

Thermal expansion of bulk ZnSe crystal, grown by physical vapour transport technique, is experimentally measured for various temperatures and molecular dynamics simulation using a three body Tersoff potential is also developed for the same. The resulting expansivity compares well with our experimental results and other reported values.     

LncRNA PVT1 promotes the progression of ovarian cancer by activating TGF-β pathway via miR-148a-3p/AGO1 axis

Ovarian cancer is a lethal gynaecologic malignancy with poor diagnosis and prognosis. The long non-coding RNA plasmacytoma variant translocation1 (PVT1) and argonaute 1 (AGO1) are associated with carcinogenesis and chemoresistance; however, the relationship between PVT1 and AGO1 and the downstream mechanisms in ovarian cancer remains poorly known. PVT1 and AGO1 expression was assessed through RT-qPCR and Western blotting in both human tissues and cell lines. The viability and proliferation of ovarian cancer cells were determined by CCK-8 assay and TUNEL assay in vitro and immunohistochemistry in vivo. Cell invasion and migration were investigated through transwell and wound-healing assays. The roles and mechanisms of AGO1 on cell functions were further probed via gain- and loss-of-function analysis. We reveal that PVT1 expression was significantly increased in ovarian cancer tissues which is associated with advanced FIGO stage, lymph-node metastasis, poor survival rate, and high expression of AGO1. PVT1 or AGO1 knockdown significantly reduced the cell viability and increased the cell apoptosis and inhibited ovarian tumour growth and proliferation. Furthermore, we discovered that PVT1 up-regulated the expression of AGO1 and thus regulated the transforming growth factor-β (TGF-β) pathway to promote ovarian cancer progression through sponging miR-148a-3p. Additionally, the activation of ERK1/2, smad2 and smad4 is observed to be related to the PVT1/miR-148a-3p/AGO1/TGF-β pathway-induced cascades. Taken together, the present study reveals that PVT1/miR-148a/AGO1 axis plays an important role in the progression of ovarian cancer and emphasize the potential as a target of value for ovarian cancer therapy.