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•Circular RNAs in human HCC were identified using RNA-sequencing.•Circular RNA cSMARCA5 was downregulated in HCC and associated with poor prognosis.•Downregulation of cSMARCA5 in HCC ...was attributed to the upregulation of DHX9.•cSMARCA5 inhibited HCC growth and metastasis both in vitro and in vivo.•cSMARCA5 acted as the sponge of miR-17-3p and miR-181b-5p to upregulate TIMP3.
In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of circRNAs to hepatocellular carcinoma (HCC) remain largely unknown.
cSMARCA5 (a circRNA derived from exons 15 and 16 of the SMARCA5 gene, hsa_circ_0001445) was identified by RNA-sequencing and validated by quantitative reverse transcription PCR. The role of cSMARCA5 in HCC progression was assessed both in vitro and in vivo. circRNAs in vivo precipitation, luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridization were conducted to evaluate the interaction between cSMARCA5 and miR-17-3p/miR-181b-5p.
The expression of cSMARCA5 was lower in HCC tissues, because of the regulation of DExH-Box Helicase 9, an abundant nuclear RNA helicase. The downregulation of cSMARCA5 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival and recurrence-free survival in patients with HCC after hepatectomy. Our in vivo and in vitro data indicated that cSMARCA5 inhibits the proliferation and migration of HCC cells. Mechanistically, we found that cSMARCA5 could promote the expression of TIMP3, a well-known tumor suppressor, by sponging miR-17-3p and miR-181b-5p.
These results reveal an important role of cSMARCA5 in the growth and metastasis of HCC and provide a fresh perspective on circRNAs in HCC progression.
Herein, we studied the role of cSMARCA5, a circular RNA, in hepatocellular carcinoma. Our in vitro and in vivo data showed that cSMARCA5 inhibits the growth and migration of hepatocellular carcinoma cells, making it a potential therapeutic target.
Tumor cells with stemness (stem‐cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. ...Genome‐wide analyses were applied to identify tumor‐associated lncRNA‐DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down‐ and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor‐bearing mice were used to determine therapeutic effects. We found that lncRNA‐DANCR is overexpressed in stem‐like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra‐/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem‐cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)−214, miR‐320a, and miR‐199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. Conclusions: These studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC. (Hepatology 2016;63:499–511)
N6‐Methyladenosine (m6A) modification has been implicated in many biological processes. However, its role in cancer has not been well studied. Here, we demonstrate that m6A modifications are ...decreased in hepatocellular carcinoma, especially in metastatic hepatocellular carcinoma, and that methyltransferase‐like 14 (METTL14) is the main factor involved in aberrant m6A modification. Moreover, METTL14 down‐regulation acts as an adverse prognosis factor for recurrence‐free survival of hepatocellular carcinoma and is significantly associated with tumor metastasis in vitro and in vivo. We confirm that METTL14 interacts with the microprocessor protein DGCR8 and positively modulates the primary microRNA 126 process in an m6A‐dependent manner. Further experiments show that microRNA 126 inhibits the repressing effect of METTL14 in tumor metastasis. Conclusion: These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m6A modification in tumor progression. (Hepatology 2017;65:529‐543).
To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were ...increased in HBV‐related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV‐related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha‐fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 95% confidence interval, CI: 0.819–0.907 vs. 0.790 0.738–0.842, p = 0.036 in training set; 0.843 0.796–0.890 vs. 0.747 0.691–0.804, p = 0.011 in validation set 1 and 0.864 0.830–0.898 vs. 0.769 0.728–0.810, p < 0.001 in validation set 2). CircPanel also performed well in detecting Small‐HCC (solitary, ≤3 cm), AFP‐negative HCC and AFP‐negative Small‐HCC.
What's new?
To date, one limitation in the treatment of hepatocellular carcinoma (HCC) is the lack of serum biomarkers with satisfactory diagnostic accuracy. Here, the authors explored whether plasma circRNAs can be biomarkers to diagnose hepatitis B virus‐related HCC in 1155 participants from three hospitals in China. They identified a plasma circRNA panel (CircPanel, including hsa_circ_0000976, hsa_circ_0007750, and hsa_circ_0139897) that showed higher accuracy than the clinically‐used serum biomarker AFP in distinguishing individuals with HCC or Small‐HCC from controls and performed well in diagnosing AFP‐negative HCC and AFP‐negative Small‐HCC. Altogether, the findings point to CircPanel as a promising potential biomarker in HCC diagnosis.
Genes that are indispensable for survival are essential genes. Many features have been proposed for computational prediction of essential genes. In this paper, the least absolute shrinkage and ...selection operator method was used to screen key sequence-based features related to gene essentiality. To assess the effects, the selected features were used to predict the essential genes from 31 bacterial species based on a support vector machine classifier. For all 31 bacterial objects (21 Gram-negative objects and ten Gram-positive objects), the features in the three datasets were reduced from 57, 59, and 58, to 40, 37, and 38, respectively, without loss of prediction accuracy. Results showed that some features were redundant for gene essentiality, so could be eliminated from future analyses. The selected features contained more complex (or key) biological information for gene essentiality, and could be of use in related research projects, such as gene prediction, synthetic biology, and drug design.
The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is one of the greatest threats to soybean production, and both trend analysis and periodic analysis of its population dynamics are ...important for integrated pest management (IPM). Based on systematically investigating soybean aphid populations in the field from 2018 to 2020, this study adopted the inverse logistic model for the first time, and combined it with the classical logistic model to describe the changes in seasonal population abundance from colonization to extinction in the field. Then, the increasing and decreasing phases of the population fluctuation were divided by calculating the inflection points of the models, which exhibited distinct seasonal trends of the soybean aphid populations in each year. In addition, multifactor logistic models were then established for the first time, in which the abundance of soybean aphids in the field changed with time and relevant environmental conditions. This model enabled the prediction of instantaneous aphid abundance at a given time based on relevant meteorological data. Taken as a whole, the successful approaches implemented in this study could be used to build a theoretical framework for practical IPM strategies for controlling soybean aphids.
Abstract
Background
Panic disorder (PD) is thought to be related with deficits in emotion regulation, especially in cognitive reappraisal. According to the cognitive model, PD patients’ intrinsic and ...unconscious misappraisal strategies are the cause of panic attacks. However, no studies have yet been performed to explore the underlying neuromechanism of cognitive reappraisal that occur on an unconscious level in PD patients.
Methods
Twenty-six patients with PD and 25 healthy controls (HC) performed a fully-verified event-block design emotional regulation task aimed at investigating responses of implicit cognitive reappraisal during an fMRI scan. Participants passively viewed negatively valanced pictures that were beforehand neutrally, positively, or adversely portrayed in the task.
Results
Whole-brain analysis of fMRI data showed that PD patients exhibited less activation in the right dorsolateral prefrontal cortex (dlPFC) and right dorsomedial prefrontal cortex (dmPFC) compared to HC, but presented greater activation in parietal cortex when negative pictures were preceded by positive/neutral vs negative descriptions. Simultaneously, interactive effects of Group × Condition were observed in the right amygdala across both groups. Furthermore, activation in dlPFC and dmPFC was is negatively correlated to severity of anxiety and panic in PD when negative images were preceded by non-negative vs negative descriptions.
Conclusions
Emotional dysregulation in PD is likely the result of deficient activation in dlPFC and dmPFC during implicit cognitive reappraisal, in line with impaired automatic top-down regulation. Correlations between severity of anxiety and panic attack and activation of right dlPFC and dmPFC suggest that the failure to engage prefrontal region during implicit cognitive reappraisal might be associated wtih the severity of anxiety and panic; such functional patterns might be the target of possible treatments.
Hepatocellular carcinoma (HCC), the second leading cause of cancer death worldwide, alone accounts for over half (466,100) of new cancer cases and 422,100 deaths based on the average year incidence ...rates of 2009 to 2011 in China. Due to unclear and complex underlying mechanisms for HCC development, effective therapy for HCC is still unavailable. The Wnt-beta-catenin pathway is a critical contributor of HCC pathogenesis: 40-70% of HCCs from patients harbor the nuclear accumulation of beta-catenin protein. However, the mechanisms for beta-catenin activation are not fully understood. The deletion of EHMT2 in Hep3B and Huh1 cells was achieved by transiently transfecting cells with pX459 plasmids, which carry EHMT2 specific small guide RNA (sgRNA) sequences for Cas9 protein. All experiments were performed in triplicate and repeated more than three times. In the present study, we observed that EHMT2 (but not EHMT1) mRNA and protein levels were significantly elevated in HCC compared with normal controls. Next, the results of Ki67 staining, as well as MTT, soft-agar and xenograft assays, in wild-type and EHMT2.sup.-/- Hep3B and Huh1 cancer stem cells collectively revealed that the elevation of EHMT2 expression is required for the tumorigenesis of HCC. Meanwhile, we found that elevated EHMT2 expression contributes to the activation of Wnt-beta-catenin signaling: deletion of EHMT2 in Hep3B or Huh1 cells promoted the cytoplasmic localization of beta-catenin and restrained the expression of Wnt-beta-catenin signaling targets such as Myc, CCND1, MMP-7, etc. We demonstrated that EMHT2 directly mediates the H3K9me2 methylation of the APC promoter to epigenetically silence its expression. More intriguingly, our findings also showed that UNC0642, a specific inhibitor of EHMT2, exhibits anti-tumorigenesis effects in HCC both in vitro and in vivo, which were largely abolished by deletion of EHMT2 or overexpression of APC in Hep3B and Huh1 cells. Altogether, our observations emphasize that the EHMT2-APC axis is a critical contributor to Wnt-beta-catenin pathway activation in HCC, and UNC0642 may be a potential candidate for target drug treatment of HCC.
Dysregulation of the neddylation pathway is related to various cancers. However, the specific role of the neddylation pathway in human hepatocellular carcinoma (HCC) remains largely unclear. In this ...study, the neddylation pathway in HCC and adjacent noncancerous liver (ANL) tissues was evaluated by immunohistochemistry (IHC), Western blotting, and qRT‐PCR (quantitative real‐time polymerase chain reaction). The results showed that the entire neddylation pathway, including NEDD8 (the IHC staining of NEDD8 represents the global‐protein neddylation), E1 NEDD8‐activating enzymes (NAE1 and UBA3), E2 NEDD8‐conjugating enzymes (UBE2F and UBE2M), E3 NEDD8‐ligases (MDM2, RBX1 and RNF7), and deneddylation enzymes (COPS5, UCHL1 and USP21), was overactivated in HCC. Furthermore, the upregulation of NEDD8 in HCC was correlated with aggressive characteristics and was an independent risk factor for overall survival (OS) and recurrence‐free survival (RFS) in patients with HCC after hepatectomy. The upregulation of NAE1, UBE2M, and UCHL1 in HCC was associated with aggressive characteristics and poor OS and RFS in patients with HCC after hepatectomy. In conclusion, our research reveals that the entire neddylation pathway is overactivated in HCC and associated with clinical characteristics and prognosis of patients with HCC.
The entire neddylation pathway is overactivated in human HCC tissues. The overactivation of neddylation pathway is associated with poor prognosis and aggressive characteristics.
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