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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)
In a previous study, the early ripening of Kyoho grape following H
O
treatment was explored at the physiological level, but the mechanism by which H
O
promotes ripening at the molecular level is ...unclear. To reveal the molecular mechanism, RNA-sequencing analysis was conducted on the different developmental stages of Kyoho berry treated with H
O
.
In the comparison of treatment and control groups, 406 genes were up-regulated and 683 were down-regulated. Time course sequencing (TCseq) analysis showed that the expression patterns of most of the genes were similar between the treatment and control, except for some genes related to chlorophyll binding and photosynthesis. Differential expression analysis and the weighted gene co-expression network were used to screen significantly differentially expressed genes and hub genes associated with oxidative stress (heat shock protein, HSP), cell wall deacetylation (GDSL esterase/lipase, GDSL), cell wall degradation (xyloglucan endotransglucosylase/ hydrolase, XTH), and photosynthesis (chlorophyll a-b binding protein, CAB1). Gene expression was verified with RT-qPCR, and the results were largely consistent with those of RNA sequencing.
The RNA-sequencing analysis indicated that H
O
treatment promoted the early ripening of Kyoho berry by affecting the expression levels of HSP, GDSL, XTH, and CAB1 and- photosynthesis- pathways.
The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and ...metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss‐of‐function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase‐2, ‐7, and ‐9 which required PI3K‐AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K‐AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K‐AKT signaling pathway.
In this work, silicone polymer (PSOL)/carbon fiber (CF)/epoxy (EP) composites were prepared by introducing PSOL as interfacial modifiers into CF/EP composites. The mechanical and dynamic mechanical ...properties of the composites were investigated, and the optimum content of the PSOL modification was obtained. The impact of EP on the wettability of CF was compared before and after adding PSOL. The micromorphology of CF/EP composites was also observed. The consequences demonstrate that the interfacial bonding ability between CF and matrix was improved after adding PSOL. The interlaminar shear strength, tensile strength, elongation at break and flexural strength of PSOL/CF/EP composites were increased by 23.28%, 18.49%, 38.45% and 11.23%, respectively. Furthermore, the original thermal stability of the composite was preserved after the modification of PSOL.
The mechanical properties of silicone polymer modified carbon fiber/epoxy composites.
5-Azacytidine (5-azaC) promotes the development of 'Kyoho' grape berry but the associated changes in gene expression have not been reported. In this study, we performed transcriptome analysis of ...grape berry at five developmental stages after 5-azaC treatment to elucidate the gene expression networks controlling berry ripening.
The expression patterns of most genes across the time series were similar between the 5-azaC treatment and control groups. The number of differentially expressed genes (DEGs) at a given developmental stage ranged from 9 (A3_C3) to 690 (A5_C5). The results indicated that 5-azaC treatment had not very great influences on the expressions of most genes. Functional annotation of the DEGs revealed that they were mainly related to fruit softening, photosynthesis, protein phosphorylation, and heat stress. Eight modules showed high correlation with specific developmental stages and hub genes such as PEROXIDASE 4, CAFFEIC ACID 3-O-METHYLTRANSFERASE 1, and HISTONE-LYSINE N-METHYLTRANSFERASE EZA1 were identified by weighted gene correlation network analysis.
5-AzaC treatment alters the transcriptional profile of grape berry at different stages of development, which may involve changes in DNA methylation.
AIM:To compare clinical outcomes between surgical resection(RES)and nonsurgical-RES(nRES)ablation therapies for small hepatocellular carcinoma(HCC).METHODS:MEDLINE,Embase and Cochrane Library ...databases were systematically searched for studies of RES and nRES treatments for small HCC between January 2003 and October 2013.The clinical outcome measures evaluated included overall survival rate,disease-free survival rate,adverse events,and local recurrence rate.Odds ratios(ORs)with 95%CIs were calculated using either the fixed effects model or random effects model.Theχ2 and I2 tests were calculated to assess the heterogeneity of the data.Funnel plots were used to assess the risk of publication bias.RESULTS:Our analysis included 12 studies that consisted of a total of 1952 patients(RES vs nRES),five studies that consisted of 701 patientsradiofrequency ablation(RFA)vs percutaneous ethanol injection(PEI),and five additional studiesRFA vs RFA+transcatheter arterial chemoembolization(TACE)that all addressed the treatment of small HCC.For cases of RES vs nRES,there was no significant difference in the 1-year(OR=0.99,95%CI:0.87-1.12,P=0.85)or 3-year(OR=0.97,95%CI:0.84-1.11,P=0.98)overall survival rate;however,there was a significant increase in the RES group in the 5-year overall survival rate(OR=0.81,95%CI:0.68-0.95,P=0.01).The 1-year(OR=0.94,95%CI:0.82-1.08,P=0.37)and 5-year(OR=0.99,95%CI:0.85-1.14,P=0.85)disease-free survival rates showed no significant differences between the two groups.The3-year disease-free survival rate(OR=0.81,95%CI:0.69-0.96;P=0.02)was higher in the RES group.For cases of RFA vs PEI,our data analysis indicated that RFA treatment was associated with significantly higher2-year(OR=0.76,95%CI:0.58-0.99,P=0.043)and3-year(OR=0.73,95%CI:0.54-0.98,P=0.039)overall survival rates;however,there were no significant differences in the 1-year(OR=0.92,95%CI:0.72-1.17,P=0.0502)overall survival rate or incidence of adverse events(OR=1.84,95%CI:0.76-4.45,P=0.173).For cases of RFA vs RFA+TACE,there were no significant differences in the 1-year(OR=1.17,95%CI:0.88-1.56,P=0.27)or 3-year(OR=1.25,95%CI:0.90-1.73,P=0.183)overall survival rate;however,the 5-year overall survival rate(OR=3.19,95%CI:1.51-6.74,P=0.002)in patients treated by RFA+TACE was higher than that treated by RFA alone.CONCLUSION:Surgical resection is superior to nonsurgical ablation for the treatment of small HCC.Among the studies analyzed,RFA is the most efficacious single nonsurgical ablation treatment.
N6-methyladenosine (m6A) has been reported as an important mechanism of post-transcriptional regulation. Programmed death ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor ...cells that promotes immune evasion. In addition, seven in absentia homolog 2 (Siah2), a RING E3 ubiquitin ligase, has been involved in tumorigenesis and cancer progression. However, the role of m6A-METTL14-Siah2-PD-L1 axis in immunotherapy remains to be elucidated. In this study, we showed that METTL14, a component of the m
A methyltransferase complex, induced Siah2 expression in cholangiocarcinoma (CCA). METTL14 was shown to enrich m
A modifications in the 3'UTR region of the Siah2 mRNA, thereby promoting its degradation in an YTHDF2-dependent manner. Furthermore, co-immunoprecipitation experiments demonstrated that Siah2 interacted with PD-L1 by promoting its K63-linked ubiquitination. We also observed that
and
Siah2 knockdown inhibited T cells expansion and cytotoxicity by sustaining tumor cell PD-L1 expression. The METTL14-Siah2-PD-L1-regulating axis was further confirmed in human CCA specimens. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with low Siah2 levels were more sensitive to anti-PD1 immunotherapy. Taken together, our results evidenced a new regulatory mechanism of Siah2 by METTL14-induced mRNA epigenetic modification and the potential role of Siah2 in cancer immunotherapy.
MicroRNAs (miRNAs) serve an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-197-3p has been reported in various human malignancies. However, the role of ...miR-197-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. The present study demonstrated that miR-197-3p was downregulated in HCC tissues and that the low level of miR-197-3p expression in HCC tumours correlated with aggressive clinicopathological characteristics; thus, miR-197-3p may serve as a predictor for poor prognosis in patients with HCC. Additionally, miR-197-3p markedly inhibited the metastasis of HCC cells
and
. Bioinformatics analysis further identified zinc finger protein interacted with K protein 1 (ZIK1) as a novel target of miR-197-3p in HCC cells. These findings suggest that miR-197-3p may regulate the survival of HCC cells, partially through the downregulation of ZIK1. Therefore, the miR-197-3p/ZIK1 axis may serve as a novel therapeutic target in patients with HCC.
Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies ...still need to be further studies.
This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR).
Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399,
=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE.
Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.
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