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.
Background and Aims
HBV‐pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the ...emergence of viral mutations. However, the contributions of HBV‐pgRNA to HCC remain open for study.
Approach and Results
Double‐center cohorts of serum samples with undetectable serum HBV‐DNA (below the lower limit of detection) were obtained from long‐term NA‐treated (≥48 weeks) HBV‐related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long‐term NA therapy with undetectable serum HBV‐DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up‐regulate the expression of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), a well‐proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)‐α‐2a could degrade the stability of pgRNA through increasing its N6‐methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long‐term NA therapy with undetectable serum HBV‐DNA; and the pgRNA‐IGF2BP3 axis plays an important role in the development of HBV‐related HCC. Moreover, IFN‐α‐2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV‐related HCC.
Conclusions
In conclusion, our studies reveal a significance and mechanism of HBV‐pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV‐related HCC.
Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) ...remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.
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.
Porphyrinic covalent organic frameworks (COFs) have emerged as prospective materials in photodynamic and photothermal sterilization. However, it is still a great challenge to construct an efficient ...COF-based sterilizing agent with good photothermal and photodynamic properties and bacterial targeting ability. Herein, we report a multifunctional porphyrin-COF for bacterial-targeted and reaction-enhanced synergistic phototherapy/chemotherapy for sterilization and wound healing. The ordered crystal structure of the porphyrin-COF not only effectively avoids the self-aggregation-induced quenching of the porphyrin monomer, but also facilitates the storage and transport of singlet oxygen. The acrylate substituent in the other monomer serves as a bacterial targeting moiety and the
in situ
reaction site with the sulfhydryl group of the bacterial surface protein
via
a Michael addition reaction, thus fixing the bacteria on the surface of COF and making them lose the colonization ability. Furthermore, the bonding of COF and bacteria further amplifies the therapeutic efficiency of phototherapy. Therefore, the developed multifunctional sterilization platform not only provides a new strategy for the design of novel bactericidal materials but also broadens the biological applications of COF-based materials.
An acrylate-functionalized porphyrin-covalent organic framework with bacterial-targeting and reaction-enhanced synergistic phototherapy/chemotherapy features was constructed for sterilization and wound healing.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and current treatments exhibit limited efficacy against advanced HCC. The majority of cancer-related deaths are ...caused by metastasis from the primary tumor, which indicates the importance of identifying clinical biomarkers for predicting metastasis and indicating prognosis. Patient-derived cells (PDCs) may be effective models for biomarker identification. In the present study, a wound healing assay was used to obtain 10 fast-migrated and 10 slow-migrated PDC cultures from 36 HCC samples. MicroRNA (miRNA) signatures in PDCs and PDC-derived exosomes were profiled by microRNA-sequencing. Differentially expressed miRNAs between the low- and fast-migrated groups were identified and further validated in 372 HCC profiles from The Cancer Genome Atlas (TCGA). Six exosomal miRNAs were identified to be differentially expressed between the two groups. In the fast-migrated group, five miRNAs (miR-140-3p, miR-30d-5p, miR-29b-3p, miR-130b-3p and miR-330-5p) were downregulated, and one miRNA (miR-296-3p) was upregulated compared with the slow-migrated group. Pathway analysis demonstrated that the target genes of the differentially expressed miRNAs were significantly enriched in the 'focal adhesion' pathway, which is consistent with the roles of these miRNAs in tumor metastasis. Three miRNAs, miR-30d, miR-140 and miR-29b, were significantly associated with patient survival. These findings indicated that these exosomal miRNAs may be candidate biomarkers for predicting HCC cell migration and prognosis and may guide the treatment of advanced HCC.
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.
Objective:
To evaluate the importance of preoperative blood platelet to lymphocyte ratio (PLR) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver surgery and ...to examine the connection with CD8
+
lymph cell infiltration.
Methods:
Between 2009 and 2014, consecutive HCC patients who received curative liver surgery were included into this retrospective study. Baseline clinicopathological characteristics were analyzed to identify predictors of recurrence-free and overall patient survival rate after liver resection. The samples of all patients were under Tissue Microarray (TMA) construction and immunohistochemical staining for CD8+.The association of the number of CD8+T-cells in the cancer nests and peritumoral stroma with PLR level was analyzed.
Results:
A total of 1,174 HBV-related HCC patients who received a liver resection without any peri-operative adjuvant therapy were enrolled into this retrospective study. Univariate and Multivariate analysis using Cox regression model showed that PLR was an independent factor affecting recurrence and overall survivals. The optimal cutoff of PLR using the receiver operating characteristic curve was 150. There were 236 patients (20.1%) who had a PLR of 150 or more. The 5-year survival rate after liver resection was 71.8% in patients with a PLR of < 150 and it was 57.2% in those with a PLR of 150 or more (
P
< 0.001). Both 5-year recurrence-free and overall survival rates in liver cancer stage A patients at Barcelona Clinic with different PLR group were also significantly different (
P
= 0.007 for recurrence and
P
= 0.001 for overall survival). Similar results were also observed in stage B patients (
P
< 0.001 for recurrence and
P
= 0.033 for overall survival). To determine the association between PLR and the severity of liver inflammation, an immuno-histological examination using CD8
+
staining was performed on the liver specimens of 1,174 patients. Compared with low PLR (<150) group, more CD8
+
T-cells were found in the peritumoral tissue in high PLR (≥ 150) group.
Conclusions:
PLR played as an independent factor for predicting the survival after hepatectomy for HCC patients. A high PLR was associated with an accumulation of CD8
+
T-cells in the peritumoral stroma.
BACKGROUND:Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high ...preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels.
METHODS:In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis.
RESULTS:The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 95% confidence interval (CI), 0.409–0.884; P = 0.010 and 0.509 (95% CI, 0.333–0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio HR = 0.316, 95% CI 0.157–0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493–1.240; P = 0.296).
CONCLUSIONS:In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.
Display omitted
•A ratiometric aptasensor with no need for real-time excitation and sample separation was developed for accurate detection of OTA.•The developed aptasensor combines the features of ...non-autofluorescence, exogenous interference-free as well as high specificity.•The developed aptasensor has a lower detection limit and a wider detection range than some recently reported methods.•The developed ratiometric aptasensor has good universality by replacing aptamer and corresponding complementary chain.
Accurate and sensitive detection of ochratoxin A (OTA) is highly necessary due to its high carcinogenicity, teratogenicity and mutagenicity. Herein, we reported an exogenous interference and autofluorescence-free ratiometric aptasensor based on dual-colored persistent luminescent nanoparticles for precise detection of OTA. Green-emitting ZnGeO:Mn bonded with OTA aptamer and BHQ1-modified complementary base was acted as detection and specific recognition probe (ZGM@BHQ1). Quaternary ammonium modified ZnGaGeO:Cr with red emission was employed as reference probe and further bonded to ZGM@BHQ1 through electrostatic interaction to construct the ratiometric aptasensor. The developed ratiometric aptasensor was free from real-time excitation, external interference and autofluorescence and gave low detection limit of 3.4 pg mL−1, wide linearity in the range of 0.01–50 ng mL−1 and high precision of 3.1 % (11 replicate determinations, at 1 ng mL−1 level). The applicability of the aptasensor was successfully demonstrated by analyzing OTA in in grain samples with recoveries of 97.6 %-105.2 %.
PDF
