[Retracted] Upregulation of the δ opioid receptor in liver cancer promotes liver cancer progression both in vitro and in vivo.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the western blotting data shown in Fig. 1C on p. 1284 for the control ß­actin protein bands were strikingly similar to bands appearing in another article written by different authors at different research institutes, which had already been submitted for consideration for publication (Li ZH, Yu Y, Du C, Fu H, Wang J and Tian Y: RNA interference­mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest. Oncol Lett 5: 1290­1294, 2013). Owing to the fact that the contentious data in the above article had already been submitted for publication elsewhere prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 43: 1281­1290, 2013; DOI: 10.3892/ijo.2013.2046].

[Retracted] Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug­resistant human hepatocellular carcinoma cells to 5­FU.

Subsequently to the publication of the above article, and a Corrigendum that was published with the intention of showing corrected data for the flow cytometric plots shown in Fig. 3 (DOI: 10.3892/mmr.2018.9415; published online on August 21, 2018), it was drawn to the Editors' attention by a concerned reader that the ß­actin agarose gel electrophoretic blots shown in Fig. 1A were strikingly similar to data appearing in different form in another article by different authors at a different research institute which had already been published elsewhere prior to this paper's submission to Molecular Medicine Reports. Owing to the fact that the contentious data had already been published else prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 13: 59­66, 2016; DOI: 10.3892/mmr.2015.4511].

Shifts in the bacterial community caused by combined pollutant loads in the North Canal River, China.

A typical anthropogenically disturbed urban river polluted by a combination of conventional pollutants (nitrogen and phosphorus pollution) and heavy metals was investigated along a 238 km stretch. Changes in the bacterial community were evaluated using high-throughput sequencing, and the relationships between bacteria, heavy metals, and conventional pollutants were investigated. There was large spatial heterogeneity in the bacterial community along the river, and bacterial diversity in the upstream and midstream sections was much higher than in the downstream section. Heavy metals and conventional pollutants both exhibited close correlations with bacterial diversity and composition. For instance, potential fecal indicator bacteria, sewage indicator bacteria and pathogenic bacteria, such as Ruminococcus and Pseudomonas, were closely associated with Cu, Zn, and NH4+-N. Rather than conventional pollutants, heavy metals were the main driving factors of the microbial community characteristics. These results confirm that bacterial communities play a crucial role in biogeochemical cycles. Therefore, heavy metals could be used as biomarkers of complex pollution to indicate the pollution status of riverine ecosystems and contribute to the restoration of habitats in anthropogenically disturbed urban rivers.

Preoperative contrast-enhanced computed tomography-based radiomics model for overall survival prediction in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with a rising incidence worldwide. The prognosis of HCC patients after radical resection remains poor. Radiomics is a novel machine learning method that extracts quantitative features from medical images and provides predictive information of cancer, which can assist with cancer diagnosis, therapeutic decision-making and prognosis improvement. AIM: To develop and validate a contrast-enhanced computed tomography-based radiomics model for predicting the overall survival (OS) of HCC patients after radical hepatectomy. METHODS: A total of 150 HCC patients were randomly divided into a training cohort (n = 107) and a validation cohort (n = 43). Radiomics features were extracted from the entire tumour lesion. The least absolute shrinkage and selection operator algorithm was applied for the selection of radiomics features and the construction of the radiomics signature. Univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors and develop the predictive nomogram, incorporating clinicopathological characteristics and the radiomics signature. The accuracy of the nomogram was assessed with the concordance index, receiver operating characteristic (ROC) curve and calibration curve. The clinical utility was evaluated by decision curve analysis (DCA). Kaplan-Meier methodology was used to compare the survival between the low- and high-risk subgroups. RESULTS: In total, seven radiomics features were selected to construct the radiomics signature. According to the results of univariate and multivariate Cox regression analyses, alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR) and radiomics signature were included to build the nomogram. The C-indices of the nomogram in the training and validation cohorts were 0.736 and 0.774, respectively. ROC curve analysis for predicting 1-, 3-, and 5-year OS confirmed satisfactory accuracy [training cohort, area under the curve (AUC) = 0.850, 0.791 and 0.823, respectively; validation cohort, AUC = 0.905, 0.884 and 0.911, respectively]. The calibration curve analysis indicated a good agreement between the nomogram-prediction and actual survival. DCA curves suggested that the nomogram had more benefit than traditional staging system models. Kaplan-Meier survival analysis indicated that patients in the low-risk group had longer OS and disease-free survival (all P < 0.0001). CONCLUSION: The nomogram containing the radiomics signature, NLR and AFP is a reliable tool for predicting the OS of HCC patients.

Evaluation of water quality at national scale from 2011 to 2021: Advances and challenges.

More environmental policies and larger investments in protecting the aquatic environment in China have been made in the last decade than previously. It is important to assess how this will affect river water quality. Here, changes in water quality in China between 2011 and 2021 are assessed. Water bodies meeting class III or better defined in the Chinese Environmental Quality Standards for Surface Water (GB3838-2002) were labeled WQI, water bodies meeting class V or better but below class III were labeled WQII, and water bodies below class V were labeled WQIII. The percentage of WQI water bodies increased from 66.1 % in 2011 to 81.0 % in 2021, and the percentages of WQII and WQIII water bodies decreased between 2011 and 2021. The percentage of WQI water bodies increased more quickly and the percentage WQIII water bodies decreased more quickly after 2017 than between 2011 and 2016. The percentages of WQI water bodies in the Northwest River Basin (RB), Pearl RB, Southeast RB, Southwest RB, and Yangtze RB were >80 %, and were higher than the percentages of WQI water bodies in the other five RBs. The percentages of WQI and WQII water bodies increased but the percentage of WQIII water bodies decreased in the Hai RB. The percentage of WQI water bodies increased but the percentages of WQII and WQIII water bodies decreased in the Huai RB, Liao RB, Yangtze RB, and Yellow RB. The river monitoring capacity increased and pollution sources, particularly point sources, became more controlled, and this improved river water quality. River management in China has passed the first stage of controlling pollution sources after 10 years of centralized management. The next stage should be focused on strengthening control of non-point sources of pollution and rehabilitating ecological systems to improve river health.

Accumulation and potential ecological risks of Heavy Metals in sediments from Rivers in the Beijing-Tianjin Area.

Human activities can introduce heavy metals to water bodies, where they are then deposited in sediments. The risks, spatial distributions, and toxicities of heavy metals in sediment were investigated along the North Canal in the densely Beijing-Tianjin area. The average geoaccumulation index ranged from 0.2 to 2.91 and the highest value was obtained for Cd. All the pollution load indexes were greater than one, indicating that the heavy metals originated from anthropogenic sources. The risk indexes at three sampling points were greater than 300, indicating high potential ecological risk. Two probable effect concentration quotient values greater than 0.5, suggesting potential toxicity to certain sediment-dwelling organisms. Identification and evalution heavy metals could assist in improvement of the water quality, and support management strategies to restore the environment.

A new model based on gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts prognostic outcome after curative resection of solitary hepatocellular carcinoma.

BACKGROUND: This study intends to explore the potential clinical value of gamma-glutamyl transpeptidase to platelet ratio (GPR) and the new multi-factor scoring model for recurrence and prognosis prediction in solitary HCC patients who received radical resection. METHODS: This study retrospectively analyzed 295 HCC patients after curative resection. According to the Receiver Operating Characteristic (ROC) curve, the optimal cut-off value of GPR for predicting prognosis of HCC after resection was determined. The Kaplan Meier method and Cox regression analysis were performed to assess the important potential factors in the prognosis of HCC and determine the independent risk factors. Assign a value to each independent risk factor and establish a new scoring model. Then, using GPR and the new scoring model to evaluate overall survival (OS) and postoperative recurrence probability. RESULTS: When GPR's cut-off value was selected as 0.30, its predictive efficiency for postoperative prognosis was more favorable than those of other cut-off values (0.76, 0.84 and 0.94). GPR, tumor size, microvascular invasion and neutrophil to lymphocyte ratio (NLR) were identified as independent prognostic predictors. Using these variables, a novel prognostic scoring model was devised and established to identify different levels of risk: high, intermediate and low risk groups. We found that patients with high GPR level and of high risk group would have a poorer OS and a higher recurrence rate after radical resection. CONCLUSIONS: GPR may serve as a promising predictor for postoperative prognosis and recurrence probability of HCC, and the new prognostic scoring model may be available for postoperative management among HCC patients.

Fibrinogen/Lymphocyte Count Ratio Can Be Used as a New Indicator of Prognosis in Patients with Hepatocellular Carcinoma After Radical Resection.

PURPOSE: Preoperative fibrinogen levels are associated with the development, recurrence and metastasis of malignant tumors. This study was designed to investigate the clinical value of preoperative fibrinogen/lymphocyte count ratio (FLR) index in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The clinical data of 479 patients with HCC who underwent radical resection were retrospectively analyzed. The correlation between FLR and clinicopathological features was analyzed by chi-square test or non-parametric test. The overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method. RESULTS: The optimal cut-off value of FLR was determined as 1.6 according to the receiver operating characteristic curve (ROC) analysis, in order to predict prognosis for HCC patients after radical resection. It was further found that FLR level was correlated with tumor size, TNM stage, microvascular invasion and prognosis. Multivariate Cox regression analyses found that FLR was an independent predictor for postoperative OS (overall survival) (p = 0.002) and PFS (progression-free survival) (p = 0.001) in patients with HCC; and the 1-, 3- and 5-year OS and PFS of HCC patients in the FLR ≤1.6 level group were significantly higher than those in the FLR >1.6 level group. CONCLUSION: Preoperative FLR level is a novel and effective predictor of prognosis in patients with HCC, and elevated FLR level is associated with poor prognosis in patients with HCC.

Correction: JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.3713.].

[Corrigendum] Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug­resistant human hepatocellular carcinoma cells to 5­FU.

After the publication of the article, the authors realized that they had inadvertently included the incorrect data for the 'siDOR+5­fu group' in the flow cytometric plots featured in Fig. 3A. A new version of Fig. 3 is provided, which contains the correct data for the 'siDOR+5­fu group' experiment. The authors regret this error, and apologize to the readers for any inconvenience caused. [the original article was published in the Molecular Medicine Reports 13: 59­66, 2016; DOI: 10.3892/mmr.2015.4511].

Preoperative prediction of hepatocellular carcinoma with portal vein tumor thrombus based on conventional data.

Hepatocellular carcinoma (HCC) has a high predilection with portal vein tumor thrombosis (PVTT). However, part of the PVTT type can be found only under the microscopy, which was namely as type I0. The objective of this study was to establish a simple and inexpensive non-invasive model to predict the presentation of PVTT at HCC patients. A total of 815 HCC patients were retrospectively evaluated and randomly assigned into 2 groups: the training group (n = 408) and validation group (n = 407). A new index model, namely WγAL, was built to predict the presence of PVTT in the training subjects and was further validated in the validation subjects. At the optimal cutoff of 8.90, WγAL identified patients with a hazard ratio (HR) of 7.139 for the presence of PVTT. The area under receiver operating characteristic (AUROC) of WγAL was 0.795 (sensitivity: 71.9%; specificity: 78.6%) for differentiation between PVTT and non-PVTT patients in the training group. The AUROC of WγAL in differentiating patients with PVTT type I0 from non-PVTT patients was 0.748 (sensitivity: 72.1%; specificity: 68.4%) with an HR of 5.355. In addition, WγAL > 8.90 was significantly associated with large tumors, multiple tumor numbers, TNM stage III-IV, metastasis, and overall survival in HCC patients. The novel predictive model represents a simple and inexpensive model that can identify the presence of PVTT in HCC patients with a high degree of accuracy, with important clinical significance in the future therapeutic management of HCC patients.

DADLE improves hepatic ischemia/reperfusion injury in mice via activation of the Nrf2/HO­1 pathway.

Hepatic ischemia/reperfusion (I/R) injury is a common pathophysiological process that occurs following liver surgery, which is associated with oxidative stress, and can cause acute liver injury and lead to liver failure. Recently, the development of drugs for the prevention of hepatic I/R injury has garnered interest in the field of liver protection research. Previous studies have demonstrated that [D­Ala2, D­Leu5]­Enkephalin (DADLE) exerts protective effects against hepatic I/R injury. To further clarify the specific mechanism underlying the effects of DADLE on hepatic I/R injury, the present study aimed to observe the effects of various doses of DADLE on hepatic I/R injury in mice. The results indicated that DADLE, at a concentration of 5 mg/kg, significantly reduced the levels of alanine aminotransferase and aspartate aminotransferase in the serum, and the levels of malondialdehyde in the liver homogenate. Conversely, the levels of glutathione, catalase and superoxide dismutase in the liver homogenate were increased. In addition, DADLE was able to promote nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation and upregulate the expression of heme oxygenase (HO)­1, which is a factor downstream of Nrf2, thus improving hepatic I/R injury in mice. In conclusion, the present study demonstrated that DADLE was able to significantly improve hepatic I/R injury in mice, and the specific mechanism may be associated with the Nrf2/HO­1 signaling pathway.

Up-regulation of BRCA1-associated RING Domain 1 Promotes Hepatocellular Carcinoma Progression by Targeting Akt Signaling.

The present study was designed to investigate the potential clinical, pathological, prognostic value, role and mechanism of BRCA1-associated RING Domain 1 (BARD1) in Hepatocellular carcinoma (HCC). Quantitative real-time PCR and immunohistochemistry were performed to evaluate the expression of BARD1 mRNA and protein. The expression of BARD1 in the HCC tissue samples was markedly higher than that in the adjacent noncancerous liver tissues. Elevated BARD1 expression was positively correlated with tumor-node-metastasis stage, Barcelona-Clinic Liver Cancer stage, hepatitis B surface antigen, large tumor size, serum alpha-fetoprotein levels, and serum aspartate aminotransferase levels. Univariate and multivariate analyses revealed the BARD1 was an independent predictor for decreased progression-free survival and overall survival in HCC. In vitro experiments demonstrated that knocking down BARD1 significantly inhibited the proliferation, invasion and migration of HCC cells. Moreover, silencing BARD1 inhibit the signaling pathway via decreased the levels of Akt, mTOR, and MMP-9 and inhibited the phosphorylation of Akt (Ser473) and mTOR (Ser2248). Collectively, our findings suggest that BARD1 may be a novel diagnostic and prognostic biomarker of HCC, and up-regulation of BARD1 can contribute to HCC progression by targeting Akt signaling.

Upregulation of Akt/NF-κB-regulated inflammation and Akt/Bad-related apoptosis signaling pathway involved in hepatic carcinoma process: suppression by carnosic acid nanoparticle.

Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death and its incidence is increasing in many countries, becoming a serious threat to human health. Many researches focused on the treatment and prevention of liver cancer. However, due to the underlying molecular mechanism of liver cancer still not fully understood, the studies and development of treatments were forced to be delayed. Akt has been suggested to play an essential role in the progression of inflammation response and apoptosis. Hence, in this study, Akt-knockout mice and cells of liver cancer were used as a model to investigate the molecular mechanism of Akt-associated inflammatory and apoptotic signaling pathway linked with NF-κB and Bcl-2-associated death promoter (Bad) for the progression of liver cancer. Carnosic acid (CA), as a phenolic diterpene with anticancer, antibacterial, antidiabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Administration of CA nanoparticles was sufficient to lead to considerable inhibition of liver cancer progression. The results indicated that, compared to the normal liver cells, the expression of Akt was significantly higher in liver cancer cell lines. Also, we found that Akt-knockout cancer cell lines modulated inflammation response and apoptosis via inhibiting NF-κB activation and inducing apoptotic reaction. Our results indicated that the downstream signals, including cytokines regulated by NF-κB and caspase-3-activated apoptosis affected by Bad, were re-modulated for knockout of Akt. And CA nanoparticles, acting as Akt-knockout, could inhibit inflammation and accelerate apoptosis in liver cancer by altering NF-κB activation and activating caspase-3 through Bad pathway. These findings demonstrated that the nanoparticulate drug CA performed its effective role owing to its ability to reduce inflammatory action and enhance apoptosis for the overexpression of NF-κB and Bad via Akt signaling pathway, playing a direct role in liver cancer progression. Thus, nanoparticle CA might be an important and potential choice for the clinical treatment in the future.

Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell-Like Behaviors in Hepatocellular Carcinoma.

The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. ©2016 AACR.

HOXA7 plays a critical role in metastasis of liver cancer associated with activation of Snail.

BACKGROUND: Liver cancer is one of the main causes of cancer-related death in human. HOXA7 has been proved to be related with several cancers. METHOD: The expression levels of HOXA7 were examined by Western blot, qRT-PCR or ICH. MTT was used to detect the proliferative rate of liver cancer cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of liver cancer cells were revealed in BALB/c nude mice. RESULTS: In this report, we revealed that HOXA7 promoted metastasis of HCC patients. First, increased levels of HOXA7 were examined in liver cancer especially in metastatic liver cancer. Moreover, higher expression level of HOXA7 was associated with poorer prognosis of liver cancer patients. Overexpression of HOXA7 significantly enhanced proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo meanwhile silencing HOXA7 significantly inhibited the aboves abilities of liver cancer cells. In this research, we identified that HOXA7 performed its oncogenic characteristics through activating Snail. CONCLUSION: Collectively, we identify the critical role and possible mechanism of HOXA7 in metastasis of liver cancer which suggest that HOXA7 may be a potential therapeutic target of liver cancer patients.

MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignant tumors. In the present study, we analyzed the role miR-155-3p plays in Hepatocellular carcinoma (HCC), which has been reported participation in some other types of cancer. METHODS: qRT-PCR was used to measure the levels of miR-155-3p in HCC specimens and HCC cell lines. Overexpression of miR-155-3p and miR-155-3p inhibitor were transfected into HCC cell lines to investigate its role in HCC. Colony formation assay and 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays were used to analyses cell proliferation in vitro. In vivo tumor formation assays were performed in BALB/c nude mice. Luciferase reporter assay was carried out to measure the translation of F-Box and WD repeat romain containing 7 (FBXW7). RESULTS: We found that miR-155-3p was remarkably upregulated both in HCC tissue and cell lines. Overexpression of miR-155-3p enhanced HCC cell proliferation in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155-3p is correlated with decreased levels FBXW7 mainly through inhibiting the expression of FBXW7. CONCLUSIONS: Our studies suggest that miR-155-3p plays an important role in the pathogenesis of HCC and implicates its potential applications in the treatment of HCC cancer.

Overexpression of CTNND1 in hepatocellular carcinoma promotes carcinous characters through activation of Wnt/ß-catenin signaling.

BACKGROUND: Increasing evidence supports the association of CTNND1 with tumor development and progression. However, the mechanism and clinical significance of CTNND1 deregulation in hepatocellular carcinoma (HCC) remains unknown. In this study, we aim to investigate the role of CTNND1 in HCC. METHODS: qRT-PCR and immunohistochemical analyses were used to measure the levels of CTNND1 in HCC specimens and HCC cell lines. CTNND1 and shCTNND1 were transfected into HCC cell lines to investigate its role in HCC. Cell migration and invasion were measured by Transwell and Matrigel analyses in vitro. In vivo metastasis assays were performed in SCID mice. RESULTS: In clinical HCC samples, we found that CTNND1 expression was significantly up-regulated in cancer lesions compared with paired normal liver tissues. By silencing or overexpressing CTNND1 in HCC cells, we found that CTNND1 could promote cell proliferation, migration, and invasion in vitro. An in-vivo assay showed that CTNND1 dramatically promoted HCC cell tumor formation and metastasis. Moreover, CTNND1 promoted HCC metastasis, at least in part, by indirectly enhancing Wnt/ß-catenin signaling. Consistent with these results, the expression of CTNND1 was positively correlated with ß-catenin, WNT11, Cyclin D1, and BMP7 expression in human HCC specimens. CONCLUSIONS: Our study provides evidence that CTNND1 functions as a novel tumor oncogene in HCC, and may be a potential therapeutic target for HCC management.

Downregulation of δ opioid receptor by RNA interference enhances the sensitivity of BEL/FU drug­resistant human hepatocellular carcinoma cells to 5­FU.

δ opioid receptor (DOR) was the first opioid receptor of the G protein­coupled receptor family to be cloned. Our previous studies demonstrated that DOR is involved in regulating the development and progression of human hepatocellular carcinoma (HCC), and is involved in the regulation of the processes of invasion and metastasis of HCC cells. However, whether DOR is involved in the development and progression of drug resistance in HCC has not been reported and requires further elucidation. The aim of the present study was to investigate the expression levels of DOR in the drug­resistant HCC BEL­7402/5­fluorouracil (BEL/FU) cell line, and its effects on drug resistance, in order to preliminarily elucidate the effects of DOR in HCC drug resistance. The results of the present study demonstrated that DOR was expressed at high levels in the BEL/FU cells, and the expression levels were higher, compared with those in normal liver cells. When the expression of DOR was silenced, the proliferation of the drug­resistant HCC cells were unaffected. However, when the cells were co­treated with a therapeutic dose of 5­FU, the proliferation rate of the BEL/FU cells was significantly inhibited, a large number of cells underwent apoptosis, cell cycle progression was arrested and changes in the expression levels of drug­resistant proteins were observed. Overall, the expression of DOR was upregulated in the drug­resistant HCC cells, and its functional status was closely associated with drug resistance in HCC. Therefore, DOR may become a recognized target molecule with important roles in the clinical treatment of drug­resistant HCC.