Research

18 pages, 6641 KiB

Open AccessArticle

AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway

by Maheshkumar Kannan, Sridharan Jayamohan, Rajesh Kannan Moorthy, Siva Chander Chabattula, Mathan Ganeshan and Antony Joseph Velanganni Arockiam

Int. J. Mol. Sci. 2019, 20(22), 5526; https://doi.org/10.3390/ijms20225526 - 06 Nov 2019

Cited by 20 | Viewed by 4179 | Retraction

Abstract

Hepatocellular carcinoma (HCC) is the third leading malignancy worldwide, causing mortality in children and adults. AEG-1 is functioned as a scaffold protein for the proper assembly of RNA-induced silencing complex (RISC) to optimize or increase its activity. The increased activity of oncogenic miRNAs [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading malignancy worldwide, causing mortality in children and adults. AEG-1 is functioned as a scaffold protein for the proper assembly of RNA-induced silencing complex (RISC) to optimize or increase its activity. The increased activity of oncogenic miRNAs leads to the degradation of target tumor suppressor genes. miR-221 is an oncogenic miRNA, that plays a seminal role in carcinogenesis regulation of HCC. However, the molecular mechanism and biological functions of the miR-221/AEG-1 axis have not been investigated extensively in HCC. Here, the expression of miR-221/AEG-1 and their target/associate genes was analyzed by qRT-PCR and Western blot. The role of the miR-221/AEG-1 axis in HCC was evaluated by proliferation assay, migration assay, invasion assay, and flow cytometry analysis. The expression level of miR-221 decreased in AEG-1 siRNA transfected HCC cells. On the other hand, there were no significant expression changes of AEG-1 in miR-221 mimic and miR-221 inhibitor transfected HCC cells and inhibition of miR-221/AEG-1 axis decreased cell proliferation, invasion, migration, and angiogenesis and induced apoptosis, cell cycle arrest by upregulating p57, p53, PTEN, and RB and downregulating LSF, MMP9, OPN, Bcl-2, PI3K, AKT, and LC3A in HCC cells. Furthermore, these findings suggest that the miR-221/AEG-1 axis plays a seminal oncogenic role by modulating PTEN/PI3K/AKT signaling pathway in HCC. In conclusion, the miR-221/AEG-1 axis may serve as a potential target for therapeutics, diagnostics, and prognostics of HCC. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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15 pages, 1541 KiB

Open AccessArticle

Genetic Variants in the Promoter Region of the Macrophage Migration Inhibitory Factor are Associated with the Severity of Hepatitis C Virus-Induced Liver Fibrosis

by Theresa Hildegard Wirtz, Petra Fischer, Christina Backhaus, Irina Bergmann, Elisa Fabiana Brandt, Daniel Heinrichs, Maria Teresa Koenen, Kai Markus Schneider, Thomas Eggermann, Ingo Kurth, Christian Stoppe, Jürgen Bernhagen, Tony Bruns, Janett Fischer, Thomas Berg, Christian Trautwein and Marie-Luise Berres

Int. J. Mol. Sci. 2019, 20(15), 3753; https://doi.org/10.3390/ijms20153753 - 31 Jul 2019

Cited by 5 | Viewed by 3497

Abstract

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF)—rs755622 and rs5844572—exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver [...] Read more.

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF)—rs755622 and rs5844572—exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT_5–8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (<F2) (p = 0.04). Comparable tendencies were observed in the second independent cohort, where fibrosis was assessed using transient elastography. However, once cirrhosis had been established, the C/C genotype and higher microsatellite repeats correlated with impaired liver function and a higher prevalence of hepatocellular carcinoma. Our study demonstrates that specific MIF polymorphisms are associated with disease severity and complications of HCV-induced fibrosis in a stage- and context-dependent manner. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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14 pages, 1866 KiB

Open AccessArticle

Hexokinase-II Inhibition Synergistically Augments the Anti-tumor Efficacy of Sorafenib in Hepatocellular Carcinoma

by Jeong-Ju Yoo, Su Jong Yu, Juri Na, Kyungmin Kim, Young Youn Cho, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Yoon Jun Kim, Hyewon Youn and Jung-Hwan Yoon

Int. J. Mol. Sci. 2019, 20(6), 1292; https://doi.org/10.3390/ijms20061292 - 14 Mar 2019

Cited by 30 | Viewed by 4432

Abstract

This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor [...] Read more.

This study aimed to examine whether inhibition of hexokinase (HK)-II activity enhances the efficacy of sorafenib in in-vivo models of hepatocellular carcinoma (HCC), and to evaluate the prognostic implication of HK-II expression in patients with HCC. We used 3-bromopyruvate (3-BP), a HK-II inhibitor to target HK-II. The human HCC cell line was tested as both subcutaneous and orthotopic tumor xenograft models in BALB/c nu/nu mice. The prognostic role of HK-II was evaluated in data from HCC patients in The Cancer Genome Atlas (TCGA) database and validated in patients treated with sorafenib. Quantitative real-time PCR, western blot analysis, and immunohistochemical staining revealed that HK-II expression is upregulated in the presence of sorafenib. Further analysis of the endoplasmic reticulum-stress network model in two different murine HCC models showed that the introduction of additional stress by 3-BP treatment synergistically increased the in vivo/vitro efficacy of sorafenib. We found that HCC patients with increased HK-II expression in the TCGA database showed poor overall survival, and also confirmed similar results for TCGA database HCC patients who had undergone sorafenib treatment. These results suggest that HK-II is a promising therapeutic target to enhance the efficacy of sorafenib and that HK-II expression might be a prognostic factor in HCC. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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13 pages, 2566 KiB

Open AccessArticle

Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma

by Anna Weis, Louise Marquart, Diego A. Calvopina, Berit Genz, Grant A. Ramm and Richard Skoien

Int. J. Mol. Sci. 2019, 20(4), 864; https://doi.org/10.3390/ijms20040864 - 17 Feb 2019

Cited by 38 | Viewed by 4811

Abstract

Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 [...] Read more.

Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were subdivided into 3 cohorts: Mild disease (fibrosis stage F0-2; n = 20); cirrhosis (n = 20); and cirrhosis with HCC (n = 20). Circulating miRNA signatures were determined using a liver-specific real-time quantitative reverse transcription PCR (qRT-PCR) microarray assessing 372 miRNAs simultaneously. Differentially-expressed miRNA candidates were independently validated using qRT-PCR. Serum miRNA-409-3p was increased in cirrhosis versus mild disease. In HCC versus cirrhosis, miRNA-486-5p was increased, whereas miRNA-122-5p and miRNA-151a-5p were decreased. A logistic regression model-generated panel, consisting of miRNA-122-5p + miRNA-409-3p, distinguished cirrhosis from mild disease (area under the curve, AUC = 0.80; sensitivity = 85%, specificity = 70%; p < 0.001). When combined with FIB-4 or APRI, performance was improved with AUC = 0.89 (p < 0.001) and 0.87 (p < 0.001), respectively. A panel consisting of miRNA-122-5p + miRNA-486-5p + miRNA-142-3p distinguished HCC from cirrhosis (AUC = 0.94; sensitivity = 80%, specificity = 95%; p < 0.001), outperforming AFP (AUC = 0.64, p = 0.065). Serum miRNAs are differentially expressed across the spectrum of disease severity in CHC. MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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14 pages, 3319 KiB

Open AccessArticle

Intestinal Microbiota Protects against MCD Diet-Induced Steatohepatitis

by Kai Markus Schneider, Antje Mohs, Konrad Kilic, Lena Susanna Candels, Carsten Elfers, Eveline Bennek, Lukas Ben Schneider, Felix Heymann, Nikolaus Gassler, John Penders and Christian Trautwein

Int. J. Mol. Sci. 2019, 20(2), 308; https://doi.org/10.3390/ijms20020308 - 14 Jan 2019

Cited by 43 | Viewed by 7373

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in western countries, with a continuously rising incidence. Gut-liver communication and microbiota composition have been identified as critical drivers of the NAFLD progression. Hence, it has been shown that microbiota depletion can ameliorate high-fat diet or western-diet induced experimental Non-alcoholic steatohepatitis (NASH). However, its functional implications in the methionine-choline dietary model, remain incompletely understood. Here, we investigated the physiological relevance of gut microbiota in methionine-choline deficient (MCD) diet induced NASH. Experimental liver disease was induced by 8 weeks of MCD feeding in wild-type (WT) mice, either with or without commensal microbiota depletion, by continuous broad-spectrum antibiotic (AB) treatment. MCD diet induced steatohepatitis was accompanied by a reduced gut microbiota diversity, indicating intestinal dysbiosis. MCD treatment prompted macroscopic shortening of the intestine, as well as intestinal villi in histology. However, gut microbiota composition of MCD-treated mice, neither resembled human NASH, nor did it augment the intestinal barrier integrity or intestinal inflammation. In the MCD model, AB treatment resulted in increased steatohepatitis activity, compared to microbiota proficient control mice. This phenotype was driven by pronounced neutrophil infiltration, while AB treatment only slightly increased monocyte-derived macrophages (MoMF) abundance. Our data demonstrated the differential role of gut microbiota, during steatohepatitis development. In the context of MCD induced steatohepatitis, commensal microbiota was found to be hepatoprotective. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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Review

Jump to: Research, Other

27 pages, 2571 KiB

Open AccessReview

Treatment Strategies for Hepatocellular Carcinoma—A Multidisciplinary Approach

by Isabella Lurje, Zoltan Czigany, Jan Bednarsch, Christoph Roderburg, Peter Isfort, Ulf Peter Neumann and Georg Lurje

Int. J. Mol. Sci. 2019, 20(6), 1465; https://doi.org/10.3390/ijms20061465 - 22 Mar 2019

Cited by 159 | Viewed by 10905

Abstract

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and its mortality is third among all solid tumors, behind carcinomas of the lung and the colon. Despite continuous advancements in the management of this disease, the prognosis for HCC remains inferior compared to other tumor entities. While orthotopic liver transplantation (OLT) and surgical resection are the only two curative treatment options, OLT remains the best treatment strategy as it not only removes the tumor but cures the underlying liver disease. As the applicability of OLT is nowadays limited by organ shortage, major liver resections—even in patients with underlying chronic liver disease—are adopted increasingly into clinical practice. Against the background of the oftentimes present chronical liver disease, locoregional therapies have also gained increasing significance. These strategies range from radiofrequency ablation and trans-arterial chemoembolization to selective internal radiation therapy and are employed in both curative and palliative intent, individually, as a bridging to transplant or in combination with liver resection. The choice of the appropriate treatment, or combination of treatments, should consider the tumor stage, the function of the remaining liver parenchyma, the future liver remnant volume and the patient’s general condition. This review aims to address the topic of multimodal treatment strategies in HCC, highlighting a multidisciplinary treatment approach to further improve outcome in these patients. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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30 pages, 2735 KiB

Open AccessReview

Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis

by Aldona Kasprzak and Agnieszka Adamek

Int. J. Mol. Sci. 2019, 20(6), 1288; https://doi.org/10.3390/ijms20061288 - 14 Mar 2019

Cited by 60 | Viewed by 5499

Abstract

Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), [...] Read more.

Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis. Analysis of mucin expression in PLC has both basic research and clinical value. Mucins may act as oncogenes and tumour-promoting (e.g., MUC1, MUC13), and/or tumour-suppressing factors (e.g., MUC15). Given their role in promoting PLC progression, both classic (MUC1, MUC2, MUC4, MUC5AC, MUC6) and currently tested mucins (e.g., MUC13, MUC15, MUC16) have been proposed to be important diagnostic and prognostic markers. The purpose of this review was to summarize and update the role of classic and currently tested mucins in pathogenesis of PLC, with explaining the mechanisms of their action in HCC carcinogenesis. It also focuses on determination of the diagnostic and prognostic role of these glycoproteins in PLC, especially focusing on HCC, CC and other hepatic tumours with- and without biliary differentiation. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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23 pages, 527 KiB

Open AccessReview

Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications

by Pil Soo Sung and Jeong Won Jang

Int. J. Mol. Sci. 2018, 19(11), 3648; https://doi.org/10.3390/ijms19113648 - 19 Nov 2018

Cited by 33 | Viewed by 6633

Abstract

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune [...] Read more.

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer. Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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Other

Jump to: Research, Review

1 pages, 152 KiB

Open AccessRetraction

Retraction: Kannan et al. AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway. Int. J. Mol. Sci. 2019, 20, 5526

by International Journal of Molecular Sciences Editorial Office

Int. J. Mol. Sci. 2022, 23(12), 6606; https://doi.org/10.3390/ijms23126606 - 14 Jun 2022

Cited by 3 | Viewed by 1444

Abstract

The journal retracts the article, “AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway” [...] Full article

(This article belongs to the Special Issue Liver Cirrhosis and Hepatocellular Carcinoma: Pathogenesis, Diagnosis and Treatment)

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