From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Ramakrishna, Gayatri; Rastogi, Archana; Trehanpati, Nirupama; Sen, Bijoya; Khosla, Ritu; Sarin, Shiv Kumar

doi:10.1159/000343852

Cited by 182 publications

(133 citation statements)

References 76 publications

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“…Given the fact that a single miR targets multiple kinds of mRNA, constitutive activation of multiple molecules may act in concert to restore the sensitivity of HCC to sorafenib [56]. Studies on molecular biology and signal transduction are a key issue to understanding the efficacy of systemic therapy to HCC [57,58,59,60]. …”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Nishida

Kitano

Sakurai

et al. 2015

Dig Dis

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, and prognosis remains unsatisfactory when the disease is diagnosed at an advanced stage. Many molecular targeted agents are being developed for the treatment of advanced HCC; however, the only promising drug to have been developed is sorafenib, which acts as a multi-kinase inhibitor. Unfortunately, a subgroup of HCC is resistant to sorafenib, and the majority of these HCC patients show disease progression even after an initial satisfactory response. To date, a number of studies have examined the underlying mechanisms involved in the response to sorafenib, and trials have been performed to overcome the acquisition of drug resistance. The anti-tumor activity of sorafenib is largely attributed to the blockade of the signals from growth factors, such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor, and the downstream RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade. The activation of an escape pathway from RAF/MEK/ERK possibly results in chemoresistance. In addition, there are several features of HCCs indicating sorafenib resistance, such as epithelial-mesenchymal transition and positive stem cell markers. Here, we review the recent reports and focus on the mechanism and prediction of chemoresistance to sorafenib in HCC.

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Section: Introductionmentioning

confidence: 99%

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Nishida

Kitano

Sakurai

et al. 2015

Dig Dis

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“…Several reports have suggested that hepatocarcinogenesis involves multiple molecular pathways with the accumulation of genetic and epigenetic alterations, including point mutations and abnormal DNA methylation [3,4,5,6]. …”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Profiling of DNA Methylation and Tumor Progression in Human Hepatocellular Carcinoma

Nishida

Nishimura²,

Nakai³

et al. 2014

Dig Dis

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Objective: To clarify the progression pattern of abnormal DNA methylation during the development of hepatocellular carcinoma (HCC) using a comprehensive methylation assay. Methods: We used an Infinium HumanMethylation450 BeadChip array that can analyze >485,000 CpG sites distributed throughout the genome for a comprehensive methylation study of 117 liver tissues consisting of 59 HCC and 58 noncancerous livers. Altered DNA methylation patterns during tumor progression were also analyzed. Results: We identified 38,330 CpG sites with significant differences in methylation levels between HCCs and noncancerous livers (DM-CpGs) using strict criteria. Of the DM-CpGs, 92% were hypomethylated and only 3,051 CpGs (8%) were hypermethylated in HCC. The DM-CpGs were more prevalent within intergenic regions with isolated CpGs. In contrast, DM-CpGs that were hypermethylated in HCC were predominantly located within promoter regions and CpG islands (p < 0.0001). The association between methylation profiles of DM-CpGs and tumor size was statistically significant, especially in hepatitis C virus (HCV)-positive cases (p = 0.0001). Conclusions: We clarified the unique characteristics of DM-CpGs in human HCCs. The stepwise progression of alterations in DNA methylation was a common feature of HCV-related hepatocarcinogenesis.

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“…Taken together, this observed activation of NF-κB may be attributed to the fact that HCC commonly arises in a setting of chronic inflammation and subsequent liver fibrosis and cirrhosis (Ramakrishna et al, 2013). It was found that in HBV-induced hepatocarcinogenesis, the oncogenic HBV X protein activates the NF-κB signaling pathway through the upregulation of TANK-binding kinase 1 (TBK1), thus promoting progression of HCC via proliferative and antiapoptotic effects, as well as triggering the spread of tumor cells (Kim et al, 2010 andZhang et al, 2010).…”

Section: Resultsmentioning

confidence: 93%

Activity and Expression Pattern of NF-κB/P65 in Peripheral Blood from Hepatocellular Carcinoma Patients - Link to Hypoxia Inducible Factor -1α

Gaballah¹,

Zakaria²,

Ismail³

2014

Asian Pacific Journal of Cancer Prevention

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Background: Hepatocellular carcinoma is a complex and heterogeneous tumor with poor prognosis due to frequent intrahepatic spread and extrahepatic metastasis. The molecular mechanisms underlying HCC pathogenesis still remain obscure. Objectives: We aimed to investigate the abundance and the DNA binding activity of nuclear factor kappa B/p65 subunit in peripheral blood mononuclear cells from patients with HCC and to assess its prognostic significance and association with hypoxia inducible factor one alpha (HIF-1α) in blood. Subjects and methods: This study was carried out on 40 patients classified equally into liver cirrhosis (group I) and HCC (group II), in addition to 20 healthy volunteers (group III). All groups were subjected to measurement of NF-κB /P65 subunit expression levels by real time-PCR, and DNA binding activity was evaluated by transcription factor binding immunoassay. Serum HIF-1α levels were estimated by enzyme-linked immunosorbent assay (ELISA). Significant increase of both the expression level and DNA binding activity of NF-κB /P65 subunit together with serum HIF-1 alpha levels was noted in HCC patients compared to liver cirrhosis and control subjects, with significant positive correlation with parameters for bad prognosis of HCC. In conclusion, NF-κB signaling is activated in HCC and associated with disease prognosis and with high circulating levels of HIF-1 alpha.

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From Cirrhosis to Hepatocellular Carcinoma: New Molecular Insights on Inflammation and Cellular Senescence

Cited by 182 publications

References 76 publications

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Molecular Mechanism and Prediction of Sorafenib Chemoresistance in Human Hepatocellular Carcinoma

Genome-Wide Profiling of DNA Methylation and Tumor Progression in Human Hepatocellular Carcinoma

Activity and Expression Pattern of NF-κB/P65 in Peripheral Blood from Hepatocellular Carcinoma Patients - Link to Hypoxia Inducible Factor -1α

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