Gene expression, regulation of DEN and HBx induced HCC mice models and comparisons of tumor, para-tumor and normal tissues

Tang, Qin; Wang, Qi; Zhang, Qiong; Lin, Sheng‐Yan; Zhu, Yanhong; Yang, Xiangliang; Guo, An‐Yuan

doi:10.1186/s12885-017-3860-x

Cited by 20 publications

(21 citation statements)

References 47 publications

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“…may be due to heterogeneous disease backgrounds of the patients in the analyzed cohorts. In addition, a recent study on DEN‐induced hepatoma in mice showed that expression of miR‐146b‐5p is stronger in the highly inflammatory para‐tumor tissue compared to normal and tumor tissue, in line with a considerable impact of the tumor environment on the modulation of miR‐146b‐5p expression.…”

Section: Discussionmentioning

confidence: 83%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPSmediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p). K E Y W O R D Shepatocarcinogenesis, IL-6-type cytokines, liver, microRNAs, miR-146a-5p steatohepatitis; NF B, nuclear factor kappaB; OSM, oncostatin M; PPP2R1B, protein phosphatase 2 scaffold subunit Abeta; pre-miRNA, precursor-miRNA; pri-miRNA, primary-miRNA; SRPRB, SRP receptor beta subunit; STAT, signal transducer and activator of transcription; TNF , tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TSS, transcription starting site This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 83%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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“…On the contrary, both models shared common deregulated genes involved in metabolic pathways and redox processes. Moreover, early growth response 1 'Egr1', activating transcription factor 3 'Atf3' and Kruppel-like factor 4 'Klf4' resulted as the main regulatory factors in HBX mice controlling cancer-associated signaling pathways, such as PI3K/AKT, MAPK, Ras, and p53, which role in hepatocarcinogenesis is well established [59]. Notably, several oncogenes and tumor-suppressor (TS) genes deregulated in human HCC were controlled by these transcription factors, highlighting the reliability of the HBX mouse model with respect to the human pathology.…”

Section: Hbx Transgenic Mouse and Mir-224mentioning

confidence: 99%

MicroRNAs in Animal Models of HCC

Fornari

Gramantieri

Callegari

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.

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“…Multifocal mutations can be seen even in a single tumor and tumor doubling time may vary between tumor nodules (5). It should also be noted that the tumor microenvironment has high inflammatory properties and may cause changes in tumor behavior (6). The liver, lungs, and bones are the most common sites of recurrence after LT respectively (7).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular Carcinoma with Increased AFP Levels and Extrahepatic Manifestation after Liver Transplantation: A Case of Late-Onset Recurrence

Tokmak

2019

Düzce Tıp Fakültesi Dergisi

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Liver transplantation is the best treatment modality in patients with hepatocellular carcinoma. The major concern after liver transplantation for hepatocellular carcinoma treatment is recurrence, because it's the most important factor for the long term survival. There are two forms of recurrence; early-onset (within 2 years of liver transplantation) and late-onset (after 2 years of liver transplantation). A lot of factors have been reported in the literature to foresee recurrence after liver transplantation and one of them is alpha-fetoprotein. Many studies have shown that high levels of pre-transplant alpha-fetoprotein is related to early-onset recurrence and worse outcomes in the long term. In this case report, we report a case of late-onset recurrence, despite having high levels of pre-transplant alpha-fetoprotein in contrary to the literature, and still survive with a high quality of life 6 years after transplantation.

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Gene expression, regulation of DEN and HBx induced HCC mice models and comparisons of tumor, para-tumor and normal tissues

Cited by 20 publications

References 47 publications

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

MicroRNAs in Animal Models of HCC

Hepatocellular Carcinoma with Increased AFP Levels and Extrahepatic Manifestation after Liver Transplantation: A Case of Late-Onset Recurrence

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