A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis

Han, Han; Sun, Dan; Li, Wenjuan; Shen, Hongxing; Zhu, Yahui; Li, Chen; Chen, Yuxing; Lu, Long-Feng; Li, Wenhua; Zhang, Jinxiang; Tian, Yuan; Li, Youjun

doi:10.1002/hep.26302

Cited by 85 publications

(98 citation statements)

References 46 publications

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“…C-myc is also considered to be oncogene and frequently overexpressed in HCC [39][40][41]. Our present results revealed that Ang II enhanced C-myc immunofluorescent expression in HCC cell lines and the expression was predominantly cell nucleus.…”

Section: Discussionsupporting

confidence: 62%

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Ji¹,

Wang²,

Li³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The pathogenesis of hepatocellular carcinoma (HCC) is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation. Angiotensin II (Ang II) behaves as an endogenous pro-inflammatory molecule playing a significant role in HCC, however, the molecular link between Ang II, proliferation and inflammation remains unclear. Methods: Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with Ang II at the indicated concentrations for 24, 48, 72 h. MTT, BrdU ELISA, plate colony formation assay, immunohistochemistry, ELISA, small-interfering RNA(siRNA) transfection, quantitative real-time PCR and western blot were applied to assess their functional, morphological and molecular mechanisms in HCC cell lines. Results: High expression of Ang II type 1 receptor (AT1) and low expression of AT2 in HCC cells and tissues were found. Next, Ang II could significantly enhance cell growth and proliferation. Albeit Ang II slightly increased the percentage of HCC cells in the G0/G1 phase using flow cytometry analysis, no statistically significant alterations were shown. Further studies suggested that Ang II could directly induce proliferation associated proteins C-myc and proliferating cell nuclear antigen (PCNA) expressions, and inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) productions in HCC cells. Interestingly, blocking AT1 and AT1 siRNA evidently inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cells. More importantly, these effects may be mediated by AT1/PKC/NF-κB signaling pathway in HCC cell lines. Conclusions: The results propose that Ang II/AT1/PKC/NF-κB signaling pathway is necessary for proliferation and inflammation of HCC cells, which increases our understanding of the pathogenesis and provides clues for developing new strategies against Ang II-related progress of HCC.

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Section: Discussionsupporting

confidence: 62%

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Ji¹,

Wang²,

Li³

et al. 2016

Cell Physiol Biochem

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“…MYC directly regulates the expression of genes that encode the enzymes in the nucleotide biosynthetic pathways and in the feeder pathways for the production of the precursors of all nucleotides (15,24–26), as well as coordinates RNA and protein biosynthesis (27,28). MYC also influences expression of specific microRNAs that regulate enzymes required for cell proliferation (22,29–31). …”

Section: Introductionmentioning

confidence: 99%

Regulation of mammalian nucleotide metabolism and biosynthesis

Lane

Fan

2015

Nucleic Acids Research

720

631

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Nucleotides are required for a wide variety of biological processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope tracers for delineating the biosynthetic routes of the multiple intersecting pathways and how these are quantitatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug development in diseases such as cancer.

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“…Overexpression of MYC promotes oncogenic transformation and tumorigenesis by activating the transcription of target genes that drive cell proliferation and stimulate angiogenesis and repress cell differentiation [13]. MYC is frequently overexpressed in HCC [14, 15, 16]. Tissue microarray analysis showed that up to 70% of human virus and alcohol-related HCC shows excessive activation of MYC [14].…”

Section: Introductionmentioning

confidence: 99%

CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression

Qian

Yuan

et al. 2015

Oncotarget

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Cellular senescence-inhibited gene (CSIG) protein significantly prolongs the progression of replicative senescence, but its role in tumorigenesis is unclear. To reveal the role of CSIG in HCC, we determined its expression in HCC tissues and surrounding tissues and its functions in tumor cell proliferation in vitro and in vivo. CSIG protein was overexpressed in 86.4% of the human HCC cancerous tissues as compared with matched surrounding tissues, and its protein expression was greater in HCC cells than the non-transformed hepatic cell line L02. Furthermore, upregulation of CSIG significantly increased the colony formation of SMMC7721 and HepG2 cells, and silencing CSIG could induce cell cycle arrest and cell apoptosis. The tumorigenic ability of CSIG was confirmed in vivo in a mouse xenograft model. Our results showed that CSIG promoted the proliferation of HepG2 and SMMC7721 cells in vivo. Finally, CSIG protein directly interacted with c-MYC protein and increased c-MYC protein levels; the ubiquitination and degradation of c-MYC protein was increased with knockdown of CSIG. CSIG could also increase the expression of c-MYC protein in SMMC7721 cells in vivo, and it was noted that the level of c-MYC protein was also elevated in most human cancerous tissues with high level of CSIG.

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A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis

Cited by 85 publications

References 46 publications

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

Regulation of mammalian nucleotide metabolism and biosynthesis

CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression

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