Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression

Li, Chi Han; Xu, Feiyue; Chow, Sheungching; Lu, Feng; Yin, Deling; Ng, Tzi Bun; Chen, Yangchao

doi:10.1016/j.ejca.2014.07.008

Cited by 64 publications

(38 citation statements)

References 34 publications

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“…[26][27][28][63][64][65][66][67][68][69] Particularly, Stat3 recruitment to its GAS sites at the miR-21 promoter was previously reported in breast, prostate, hepatocellular and head and neck carcinomas, as well as in transformed mammary epithelial and myeloma cells. [25][26][27][28]63,64 In transformed mammary epithelial cells, it is required to maintain the transformed state 25 and in BC cells, Stat3 binding to miR-21 promoter cooperates with NF-κB to induce invasion. 28 Our new findings revealed that Stat3 function as a TF at the miR-21 promoter drives BC metastasis.…”

Section: Discussionmentioning

confidence: 91%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.

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Section: Discussionmentioning

confidence: 91%

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

et al. 2015

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“…Patients with HBV-HCC have higher serum IL-6 levels that increase autocrine IGF1 and IGF1R expressions, and increase OCT4 and NANOG expressions in a STAT3-dependent manner. Furthermore, HBx proteins upregulate IL-6 expressions and has been shown to promote HCC development through an IL-6-mediated increase in microRNA-21 expression [38].…”

Section: Effects Of Il-6 On the Progression Of Hepatitis Bmentioning

confidence: 99%

Involvement of Interleukin 6 in Hepatitis B Viral Infection

Xia

Liu

Chen

et al. 2015

Cell Physiol Biochem

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Hepatitis B is a major global health problem and a potentially life-threatening liver infection caused by hepatitis B virus (HBV). Many cytokines including interleukin 6 (IL-6) have been shown to be involved in the HBV infection process. IL-6 is a typical cytokine made up of 184 amino acids, and the gene is located in chromosome 7p21. For healthy people, serum IL-6 levels are usually too low to be detected. However, dysregulated synthesis of IL-6 has been discovered in chronic inflammatory diseases such as hepatitis B, Crohn's disease and rheumatoid arthritis. IL-6 also plays an important role in HBV replication and in the development of hepatitis B disease. This review aims to present the latest discoveries concerning the role of IL-6 in hepatitis B disease progression, and HBV entry and replication, and evaluate polymorphisms that are associated with the development of hepatitis B disease.

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“…An example among all is miR-21, whose over-expression results into the silencing of several targets including phosphatase and tensin homolog (PTEN), programed cell death protein 4 (PDCD4), reversion-inducing-cysteine-rich protein with kazal motifs (RECK), metalloproteinase inhibitor 3 (TIMP-3), and Pellino-1 (13, 14, 29–31), but is concomitantly finely tuned by a plethora of factors whose source can either be the tumor cell itself [nuclear factor kinase B (NF-KB), hepatitis B virus X protein (HBV x)] (32, 33), or microenvironment cells [interleukin-6 (IL-6) or monocyte chemotactic protein-1 (MCP-1)] (33, 34). It is interesting to note that normal liver tissue seems to express a limited number of miRNAs, including miR-199a and miR-122 (35).…”

Section: Non-coding Rnas In Hccmentioning

confidence: 99%

Non-Coding RNAs in Primary Liver Cancer

Ghidini

Braconi

2015

Front. Med.

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Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with poor prognosis and limited therapeutic options. Over the past few years, many studies have evaluated the role of non-coding RNAs (ncRNAs) in hepatocarcinogenesis and tumor progression. ncRNAs were shown to have diagnostic, prognostic, and therapeutic potential in HCC. In this manuscript, we review the latest major discoveries concerning microRNAs and long ncRNAs in HCC pathogenesis, and discuss the potentials and the limitations for their use in clinical practice.

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Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression

Cited by 64 publications

References 34 publications

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis

Involvement of Interleukin 6 in Hepatitis B Viral Infection

Non-Coding RNAs in Primary Liver Cancer

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