Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma

Chen, Jian; Gingold, Julian A.; Su, Xiaoping

doi:10.1016/j.molmed.2019.06.007

Cited by 185 publications

(152 citation statements)

References 83 publications

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“…Protein expression of BMP-4 and BMP-7 was upregulated in HBV-related human cirrhosis/HCC samples, and the overexpression of BMP-4 and BMP-7 increased cell viability and enhanced cell migration in HCC cell-lines. [22] Moreover, Chen and coworkers reported that gene amplification and increased gene expression of BMP-5 were significant in HCC samples [66]. This is in agreement with our finding that BMP-5 may contribute to the fibrogenic and tumorigenic processes in the liver.…”

Section: Discussionsupporting

confidence: 92%

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

Yang

Chen

et al. 2020

Cancers

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Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays an important role in the development of HCC. The difficulty in detecting HCC at the early stages is one of the main reasons that the death rate approximates the incidence rate. The regulators controlling the downstream liver protein expression from HBV infection are unclear. Mass spectrometric techniques and customized programs were used to identify differentially expressed proteins which may be involved in the development of liver fibrosis and HCC progression in hepatitis B virus X protein transgenic mice (HBx mice). FSTL1, CTSB, and TGF-β enhanced the signaling pathway proteins during the pathogenesis of HBx. Missing proteins can be essential in cell growth, differentiation, Cancers 2020, 12, 409 2 of 32 apoptosis, migration, metastasis or angiogenesis. We found that LHX2, BMP-5 and GDF11 had complex interactions with other missing proteins and BMP-5 had both tumor suppressing and tumorigenic roles. BMP-5 may be involved in fibrosis and tumorigenic processes in the liver. These results provide us an understanding of the mechanism of HBx-induced disorders, and may serve as molecular targets for liver treatment.

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Section: Discussionsupporting

confidence: 92%

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

Yang

Chen

et al. 2020

Cancers

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“…103,104 Recent studies have demonstrated that TGF-B participates in tumorigenesis. 105,106 When the liver progenitor cells are stimulated by TGF-β, they are transformed into tumor-initiating cells as evidenced by TGF-β-induced changes in CD133 and CD90 expression ( Figure 3). 105 In comparison with the extrinsic effects, the intrinsic actions of TGF-β signaling are largely observed in highly invasive tumor conditions ( Figure 3).…”

Section: In the Regulation Of Hccmentioning

confidence: 99%

Molecular mechanisms of circular RNAs, transforming growth factor‐β, and long noncoding RNAs in hepatocellular carcinoma

Shang

Adzika

et al. 2019

Cancer Medicine

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At the heart of hepatocellular carcinoma (HCC) lies disruption of signaling pathways at the level of molecules, genes, and cells. Non‐coding RNAs (ncRNAs) have been implicated in the disease progression of HCC. For instance, dysregulated expression of circular RNAs (circRNAs) has been observed in patients with HCC. As such, these RNAs are potential therapeutic targets and diagnostic markers for HCC. Long non‐coding RNAs (lncRNAs), a type of ncRNA, have also been recognized to participate in the initiation and progression of HCC. Transforming growth factor‐beta (TGF‐β) is another element which is now recognized to play crucial roles in HCC. It has been implicated in many biological processes such as survival, immune surveillance, and cell proliferation. In HCC, TGF‐β promotes disease progression by two mechanisms: an intrinsic signaling pathway and the extrinsic pathway. Through these pathways, it modulates various microenvironment factors such as inflammatory mediators and fibroblasts. An interesting yet‐to‐be resolved concept is whether the HCC‐promoting role of TGF‐β pathways is limited to a subset of HCC patients or it is involved in the whole process of HCC development. This review summarizes recent advancements to highlight the roles of circRNAs, lncRNAs, and TGF‐β in HCC.

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“…CNOT7 expression was increased, whereas STAT1 expression was decreased in HCC tumor tissues. TGF‐β1 is a powerful immune suppressor secreted from cancer cells of many cancer types, including HCC [11–13,27]. Plasma concentration of TGF‐β1 was positively correlated with the degree of tumor progression in patients with lung or colorectal cancer [28].…”

Section: Discussionmentioning

confidence: 99%

“…Plasma concentration of TGF‐β1 was positively correlated with the degree of tumor progression in patients with lung or colorectal cancer [28]. TGF‐β1 inhibits cytokine secretion and cytotoxicity of NK cells [15–18,27]. NK cell function was impaired, which had been widely observed in patients with advanced cancer [29–31].…”

Section: Discussionmentioning

confidence: 99%

CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma

Ren

Cao

et al. 2020

FEBS Open Bio

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A major obstacle to effective cancer immunotherapy is the tumor immune microenvironment. Natural killer (NK) cell resistance has been suggested as a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which seemingly correlates with CNOT7 overexpression. CNOT7, a cytoplasmic mRNA deadenylase that is highly expressed in HCC, may regulate cytokine transforming growth factor‐β1 (TGF‐β1) secretion by controlling nuclear factor‐κB subunit p65 trafficking. CNOT7 depletion suppresses TGF‐β1 secretion in HCC and promotes interferon‐γ (IFN‐γ) secretion by NK cells, and we previously demonstrated that CNOT7 depletion reversed IFN‐γ resistance in HCC cells. Therefore, we hypothesized that CNOT7 depletion might reverse NK cell resistance by influencing the tumor immune microenvironment of HCC. To test this hypothesis, we examined the correlation between CNOT7, STAT1, TGF‐β1 and IFN‐γ expression with hepatitis B virus‐related cirrhosis and HCC with hepatitis B virus‐related cirrhosis. We found that modulation of CNOT7 expression alters TGF‐β1 secretion in HCC and IFN‐γ secretion in NK cells. We also examined the effects of NK cells in HepG2 cells with CNOT7 knockdown, which showed that NK cell surface CD107a expression is up‐regulated and caspase‐3 expression is significantly enhanced in CNOT7‐deficient HepG2 cells. Overall, our results show that knockdown of CNOT7 expression reverses NK cell resistance in HCC cells. Therefore, CNOT7 depletion has potential as a new adjuvant therapy in immunotherapy for HCC.

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Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma

Cited by 185 publications

References 83 publications

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

Molecular mechanisms of circular RNAs, transforming growth factor‐β, and long noncoding RNAs in hepatocellular carcinoma

CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma

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