GPR43 regulates HBV X protein (HBx)-induced inflammatory response in human LO2 hepatocytes

He, Tao; Zhang, Ning; Wang, Li; Wan, Baishun; Wang, Xiaoqian; Zhang, Ling

doi:10.1016/j.biopha.2019.109737

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…[1][2][3] Viral infections and liver fibrosis are the most common risk factors for HCC. [4][5][6] Although surgical resection and liver transplantation have been developed to treat HCC, postoperative survival of HCC patients is still not ideal due to high recurrence and rate of metastasis of HCC. [7][8][9] Therefore, there is an urgent need to understand the mechanisms underlying the initiation and development of HCC.…”

Section: Introductionmentioning

confidence: 99%

<p>KIAA1522 Promotes the Progression of Hepatocellular Carcinoma via the Activation of the Wnt/β-Catenin Signaling Pathway</p>

Jiang

Zhang

et al. 2020

OTT

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KIAA1522 was previously identified to play a crucial role in cancer development and progression. However, its functions and underlying mechanisms in hepatocellular carcinoma (HCC) remain elusive. Materials and Methods: To elucidate the role of KIAA1522 in HCC, its expression was assessed using The Cancer Genome Atlas and GEPIA databases. Next, these results were validated by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry of HCC tissues and cell lines. Flow cytometry, CCK-8, EDU, colony formation, Transwell invasion, and wound healing assays were performed to explore the function of KIAA1522 in HCC in vivo and in vitro. Finally, gene set enrichment analysis was used to identify the pathways involved. Results: Our results demonstrated that KIAA1522 was highly expressed in HCC tissues and cell lines. Furthermore, KIAA1522 overexpression was associated with unfavorable clinicopathological characteristics. Survival analyses revealed that KIAA1522 overexpression predicted lower recurrence-free and overall survival rates in patients with HCC. Functional studies suggested that KIAA1522 facilitated HCC proliferation, migration, and invasion both in vitro and in vivo. Moreover, KIAA1522 up-regulated the Wnt/β-catenin signaling pathway, as confirmed by TOP-flash/FOP-flash luciferase reporter assays and Western blotting. Conclusion: In conclusion, we highlighted the oncogenic role of KIAA1522 in HCC and determined its potential as a therapeutic target for HCC.

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Section: Introductionmentioning

confidence: 99%

<p>KIAA1522 Promotes the Progression of Hepatocellular Carcinoma via the Activation of the Wnt/β-Catenin Signaling Pathway</p>

Jiang

Zhang

et al. 2020

OTT

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“…Since HBX could alter the levels of some cytokines, such as IL-6, IL-18 and MCP-1, 16 , 17 the level of cytokines IFN-α2, INF-γ, TNF-α, MCP-1, IL-18, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23 and IL-33 were assessed among these groups in HepG2 cells among these groups ( Figure S2 ). The levels of the two cytokines, MCP-1 and IL-18, were found to be significantly different among these groups.…”

Section: Resultsmentioning

confidence: 99%

“… 46 The excessive production of ROS triggers the release of MCP-1 by inhibiting the phosphorylation of p38 and activating of the IκBα/NF-κB pathway. 17 The C1653T mutant-induced MCP-1 overexpression might contribute to the enhanced malignancy observed in these cells through the aforementioned mechanism. IL-18 is a member of the IL-1 family and is associated with hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Nonsynonymous C1653T Mutation of Hepatitis B Virus X Gene Enhances Malignancy of Hepatocellular Carcinoma Cells

Zhang¹,

Xie²,

Lai³

et al. 2022

JHC

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Purpose Functional analysis was performed to elucidate the mechanism by which hepatocellular carcinoma (HCC) outcome-associated mutation in the hepatitis B virus X ( HBx ) gene modifies the HCC process. Methods Proliferation, invasion, migration, and apoptosis assays were performed, and changes in fibrosis, intracellular reactive oxygen species (ROS), and cytokine levels were measured. The differences between variables were evaluated by Student’s t -test. Results The influence of two previously identified nonsynonymous mutation, C1653T and T1753C, on HCC cells was assessed. With regard to HBX-induced promotion of proliferation (p < 0.01), invasion (p < 0.01) and migration (p < 0.01), the C1653T mutation displayed a significant additive effect in these assays (P < 0.05). The subsequent apoptosis assay indicated that HBX could inhibit apoptosis (P < 0.01), whereas the C1653T mutation markedly amplified this effect in HCC cells (P < 0.01). Furthermore, the tumor growth-promoting effect of HBX was confirmed in a mouse xenograft model of HCC (P < 0.05), and the C1653T mutation was observed to amplify this effect (P < 0.05). To further investigate the mechanism by which the C1653T mutation enhances malignancy in HCC cells, fibrosis, intracellular ROS, and cytokine levels were measured. The C1653T mutant increased fibrosis and intracellular ROS level, and altered monocyte chemotactic protein-1 and interleukin-18 expression in HepG2 cells. Drug sensitivity test revealed that the C1653T mutation is sensitive to apatinib treatment and that overexpression of vascular endothelial growth factor might be involved in this process. Conclusion Our data indicate that the C1653T mutation of HBx promotes HCC malignancy by altering the levels of fibrosis, ROS, and some cytokines. This mutation could serve as a potential biomarker for screening HCC patients to determine apatinib treatment efficacy.

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“…In CLD, HBx expression and activity are stimulated in an environment where active immune responses trigger persistent oxidative stress [ 40 ]. HBx also promotes oxidative stress through the expression of pro-inflammatory cytokines [ 41 ] and is inhibited when oxidative stress is reduced [ 42 ]. Further, stimulation of GPR43, which binds to multiple SCFAs (acetate, propionate, and butyrate), blocks the ability of HBx to stimulate NF-κB [ 43 ], thereby attenuating these pro-inflammatory and pro-carcinogenic signaling pathways [ 43 , 44 ].…”

Section: Chronic Inflammation and “Prevention By Delay”mentioning

confidence: 99%

Short-chain fatty acids in cancer pathogenesis

Feitelson

Arzumanyan

Medhat

et al. 2023

Cancer Metastasis Rev

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Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of “health,” is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a “leaky gut,” permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.

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GPR43 regulates HBV X protein (HBx)-induced inflammatory response in human LO2 hepatocytes

Cited by 7 publications

References 29 publications

<p>KIAA1522 Promotes the Progression of Hepatocellular Carcinoma via the Activation of the Wnt/β-Catenin Signaling Pathway</p>

<p>KIAA1522 Promotes the Progression of Hepatocellular Carcinoma via the Activation of the Wnt/β-Catenin Signaling Pathway</p>

Nonsynonymous C1653T Mutation of Hepatitis B Virus X Gene Enhances Malignancy of Hepatocellular Carcinoma Cells

Short-chain fatty acids in cancer pathogenesis

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