Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production

Myojin, Yuta; Hikita, Hayato; Sugiyama, Masaya; Sasaki, Yōichi; Fukumoto, Kenji; Sakane, Sadatsugu; Makino, Yuki; Takemura, Nobuyuki; Yamada, Ryotaro; Shigekawa, Minoru; Kodama, Tatsuhiko; Sakamori, Ryotaro; Kobayashi, Shogo; Tatsumi, Tomohide; Suemizu, Hiroshi; Eguchi, Hidetoshi; Kokudo, Norihiro; Mizokami, Masashi; Takehara, Tetsuo

doi:10.1053/j.gastro.2020.12.015

Cited by 111 publications

(84 citation statements)

References 57 publications

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“…Like other members of the TGF-β superfamily, the effect of GDF15 depends on the cellular environment, the stage of the disease, and the microenvironment. At present, many studies have reported that GDF15 is upregulated in many disease processes such as heart failure ( 8 , 9 ), myocardial infarction ( 10 ), pulmonary embolism ( 11 ), liver injury ( 12 ), and so on. It may be used as a biomarker for these diseases in the future.…”

Section: Introductionmentioning

confidence: 99%

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Tang

Chen

et al. 2021

Front. Immunol.

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Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro, we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.

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Section: Introductionmentioning

confidence: 99%

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Tang

Chen

et al. 2021

Front. Immunol.

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“…In this study, "HomoloGene" and phylogenetic tree analysis data con rmed the conservation of the GDF15 protein structure across different species, suggesting that similar mechanisms might exist for the normal physiological role of GDF15. Emerging studies have reported a functional link between GDF15 and clinical diseases, especially tumors (Ratnam et al, 2017;Lodi et al, 2021;Myojin et al, 2021). Whether GDF15 can play a role in the pathogenesis of different tumors through certain common molecular mechanisms remains to be answered.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

Huai

Zhu

et al. 2021

Preprint

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Background Growth/differentiation factor 15 (GDF15) is a member of the TGF-b superfamily whose expression is increased in response to cellular stress and disease. Although emerging cell-or animal-based evidence supports the relationship between GDF15 and cancers, systematic pan-cancer analysis of GDF15 remains unavailable. Thus, we aimed to explore the prognostic and immunological roles of GDF15 across different types of tumors. Methods A comprehensive analysis of GDF15 in 33 types of cancer was performed based on the TCGA database. This involved an analysis of mRNA expression profiles, genetic alterations, methylation, prognostic values, immune infiltration analysis, potential biological pathways. Moreover, both the gain and loss of function strategies were used to assess the function of GDF15 in cell lines of hepatocellular carcinoma (HCC). Results GDF15 is highly expressed in most types of cancers, and there is a significant correlation between the expression of GDF15 and the prognosis of cancer patients. We have observed that GDF15 promotes the proliferation and invasion of HCC cell lines. Subsequently, methylation analyses suggested that high GDF15 expression likely resulted from hypomethylation, and immune infiltration analysis showed that GDF15 may have an impact on the changes in the tumor microenvironment. Moreover, enrichment analysis revealed that TGF-beta signaling and metabolism pathways were involved in the functional mechanisms of GDF15. Conclusions Our unpresented pan-cancer analysis of GDF15 offers a relatively comprehensive overview of the oncogenic roles of GDF15 in multiple human cancers. GDF15 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of GDF15 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

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“…Autophagy in HSCs leads to their activation through the upregulation of autophagy-related 7 (ATG7), thereby promoting fibrosis. Activated HSCs accelerate tumor growth and progression by releasing GDF15 in an autophagy-dependent manner [67].…”

Section: Cell Non-autonomous Signalingmentioning

confidence: 99%

Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

Nga

Tian

2021

Cells

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPRmt). The mitokines FGF21 and GDF15 are upregulated during UPRmt and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.

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Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production

Cited by 111 publications

References 57 publications

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis

Pan-cancer characterization of GDF15 as a potential prognosis and immunological biomarker

Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

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