Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

Yang, Shaojie; Pang, Liwei; Dai, Weijie; Wu, Shuodong; Ren, Tengqi; Duan, Yunlong; Zheng, Yuting; Bi, Shiyuan; Zhang, Xiaolin; Kong, Jing

doi:10.3389/fonc.2021.667730

Cited by 22 publications

(18 citation statements)

References 143 publications

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“…FOXOs function by integrating signals such as growth factors, oxidative stress, and other stimulatory signals to induce gene expression of downstream targets involved in cell cycle, metabolism, apoptosis, DNA damage, oxidative stress, and stem cell differentiation. An important regulator of FOXO is insulin signaling, which through Akt leads to FOXO1 and FOXO3 phosphorylation, binding to 14-3-3 proteins, translocation to the cytoplasm, and subsequent dissociation from 14-3-3 for ubiquitination and degradation, to inhibit FOXO-mediated transcription [ 55 , 56 ].…”

Section: The Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

“…FOXO1 and FOXO3 are the main FOXO proteins that contribute to HCC tumorigenesis and progression [ 55 ]. In HCC, hyperactive Akt signaling inhibits FOXO1 transcriptional activity, weakens defense against oxidative stress, and as FOXO1 normally suppresses the expression of epithelial mesenchymal transition (EMT)-inducing transcription factors and transforming growth factor-β (TGF-β), leads to subsequent EMT and increased HCC cell migration and invasion [ 57 ].…”

Section: The Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

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Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

et al. 2021

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Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.

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Section: The Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Section: The Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

et al. 2021

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“…As discussed earlier, the FoxO–Smad complex can block the G1/S transition by regulating the activities of the cyclin D and CDK axis. Numerous studies indicate that activated PI3K/Akt signaling phosphorylates FoxO transcription factors and prevents FoxO–Smad complex formation, effectively blunting the cytostatic responses of TGF-β [ 68 , 202 ]. Finally, the CXXC5 and KLF17 transcription factors potentiate TGF-β signaling and cytostatic responses via a positive feedback loop.…”

Section: The Role Of Tgf-β Signaling In Hccmentioning

confidence: 99%

The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications

Gungor

Uysal

Şentürk

2022

Cancers

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Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.

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“…108). A variety of multifunctional proteins have been proposed to contribute to HCC development, progression, metastasis and recurrence such as midkine, forkhead box O and osteopontin (Refs 109, 110, 111). Although great efforts have been carried out with respect to therapeutic strategy and supportive management for patients with HCC, such as surgery, chemotherapy, interventional therapy, immunotherapy and liver transplantation, the survival rate remains approximately 3–5% in developed countries.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties

Wang

Mao²,

Li³

et al. 2022

Expert Rev. Mol. Med.

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Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein and the precursor of irisin, which serves as a systemic exerkine/myokine with multiple origins. Since its discovery in 2012, this hormone-like polypeptide has rapidly evolved to a component significantly involved in a gamut of metabolic dysregulations and various liver diseases. After a decade of extensive investigation on FNDC5/irisin, we are still surrounded by lots of open questions regarding its diagnostic and therapeutic values. In this review, we first concentrated on the structure–function relationship of FNDC5/irisin. Next, we comprehensively summarised the current knowledge and research findings regarding pathogenic roles/therapeutic applications of FNDC5/irisin in the context of non-alcoholic fatty liver disease, fibrosis, liver injury due to multiple detrimental insults, hepatic malignancy and intrahepatic cholestasis of pregnancy. Moreover, the prominent molecules involved in the underlying mechanisms and signalling pathways were highlighted. As a result, emerging evidence reveals FNDC5/irisin may act as a proxy for diagnosing liver disease pathology, a sensitive biomarker for assessing damage severity, a predisposing factor for surveilling illness progression and a treatment option with protective/preventive impact, all of which are highly dependent on disease grading and contextually pathological features.

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Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

Cited by 22 publications

References 143 publications

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications

The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties

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