Prevention Strategies for Hepatocellular Carcinoma

Erstad, Derek J.; Razavi, Allen; Шен, Ли; Tanabe, Kenneth K.; Fuchs, Bryan C.

doi:10.1007/978-3-030-21540-8_13

Cited by 6 publications

(7 citation statements)

References 222 publications

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“…Hepatocellular carcinoma is associated with persistent liver damages due to viral infections, environmental chemicals, excess alcohol consumption, and metabolic syndrome, such as non-alcoholic steatohepatitis, and is manifested by liver fibrosis or cirrhosis ( Erstad et al., 2019 ; Mishra et al., 2009 ; Yang et al., 2019 ). PTEN has been shown to be mutated or lost in up to 30% of hepatocellular carcinoma ( Khalid et al., 2017 ; Parikh et al., 2010 ).…”

Section: Discussionmentioning

confidence: 99%

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The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma

et al. 2020

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Summary The PTEN gene is highly mutated in many cancers, including hepatocellular carcinoma. The PTEN protein is located at different subcellular regions—PTEN at the plasma membrane suppresses PI3-kinase signaling in cell growth, whereas PTEN in the nucleus maintains genome integrity. Here, using nuclear PTEN-deficient mice, we analyzed the role of PTEN in the nucleus in hepatocellular carcinoma that is induced by carcinogen and oxidative stress-producing hepatotoxin. Upon oxidative stress, PTEN was accumulated in the nucleus of the liver, and this accumulation promoted repair of DNA damage in wild-type mice. In contrast, nuclear PTEN-deficient mice had increased DNA damage and accelerated hepatocellular carcinoma formation. Both basal and oxidative stress-induced localization of PTEN in the nucleus require ubiquitination of lysine 13 in PTEN. Taken together, these data suggest the critical role of nuclear PTEN in the protection from DNA damage and tumorigenesis in vivo .

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Section: Discussionmentioning

confidence: 99%

“…Thus, nuclear PTEN functions as a tumor suppresser and protects against oxidative stress-induced hepatocellular carcinoma in vivo. (Erstad et al, 2019;Mishra et al, 2009;Yang et al, 2019). PTEN has been shown to be mutated or lost in up to 30% of hepatocellular carcinoma (Khalid et al, 2017;Parikh et al, 2010).…”

Section: Ll Open Access Isciencementioning

confidence: 99%

The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma

et al. 2020

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“…It is thus conceivable that persistent HCV-induced signaling alterations and deranged cytokine production may promote the development of extrahepatic manifestations in immune cells [148]. Several compounds targeting these signaling pathways have been suggested for chemoprevention of HCC (reviewed in detail in [149,150]) and targeting HCV-relevant pathways to treat established HCC have been suggested [151][152][153]. Therefore, learning from HCV-induced liver disease will help to develop novel diagnostics and personalized therapeutic concepts that may be useful to prevent and potentially also to treat HCC from other related liver disease etiologies like NAFLD.…”

Section: Clinical Implications For Biomarker Discovery To Predict Hcvmentioning

confidence: 99%

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Goto

Suarez

Wrensch

et al. 2020

IJMS

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Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.

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“…Chronic hepatic injury and inflammation, regardless of its etiology, results in an unresolved wound healing process, which paves the way for liver cancer development [ 92 , 93 ]. Pharmacological interference with this dysregulated wound healing response may restore liver parenchymal architecture and function and prevent tumor development [ 94 ]. Here we have identified CM414, a first-in-class multi-targeted small molecule inhibitor as a potential tool to explore new anti-fibrogenic therapeutic avenues.…”

Section: Discussionmentioning

confidence: 99%

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

Clavería-Cabello

Colyn

Uriarte

et al. 2020

Cancers

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Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.

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Prevention Strategies for Hepatocellular Carcinoma

Cited by 6 publications

References 222 publications

The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma

The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

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