Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model

Attia, Yasmeen M.; Tawfiq, Rasha A.; Gibriel, Abdullah Ahmed; Ali, Aya; Kassem, Dina H.; Hammam, Olfat; Elmazar, Mohamed M.

doi:10.1016/j.bcp.2021.114497

Cited by 24 publications

(17 citation statements)

References 59 publications

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“…In contrast, metabolic pathway regulators involved in homeostatic maintenance of normal liver function, particularly bile acid metabolism as indicated by fibroblast growth factor 19 (FGF19) ( 18 ) and FGF21 ( 22 ) and nuclear receptor signaling, for example, the farnesoid X receptor (FXR) pathway, were down-regulated in association with high-risk PLS-NAFLD. A transcriptional target gene signature of an FXR agonist, obeticholic acid ( 23 ), was also suppressed, suggesting that patients with high-risk PLS-NAFLD prediction may be candidates for obeticholic acid treatment. Despite no prognostic association with histological inflammation grade (table S2), PLS-NAFLD encoded diverse inflammatory pathways.…”

Section: Resultsmentioning

confidence: 99%

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease

et al. 2022

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Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)–NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 + dendritic cells and dysfunctional CD8 + T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

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Section: Resultsmentioning

confidence: 99%

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease

et al. 2022

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“…Obeticholic acid (OCA) is the most advanced FXR agonist under development (currently in phase 3 trials) and has been shown to prevent fibrotic progression in NASH in a phase 3 trial 239 . Interestingly, the intestinal/systemic activation of FXR also prevents HCC development in murine models of J o u r n a l P r e -p r o o f cholestasis 237,240,241 and NASH 242 , and might interfere with HCC progression 243 but clinical effectiveness of OCA on HCC prevention/treatment is yet to be clearly established.…”

Section: Strategies Aimed At Reversing Metabolic Dysfunction and Canc...mentioning

confidence: 99%

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions

Leslie

Geh

Elsharkawy

et al. 2022

Journal of Hepatology

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“…FXR may also have anti-tumorigenic effects, as FXR knockout mice spontaneously develop HCC when they age [132,133]. In turn, FXR agonists may reduce tumor burden in preclinical models of CCC and NASH dependent HCC [134][135][136][137].…”

Section: Bile Acid Signalingmentioning

confidence: 99%

Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies

Lee

Friedman

2021

J Intern Med

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Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model

Cited by 24 publications

References 59 publications

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions

Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies

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