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 21 publications

(16 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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“…For instance, SOCS3/JAK2/STAT3 signaling axis mediates the inhibitory role of piperlongumine in the progression of osteosarcoma [ 35 ]. SOCS3/JAK2/STAT3 signaling pathway also regulates the malignant progression of hepatocellular carcinoma [ 36 ]. Furthermore, the dysregulation of SOCS3/JAK2/STAT3 signal axis is associated with epithelial-mesenchymal transition (EMT) and metastatic ability of gallbladder cancer cells [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

LINC00893 inhibits the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway

Fan

Liu

et al. 2022

Cancer Cell Int

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Background Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 was reported to inhibit the proliferation and metastasis of papillary thyroid cancer cells, but its role in PCa has not been reported. This study aims to investigate the role and underlying mechanism of LINC00893 in regulating the progression of PCa cells. Methods We first compared LINC00893 expression levels between PCa tissues and normal prostate tissues through TCGA database. The relative LINC00893 expression levels were further validated in 66 pairs of PCa tissues and para-cancerous normal tissues, as well as in PCa cell lines. Gain-of-function experiment was performed by transfecting PCa cell with LINC00893 expression vector, and CCK (Cell count kit)-8, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, colony information and transwell assays were conducted to assess the functional phenotypes. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull-down assays were performed to evaluate the molecular interactions. Results LINC00893 was downregulated in PCa tissues and cell lines, and patients with low expression of LINC00893 were associated with a poorer overall survival rate. LINC00893 overexpression hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as the migratory ability of PCa cells, and suppressed the tumorigenesis of PCa cells in nude mice. We further demonstrated that LINC00893 acted as a sponge for miR-3173-5p and inhibited its activity, which in turn regulated the suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. Conclusions Our study demonstrated that LINC00893 suppresses the progression of PCa cells through targeting miR-3173-5p/SOCS3/JAK2/STAT3 axis. Our data uncovers a novel tumor-suppressor role of LINC00893 in PCa, which may serve as a potential strategy for targeted therapy in PCa. Grapical Abstract

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

Cited by 21 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

LINC00893 inhibits the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway

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

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