ArticleCancers2021
Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness.
Article in Cancers, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 18 citations in OpenAlex.
- Computational discovery of emodin-based anthraquinones as PARP-1 inhibitors with relevance to ovarian and prostate cancer.Scientific reports · 2026Article
- Nanocarrier-mediated targeting of NF-κB and JAK/STAT signaling pathways in hepatocellular carcinoma: mechanisms and therapeutic strategies.Journal of experimental & clinical cancer research : CR · 2026Review
- Interferon-primed immune landscapes predict immune-related adverse events during immune checkpoint inhibitor therapy.Frontiers in cell and developmental biology · 2026Article
- The role of mitochondrial DNA and RNA in promoting liver disease pathogenesis.Frontiers in cell and developmental biology · 2026Review
- A comprehensive review of immunotherapy in gastrointestinal tumors with a focus on the role of combination therapy with PARP inhibitors.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Cancer stem cells in hepatocellular carcinoma: therapy resistance and emerging treatments.Frontiers in immunology · 2025Review
- FDA greenlights momelotinib (Ojjaara) as the exclusive treatment for myelofibrosis patients battling anemia.Annals of medicine and surgery (2012) · 2024Article
- Cancer stem cells: advances in knowledge and implications for cancer therapy.Signal transduction and targeted therapy · 2024Review
- HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma.Journal of translational medicine · 2024Article
- Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications.International journal of molecular sciences · 2023Review
- Ubiquilin 1 suppresses the cancer stem cell-like traits of non-small cell lung cancer cells by regulating reactive oxygen species homeostasis.Bioengineered · 2021Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundHepatitis virus is a major risk factor for liver cancer. The mitochondrial dysfunction IFN gamma-related pathways are activated after virus infection. Jak family-related protein is involved in the downstream of IFN gamma-related pathways. However, the effect of the IFNGR-JAK-STAT pathway acting as functional regulators of their related protein expression on virus infection and hepatocellular carcinoma (HCC) remains unclear. Interestingly, the role of the DNA repair gene (PARP1) in therapy resistant cancers also has not been studied and explored well. In this study, we hypothesized that momelotinib could suppress the progression of HCC by targeting Jak family related and PARP1 DNA repair protein. Based on this observation, we link the relevant targets of the JAK family and the potential applications of targeted therapy inhibitors.
methodsWe analyzed possible synergism between momelotinib and sorafenib in hepatitis virus-associated liver cancer. Immunostaining, colony formation assay, cell invasion, migration, and tumorsphere-formation assay were used for drug cytotoxicity, cell viability, and possible molecular mechanism.
resultWe first demonstrated that the expression of Jak1 and 2 is significantly upregulated in vHCC than in nvHCC/normal liver tissues. In addition, the gene expression of IFN gamma-related pathways is activated after virus infection. Additionally, we found that momelotinib significantly inhibited the growth of HCC cells and reduces the expression of Jak2, which showed the importance of momelotinib in targeting Jak2 and reducing tumorigenesis in HCC. Meanwhile, momelotinib effectively inhibited the IFNGR-JAK-STAT pathway and reduced the migratory/invasive ability of vHCC cells through down-regulating EMT biomarkers (E-cadherin and vimentin), transcription factor (Slug), and significantly inhibits the DNA damage repair enzyme PARP1. It also induced cell apoptosis of vHCC cells. Furthermore, the combined effect of momelotinib and sorafenib both at in vitro and in vivo synergistically suppresses the proliferation of vHCC cells and effectively reduces the tumor burden.
conclusionsOur results showed that momelotinib effectively suppressed the expression of the IFNGR-JAK-STAT-PARP1 pathway, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes and inhibiting the DNA repair gene in vHCC cells, thus maximizing its therapeutic potential for patients with HCC.
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