Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness

Cherng, Yih-Giun; Chu, Yi Cheng; Yadav, Vijesh Kumar; Huang, Ting; Hsieh, Ming Shou; Lee, Kwai Fong; Lee, Wei Hwa; Yeh, Chi Tai; Ong, Jiann Ruey

doi:10.3390/cancers13112755

“…Application of etomidate to HCC cells (HepG2 and Huh-7) suppressed phosphorylation of JAK2 and STAT3, resulting in the inhibition of cell proliferation, migration, and invasion, coupled with enhanced apoptosis [ 152 ]. Similarly, momelotinib, another small-molecule JAK2 inhibitor, suppressed phosphorylated JAK2 and STAT3 levels upon treatment of HCC cells (SNU-378 and SNU-475), subsequently leading to reduced cell viability, migration, and invasion [ 153 ].…”

Section: In Vitro and In Vivo Studies Targeting The Jak/stat Signalin...mentioning

confidence: 99%

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Park,

Lee,

Lee

et al. 2023

IJMS

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

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“…Application of etomidate to HCC cells (HepG2 and Huh-7) suppressed phosphorylation of JAK2 and STAT3, resulting in the inhibition of cell proliferation, migration, and invasion, coupled with enhanced apoptosis [128]. Similarly, momelotinib, another small-molecule JAK2 inhibitor, suppressed phosphorylated JAK2 and STAT3 levels upon treatment of HCC cells (SNU-378 and SNU-475), subsequently leading to reduced cell viability, migration, and invasion [129].…”

Section: In Vitro Studies Targeting the Jak/stat Signaling Pathway In...mentioning

confidence: 99%

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Park,

Lee,

Lee

et al. 2023

Preprint

3

0

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

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“…PARP1 has been reported to be involved in a variety of biological processes, such as chromatin strengthening, stress signaling, cell survival/death, inflammation, drug resistance, and differentiation [ 16 , 17 ]. PARP1 also functions as a sensor of oxidative stress and PARP1 inhibitors have been shown to enhance the sensitivity of cancer cells to chemotherapy [ 18 ]. In addition, PARP1 regulates STAT3 [ 19 ] negatively, one of the most important transcription factors of PD-L1.…”

Section: Introductionmentioning

confidence: 99%

HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma

Jia,

Zhao,

Wang

et al. 2024

J Transl Med

4

0

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Background In HBV-associated HCC, T cells often exhibit a state of functional exhaustion, which prevents the immune response from rejecting the tumor and allows HCC to progress. Moreover, polymerase-specific T cells exhibit more severe T-cell exhaustion compared to core-specific T cells. However, whether HBV DNA polymerase drives HBV-specific CD8+ T cell exhaustion in HBV-related HCC remains unclear. Methods We constructed a Huh7 cell line stably expressing HA-HBV-DNA-Pol and applied co-culture systems to clarify its effect on immune cell function. We also examined how HBV-DNA-Pol modulated PD-L1 expression in HCC cells. In addition, HBV-DNA-Pol transgenic mice were used to elucidate the underlying mechanism of HBV-DNA-Pol/PD-L1 axis-induced T cell exhaustion. Results Biochemical analysis showed that Huh7 cells overexpressing HBV-DNA-Pol inhibited the proliferation, activation, and cytokine secretion of Jurkat cells and that this effect was dependent on their direct contact. A similar inhibitory effect was observed in an HCC mouse model. PD-L1 was brought to our attention during screening. Our results showed that the overexpression of HBV-DNA-Pol upregulated PD-L1 mRNA and protein expression. PD-L1 antibody blockade reversed the inhibitory effect of Huh7 cells overexpressing HBV-DNA-Pol on Jurkat cells. Mechanistically, HBV-DNA-Pol interacts with PARP1, thereby inhibiting the nuclear translocation of PARP1 and further upregulating PD-L1 expression. Conclusions Our findings suggest that HBV-DNA-Pol can act as a regulator of PD-L1 in HCC, thereby directing anti-cancer immune evasion, which further provides a new idea for the clinical treatment of liver cancer.

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Induced Mitochondrial Alteration and DNA Damage via IFNGR-JAK2-STAT1-PARP1 Pathway Facilitates Viral Hepatitis Associated Hepatocellular Carcinoma Aggressiveness and Stemness

Cited by 14 publications

References 38 publications

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma

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