The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity

Papadakos, Stavros P.; Dedes, Nikolaos; Kouroumalis, Elias; Theocharis, Stamatios

doi:10.3390/cancers14133150

Cited by 19 publications

(18 citation statements)

References 101 publications

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“…In its early phases, the immune system can suppress it via NLRP3 inflammasome activation and IL-18 secretion which in turn can trigger the NK cells to exert their cytotoxic potential against cancer cells. Nevertheless, continuous unprovoked activation of this inflammasome and presence of IL-1β in the tumor microenvironment can attract immunosuppressive cells including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) as well as regulatory T cells (Tregs) which promote tumor invasion and metastasis [ 27 ]. HCC typically originates on the top of chronic hepatic inflammation which is almost accompanied by a massive loss of hepatocytes and irreversible liver damage.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

et al. 2023

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it mostly arises as a consequence of persistent chronic inflammation. Recently, NLRP3 inflammasome has caught the attention of many research groups due to its involvement in different types of cancer. However, its direct role in HCC remains elusive. Our study aimed to evaluate the role of NLRP3 inflammasome and pyroptosis in HCC and to clarify the potential mechanism by which 17β-estradiol (E2) can be used as a protective factor against HCC. NLRP3, caspase-1 (CASP1) as well as gasdermin-D (GSDMD) mRNA expression levels were assessed in human HCC tissues and adjacent non-cancerous liver tissues. Also, HepG2 HCC cells were cultured and treated with E2, followed by detection of the mRNA levels of these three genes. Our results revealed that NLRP3, CASP1, and GSDMD mRNA expressions were significantly lower in HCC tissues than in controls, and this under-expression was closely correlated with advanced HCC stages and grades. In contrast, HepG2 HCC cells displayed significantly higher expression levels of NLRP3 inflammasome components and GSDMD in the two E2-treated groups compared to the untreated group. Also, NLRP3, CASP1, and GSDMD mRNA expression levels were positively correlated with each other. This study confirmed that lack of NLRP3 inflammasome is involved in HCC progression and 17β-estradiol-induced activation of NLRP3 inflammasome may be effective in HCC treatment as it inhibited tumor cell growth and proliferation by triggering CASP1-dependent pyroptosis in HCC cells.

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Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

et al. 2023

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“…Cleavage by caspase-1 turns pro-cytokines into mature IL-1β and IL-18, while the cleavage of gasdermin D leads to a programmed cell death called pyroptosis. In this canonical activation of pyroptosis, fragments of gasdermin D form pores in the plasma membrane, killing the cell and releasing IL-1β and IL-18, which aggravates inflammation [ 34 , 35 ].…”

Section: Pathogenesis Of Hccmentioning

confidence: 99%

“…Autophagy and inflammasomes are interconnected as the same mechanisms regulate them, but through different pathways. The NLRP3 inflammasome activated by DAMPS induces caspase-1, leading to pyroptosis, as mentioned above [ 34 , 35 ].…”

Section: Autophagymentioning

confidence: 99%

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

2023

Self Cite

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The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.

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“…For instance, targeting Toll-like receptor 4 (TLR4) holds potential, given its significant role in orchestrating the immune response against HCC cells [ 183 ]. Similarly, activation of the NLRP3 inflammasome has demonstrated the ability to suppress HCC growth in murine xenograft models [ 184 ]. Hence, the combination of ICIs with TLR4 inhibitors or NLRP3 activators is poised to emerge as a promising immunotherapeutic approach for HCC.…”

Section: Perspectives and Conclusionmentioning

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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The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity

Cited by 19 publications

References 101 publications

NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy

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

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