This key protein is released to promote obesity-related liver cancer progression

In recent years, non-alcoholic fatty liver disease (NAFLD) has become a growing epidemic with the unhealthy lifestyle of people.

A significant number of patients with non-alcoholic fatty liver disease will develop non-alcoholic steatohepatitis (NASH). These two liver diseases are significant risk factors for hepatocellular carcinoma (HCC) which is the most common histological subtype of liver cancer, accounting for roughly 90% of primary liver cancers and being the third leading cause of cancer-related death worldwide. However, other than eating a healthy diet and exercising, there has been no particularly effective treatment.

Researchers previously discovered that fibroblasts known as hepatic stellate cells (HSCs) age in the liver tumor microenvironment associated with obesity. This causes them to develop an aging-related secretory phenotype that releases a variety of tumor-promoting factors, but it is unclear how this process affects tumor development.

On June 25, 2022, researchers from Osaka City University in Japan published a paper in Science Immunology, a sub-journal of Science, titled Gasdermin D–mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma.

Cellular senescence is a permanent state of cell cycle arrest, which is a tumor suppressor mechanism induced by a variety of cellular stresses, including persistent DNA damage. Although senescent cells no longer proliferate, they do express a variety of secreted proteins, including inflammatory cytokines, chemokines, and proteases, resulting in the senescence-associated secretory phenotype.

Senescence-associated secretory phenotype (SASP) is a highly context-dependent phenotype that either plays a beneficial role in promoting immune system clearance of senescent cells and tissue repair, or it plays a detrimental role in promoting malignant transformation of normal tissue cells and tumor cell invasion and metastasis. However, the interaction of multiple SASP factors and their release mechanisms are unknown, particularly when a number of factors are produced concurrently in senescent cells.

To discover this mechanism, the researchers investigated obesity-induced liver cancer in a high-fat diet-fed mouse model of liver cancer. They began with a thorough gene expression analysis to determine which SASP factors are produced by hepatic stellate cells, and then looked into how they are released.

The researchers found that the SASP factor interleukin-1? (IL-1?) and the IL-1?-dependent cytokine IL-33 are two key tumor-promoting factors for liver cancer growth. Their release is triggered by lipoteichoic acid (LTA).

IL-1 is a cytokine cascade upstream regulator that plays an important role in the development of hepatocellular carcinoma. In the obesity-associated liver tumor microenvironment, IL-33 is upregulated in senescent hematopoietic stem cells and cleaved by chymotrypsin elastase family member 1 (CELA1). Due to gut barrier dysfunction caused by a high-fat diet, lipoteichoic acid is highly accumulated in the liver of obese mice, inducing senescent hepatic stellate cells to stimulate the cleavage of Gasdermin D protein (GSDMD), followed by cysteine aspartate Amino acid protease-11 (Caspase-11) cleaves the cell membrane pores formed at the end of GSDMD to release active IL-1? and IL-33. Once IL-33 is released, they activate receptor-positive regulatory T cells, suppressing the immune response to cancer cells, thereby exacerbating cancer development.

Therefore, targeting IL-33 released from senescent cells may be an effective therapy for hepatocellular carcinoma.

Professor Naoko Ohtani of Osaka City University, the study's corresponding author, noted that understanding this mechanism is a significant step forward in the fight against cancer in humans. This research uncovered an intriguing mechanism by which tumor-promoting senescence-associated secretory phenotype factors are released via cell membrane pores stimulated by gut microbial components. Inhibiting pore formation will aid in the development of effective treatments and prevention strategies for patients with NAFLD-related liver cancer.

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