Porous cells lead to poorer livers

High-fat diets weaken the intestinal barrier function, leading to the migration and accumulation of lipoteichoic acid in the liver. Accumulated lipoteichoic acid stimulates cleavage of the gasdermin D protein, forming cell membrane pores where SASP factors IL-1β and IL-33 are released from hepatic stellate cells. IL-33 activates regulatory T cells that suppress the immune response, thereby accelerating cancer development. Credit: Osaka Metropolitan University

Need another reason to think twice about ordering that extra portion of fries? This could lead to a higher risk of developing liver cancer. Cases of non-alcoholic steatohepatitis (NASH) – a type of fatty liver disease that could also lead to cancer – are on the rise and treatment remains elusive. A research group led by Osaka Metropolitan University has taken a potential step towards suppressing and treating NASH-associated liver cancer with their research in obese mice that explains the importance of pore-secreted proteins of the cell membrane formed in cells near cancer cells in the tumor microenvironment for the development of cancer. Their findings were published in Sciences Immunology.

While cancer cells themselves are obviously detrimental, neighboring cells, including cancer-associated fibroblasts in a so-called “tumor microenvironment”, may also play a role in cancer development. “In the liver associated with obesity tumor microenvironmentfibroblasts called ‘hepatic stellate cells’ become senescent,” explained lead researcher Professor Naoko Ohtani. “This causes them to exhibit a senescence-associated secretory phenotype (SASP), where they release a set of proteins that promote cancer by suppressing anti-tumor immunity.” The mechanism by which proteins such as SASP factors are released and accelerate tumor development remains unclear.

Professor Ohtani’s team attempted to discover this mechanism by feeding a high fat diet cancer-prone mice and the study of obesity-induced liver cancer. They first performed comprehensive gene expression analysis to determine which SASP factors were produced by hepatic stellate cells, and then studied how they were released.

The SASP factors IL-1β and IL-33 have been shown to be two of the main facilitators of liver cancer growth. Their release occurs in two main steps. “First, the high-fat diet weakens the gut barrier function, leading to the migration and accumulation of lipoteichoic acid in the liver,” Prof Ohtani explained. “Second, the accumulated lipoteichoic acid stimulates the cleavage of the gasdermin D protein. This, in turn, forms cell membrane pores where IL-1β and IL-33 are exported or released from hepatic stellate cells. .”

These pores play a crucial role because once IL-33 is released, it activates its positive regulatory T cells for receptors which act to suppress the immune response at cancer cells and potentially exacerbate cancer development.

Understanding this mechanism is an important step forward in humanity’s fight against cancer. “Our study revealed a very interesting mechanism by which tumor-promoting SASP factors are released through cell membrane pores formed by stimulation of the microbial component of the gut,” Professor Ohtani concluded. “Inhibition of this pore formation may facilitate prevention and therapeutic strategies for NASH-associated diseases. liver cancer the patients.”

A novel function of non-coding RNA in senescence and cancer

More information:
Ryota Yamagishi et al, release of IL-33 by gasdermin D from senescent hepatic stellate cells promotes hepatocellular carcinoma associated with obesity, Sciences Immunology (2022). DOI: 10.1126/sciimmunol.abl7209. www.science.org/doi/10.1126/sciimmunol.abl7209

Provided by Osaka Metropolitan University

Quote: Porous cells lead to poorer livers (2022, June 24) Retrieved June 24, 2022 from https://medicalxpress.com/news/2022-06-porous-cells-poorer-livers.html

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