New Role of the Innate Immune Sensor: Eliminate Liver Cancer

Researchers at UT Southwestern have discovered that an innate immune system protein that responds to intestinal microbes can suppress the most common type of liver cancer.

The study, published today in the journal eLife, determined that NLRP12, an innate immune sensor, had a protective effect against hepatocellular carcinoma (HCC), a fatal cancer associated with chronic inflammation. HCC is responsible for more than 80% of liver cancers in the United States. It is the third leading cause of cancer death in the world and the ninth leading cause in America, according to the National Cancer Institute.

NLRP12 is a member of the family of pattern recognition receptors, similar to NOD, that helps sensory microbes and other cell stimuli regulate the innate immune response – the body's first line of defense against cancer. Infection – in many ways. This latest work adds to a growing body of evidence linking inflammation to the development of tumors in the liver.

"In this study, we demonstrated that NLRP12 responds to intestinal microbes and plays a vital role in the removal of a common form of liver cancer," said Dr. Hasan Zaki, an assistant professor of pathology at UT Southwestern and corresponding author of the study.

The main risk factors for hepatocellular carcinoma are infection with hepatitis B or C virus, chronic alcohol abuse, and non-alcoholic fatty liver disease, a condition that is becoming increasingly prevalent worldwide. obesity. Although the precise mechanisms by which these conditions induce liver cancer are unknown, inflammation of the liver is considered a key player.

"Our study indicates that NLRP12 acts to suppress liver cancer by reducing inflammation and negatively regulating the signals involved in tumor progression," said Dr. Zaki, whose lab conducted experiments on mice and human cells from patients with liver cancer.

After being exposed to a chemical carcinogen, mice lacking the Nlrp12 gene (mouse version) exhibited higher levels of inflammation and increased tumor development compared to normal mice, revealed 1% of the mice. study.

To understand why this happened, the researchers examined the signals sent by the tumor cells in mice with and without the Nlrp12 gene. They found that the JNK (c-Jun N-terminal kinase) pathway, associated with liver cancer, is very active in liver tumors lacking Nlrp12, explained Dr. Zaki.

The JNK pathway can be activated by a component of the bacterial cell wall called lipopolysaccharide (LPS), he said. Dr. Zaki explained that the "good" bacteria – lining the intestine and facilitating digestion – and the "bad" pathogenic bacteria, such as Salmonella or E. coli, can release LPS.

LPS can pass from the intestine to the liver via the bloodstream and contribute to inflammation by triggering JNK and other signaling pathways. Such transport is much more common in chronically inflamed livers such as those with hepatitis or hepatic steatosis, he said.

The study data suggest that NLRP12 suppresses inflammation caused by gut microbiota and cancer-promoting signals, added Dr. Zaki, a member of the Harold C. Simmons Cancer Center.

To confirm the hypothesis cancer-intestinal inflammation hypothesis, the researchers treated mice with antibiotics to reduce levels of intestinal bacteria. "The depletion of the gut microbiota with antibiotics dramatically reduced tumor growth in mice without Nlrp12," Dr. Zaki said. "This study suggests that NLRP12 may be a potential therapeutic target, and it also indicates that finding a way to increase NLRP12 in the liver in combination with current treatments for immune checkpoint blockade could improve the treatment of the patient." liver cancer."

Immune blockade at checkpoints is a new strategy to help the body kill cancer cells through an immune response. When the strategy works, it is very effective, but often ineffective, prompting researchers to look for ways to improve it.

Dr. Zaki said his team was now exploring more precisely the precise mechanism by which NLRP12 regulates the JNK pathway.