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In a single pathogen sensor, researchers have found both a potential therapeutic target and a possible way to improve the efficacy of current immune checkpoint blockade therapies for hepatocellular carcinoma (HCC), the most common type of primary liver cancer.
Since HCC is associated with chronic inflammation, and NLRP12, a cytosolic pathogen sensor, is a negative regulator of inflammation, researchers at the University of Texas (UT) Southwestern Medical Center decided to investigate its role in HCC using mouse models of the disease. They found that mice lacking in Nlrp12 expression were extremely susceptible to HCC, with increased inflammation, hepatocyte proliferation, and tumor burden. Nlrp12-negative tumors also had increased expression of the proto-oncogenes cJun and cMyc, in addition to downregulation of the tumor suppressor p21. Yet the researchers also found a solution to this issue: treatment with antibiotics dramatically reduced the formation of tumors in Nlrp12-negative mouse livers.
"In this study, we demonstrated that NLRP12 responds to gut microbes and plays a critical role in suppressing a common form of liver cancer," stated Hasan Zaki, PhD, Assistant Professor of Pathology at UT Southwestern and corresponding author of the study, which has now been published in eLife.
During stimulation with microbial pattern molecules, the researchers noticed higher activation of JNK, which has been implicated in cancer development and progression. Causing inhibition of JNK or overexpression of NLRP12 reduced the proliferative and inflammatory responses of cultured Nlrp12-negative hepatocytes (liver cells).
"Our study indicates that NLRP12 acts to suppress liver cancer by reducing inflammation and downregulating the signals involved in tumor progression," commented Dr. Zaki. "This study suggests that NLRP12 could be a potential therapeutic target. It also indicates that finding a way to increase NLRP12 in the liver in combination with current immune checkpoint blockade therapies may improve liver cancer treatment."
For More Information
Udden SMN, Kwak Y, Godfrey V, et al (2019). NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife, 8:e40396. DOI:10.7554/eLife.40396