NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte
SM Nashir Udden,
Youn-Tae Kwak,
Victoria Godfrey,
Md Abdul Wadud Khan,
Shahanshah Khan,
Nicolas Loof,
Lan Peng,
Hao Zhu,
Hasan Zaki
Affiliations
SM Nashir Udden
Department of Pathology, UT Southwestern Medical Center, Dallas, United States
Youn-Tae Kwak
Department of Pathology, UT Southwestern Medical Center, Dallas, United States; Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
Victoria Godfrey
Department of Pathology, UT Southwestern Medical Center, Dallas, United States
Md Abdul Wadud Khan
Department of Surgical Oncology, MD Anderson Cancer Center, Houston, United States
Shahanshah Khan
Department of Pathology, UT Southwestern Medical Center, Dallas, United States
Nicolas Loof
Children's Research Institute, UT Southwestern Medical Center, Dallas, United States
Lan Peng
Department of Pathology, UT Southwestern Medical Center, Dallas, United States
Children's Research Institute, UT Southwestern Medical Center, Dallas, United States; Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States; Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, United States; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
