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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Apr 16 2019

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Hepatocytes
Hepatocellular Carcinoma
Phosphotransferases
Down-Regulation
Chemical activation
Tumors
Diethylnitrosamine
Inflammation
Pathogens
Carcinogens
Liver
Neoplasms
Anti-Bacterial Agents
Proto-Oncogenes
Molecules
Tumor Burden
Sensors
Carcinogenesis

Keywords

  • cancer biology
  • hepatocellular carcinoma
  • hepatocyte
  • immunology
  • inflammation
  • JNK
  • mouse
  • NLRP12
  • NOD-like receptors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. / Udden, Sm Nashir; Kwak, Youn Tae; Godfrey, Victoria; Khan, Md Abdul Wadud; Khan, Shahanshah; Loof, Nicolas; Peng, Lan; Zhu, Hao; Zaki, Hasan.

In: eLife, Vol. 8, 16.04.2019.

Research output: Contribution to journalArticle

Udden, Sm Nashir ; Kwak, Youn Tae ; Godfrey, Victoria ; Khan, Md Abdul Wadud ; Khan, Shahanshah ; Loof, Nicolas ; Peng, Lan ; Zhu, Hao ; Zaki, Hasan. / NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. In: eLife. 2019 ; Vol. 8.
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AU - Kwak, Youn Tae

AU - Godfrey, Victoria

AU - Khan, Md Abdul Wadud

AU - Khan, Shahanshah

AU - Loof, Nicolas

AU - Peng, Lan

AU - Zhu, Hao

AU - Zaki, Hasan

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N2 - 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.

AB - 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.

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KW - NOD-like receptors

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