The role of JNK in the development of hepatocellular carcinoma

Das, Madhumita; Garlick, David S.; Greiner, Dale L.; Davis, Roger J.

doi:10.1101/gad.1989311

Cited by 180 publications

(171 citation statements)

References 50 publications

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“…35 A dual role for JNK in development of HCC has been proposed. 36 In hepatocytes, higher JNK activity prevents HCC development while JNK activation in non-parenchymal liver cells promotes HCC development. 36 p53 is a well-known tumour suppressor that also regulates the DNA damage response.…”

Section: Discussionmentioning

confidence: 99%

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damageinduced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2 −/− ) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2 −/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2 −/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis. The initiator caspase, caspase-2, has recently emerged as a tumour suppressor with loss of this protein being associated with increased lymphomagenesis in ATM-deficient mice and Eμ-Myc transgenic mice, and MMTV/c-neu-driven mammary carcinoma. 1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes. 7,8 The major risk factors of HCC include viral hepatitis, excessive alcohol consumption, carcinogens and metabolic diseases. 7,8 Despite this, the molecular causes of the disease are relatively less understood. Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. 7-10 It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. 11-13 While loss of apoptosis would indirectly favour proliferation, this is not universa...

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Section: Discussionmentioning

confidence: 99%

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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“…However, it remains possible that JNK in stromal cells that support epithelial cell morphogenesis and differentiation (36) may play a role in the development of PIN lesions. Further studies will be required to test this hypothesis in the context of prostate cancer, but recent studies have established that JNK in stromal cells can promote carcinogenesis (9). Nevertheless, JNK in prostate epithelial cells is not required for prostate cancer development caused by Pten inactivation in mice.…”

Section: Jnk Regulates the Tumorigenic Potential Of δPten Prostate Tumormentioning

confidence: 99%

“…Thus, JNK deficiency reduces the development of Bcr/Abl-induced lymphoma (6) and KRas-induced lung tumors (7). Moreover, carcinogen-induced hepatocellular carcinoma (8)(9)(10) and skin cancer (11) can be reduced by JNK deficiency. These observations demonstrate that JNK can promote cancer.…”

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confidence: 99%

“…These observations demonstrate that JNK can promote cancer. However, loss of JNK signaling can also promote development of other tumors (2,9,(12)(13)(14)(15). These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1).…”

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confidence: 99%

“…These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1). Alternatively, these differences may reflect separate functions of JNK in tumor cells and the tumor microenvironment (9).…”

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confidence: 99%

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JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

Hübner

Mulholland

Standen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The c-Jun NH 2 -terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN signaling pathways can cooperate to regulate the progression of prostate neoplasia to invasive adenocarcinoma.T he c-Jun NH 2 -terminal kinase (JNK) signaling pathway can target members of the activating protein 1 (AP1) group of transcription factors, including ATF2, c-Jun, JunB, and JunD (1). These transcription factors represent an important component of the immediate-early gene response to mitogens and inflammatory stimuli (2). AP1 transcription factors are also implicated in dysregulated growth and tumor development (2). Significantly, JNK deficiency suppresses AP1-dependent gene expression and causes defects in cell proliferation, senescence, and apoptosis (3-5). JNK may, therefore, play a role in carcinogenesis.Studies using mouse models of cancer have confirmed that JNK can play a key role in cancer. Thus, JNK deficiency reduces the development of Bcr/Abl-induced lymphoma (6) and KRas-induced lung tumors (7). Moreover, carcinogen-induced hepatocellular carcinoma (8-10) and skin cancer (11) can be reduced by JNK deficiency. These observations demonstrate that JNK can promote cancer. However, loss of JNK signaling can also promote development of other tumors (2, 9, 12-15). These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1). Alternatively, these differences may reflect separate functions of JNK in tumor cells and the tumor microenvironment (9).Mutational inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN) frequently occurs in human prostate cancer (16)(17)(18). Mouse models of Pten deficiency in the prostate epithelium demonstrate that loss of PTEN expression is sufficient to cause activation of the AKT signaling pathway, prostatic intraepithelial neoplasia (PIN) lesions, and subsequent development of castration-resistant prostate cancer (19). Loss of PTEN function is, therefore, established to be a key step in the development of prostate cancer. Importantly, PTEN inactivation is associated with increased activity of the...

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