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Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 2011;19:629-639. (Reprinted with permission.)

Abstract

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  2. Abstract
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The human gene PTPN11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a subfraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant-active mutants, Ptpn11/Shp2 has a tumor-suppressor function in liver.

Comment

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Protein phosphorylation at tyrosine residues is a key mechanism of signal transduction during many cellular processes including inflammation, cell death, and proliferation. Therefore, deregulation or hyperactivation of tyrosine kinases is frequently associated with cancer formation.1 Tyrosine phosphorylation can be antagonized by tyrosine phosphatases. However, the precise interplay between tyrosine kinases and their respective phosphatases is still poorly understood.

Recent research has suggested that the ubiquitously expressed tyrosine phosphatase Shp2 (SH2 domain-containing protein tyrosine phosphatase-2, also known as protein tyrosine phosphatase, nonreceptor type 11/PTPN11) may act as a proto-oncogene. Dominant active mutations of Shp2 have been identified in patients with Noonan syndrome, an autosomal dominant congenital disorder resulting in, e.g., congenital heart defects, dwarfism, and hematologic abnormalities that have a high predisposition toward development of childhood leukemias as well as other types of leukemias.2, 3 Mechanistically, Shp2 seems to play a bivalent role, as it not only antagonizes tyrosine kinases, but also activates the Ras/extracellular signal-regulated kinase (ERK) pathway following stimulation by growth factors and cytokines. However, the underlying mechanisms are still largely unknown and remain controversial.4 Several lines of evidence have suggested that Shp2 is also an important antagonist of the interleukin-6 (IL-6)/glycoprotein (gp130)/Stat3 signaling pathway and acts by dephosphorylating Janus kinases (JAK) and activated Stat3 and attenuates IL-6 signaling by recruitment to tyrosine 759 on the IL-6 receptor subunit gp130.5, 6

Further insight into the function of Shp2 in the liver came from experiments performed in hepatocyte-specific Shp2 knockout mice subjected to partial hepatectomy (PH). Genetic ablation of Shp2 resulted in impaired liver regeneration following PH, most likely due to reduced ERK activation and down-regulation of immediate early genes such as c-Fos, c-Jun, and c-Myc.7 Additionally, IL-6/Stat3-dependent hepatoprotective signals were enhanced in Shp-deficient mice, confirming the hypothesis that hepatic Stat3 activity is regulated by Shp2. However, these protective signals are apparently not sufficient to support normal compensatory hepatocyte proliferation in the absence of Shp2. From these data, it could be speculated that inactivation of Shp2 would rather protect from excessive hepatocyte proliferation and thus from hepatocarcinogenesis.

By analyzing the same hepatocyte-specific Shp2 knockout mice in more detail, Bard-Chapeau et al.8 now aimed to clarify the role of Shp2 for the development of liver inflammation and liver cancer. Very surprisingly, ablation of Shp2 results in onset of spontaneous hepatitis and parenchymal necrosis in mice by the age of 2-3 months along with increased intrahepatic expression of IL-6 and tumor necrosis factor alpha (TNF). The proinflammatory properties of Shp2-deficiency are even more apparent in a model of sepsis induced by lipopolysaccharide treatment, where Shp2 knockout mice were found to be hypersensitive toward inflammatory liver injury. In agreement with earlier studies from the same group, loss of Shp2 triggers enhanced and prolonged phosphorylation of Stat3 and c-Jun N-terminal kinases (JNK), but impaired activation of the ERK signaling pathways. Hence, the Shp2 protein appears to mediate the antiinflammatory effect by keeping Stat3 and JNK in check.

The spontaneous hepatitis found in Shp2-deficient mice culminates in the development of hepatocellular adenoma with constitutive Stat3 activation after 1-1.5 years. These findings also have clinical relevance, as Bard-Chapeau et al. demonstrated that >10% of human hepatocellular carcinomas are characterized by decreased Shp2 expression. To further elucidate the postulated pro-oncogenic role of Stat3, the authors compared conditional Shp2 knockout mice with Shp2/Stat3 double knockout mice and wildtype (WT) controls in a model of chemically induced hepatocarcinogenesis by using the carcinogen diethylnitrosamine (DEN). Apparently, Shp2 acts as a tumor suppressor in the liver, as Shp2 knockout mice show strongly enhanced HCC development following DEN exposure. Bard-Chapeau et al. provided convincing evidence that the tumor-promoting properties of the Shp2 knockout are Stat3-dependent, as not only increased tumor susceptibility but also basal inflammation was largely rescued by concomitant hepatic ablation of Shp2 and Stat3. Thus, Stat3 is the actual proinflammatory mediator and main tumor promoter in Shp2-deficient mice. Unexpectedly, however, hepatic Stat3 inactivation alone was not protective in the DEN model, and even resulted in a slightly enhanced tumor formation as compared to DEN-treated WT controls. This phenomenon is contradictory to a recent study by He et al.,9 who showed a strong protection from DEN-mediated hepatocarcinogenesis in Stat3-deficient mice. However, both groups used different Stat3 knockout alleles, which might explain this discrepancy, although future work will be necessary to clarify these differences.

As usual with excellent research, the work of Bard-Chapeau et al. raises several new questions. First, it would be interesting to examine if Stat3/Shp2 double knockout mice are also protected from spontaneous hepatocarcinogenesis, which is anticipated, as these mice have markedly reduced basal liver inflammation. Moreover, the question concerning the relevant target proteins of Shp2 in hepatocytes is still open. The data presented here imply that Shp2 may inhibit Stat3 directly, e.g., by dephosphorylation. However, it cannot be excluded that Shp2 also blocks STAT-signaling further upstream by inhibiting the signal transducer gp130, as previously suggested.6 In this regard, further in vitro studies with Shp2-deficient hepatocytes may be helpful to identify all dominant-active components of the IL-6 pathway in this scenario.

The exciting data from Bard-Chapeau et al. are in line with increasing evidence that demonstrates that aberrant activation of the IL-6/gp130/Stat3 signaling pathway is a hallmark of liver cancer development in mice and man (Fig. 1). In this context, ablation of IL-6 itself was shown to be highly protective against induction of HCC by DEN in mice.10 More recently, somatic dominant active mutations of Stat3 and gp130 have been identified in human patients with hepatocellular adenomas, both resulting in constitutive activation of Stat3.11, 12 Here, we learn that hepatic tumor cells have evolved at least one more mechanism to get more activated Stat3 through the down-regulation of Shp2, although the nature of this suppressive mechanism is completely unknown. The diversity of mechanisms and factors leading to Stat3 overactivation in liver tumors is remarkable and emphasizes the need to investigate this important and critical pathway even more intensively in the context of inflammatory liver disease.

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Figure 1. The many oncogenic facets of IL-6/gp130/Stat3 signaling in the liver. IL-6 activates the transcription factor Stat3 by way of binding to the gp130/IL-6 receptor complex. Induction of Stat3 target genes may result in a proinflammatory response. However, constitutive activation of Stat3 results in chronic hepatitis and potentially liver cancer. Constitutive active somatic mutations for both Stat3 and gp130 have been identified recently in benign liver tumors. It has been demonstrated that IL-6 triggers hepatocarcinogenesis in mice. Now, it is evident that the oncogenic activity of Stat3 is under the control of the phosphatase Shp2. However, if Shp2 inhibits Stat3 directly, e.g., by dephosphorylation or indirectly by blocking upstream signal transducer such as gp130.

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References

  1. Top of page
  2. Abstract
  3. Comment
  4. References