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Researchers from Osaka University identify a novel and paradoxical mechanism by which the highly studied tumor suppressor protein p53 can induce liver tumor formation

Figure 1. Mechanism of increased liver carcinogenesis caused by constitutive p53 activation in hepatocytes.

p53 is one of the most important proteins in cancer biology. Often referred to as a “guardian of the genome”, p53 becomes activated in response to various cellular stressors like DNA damage. Its activation induces different processes, such as controlled cell death, that prevent cancer development if a cell becomes abnormal. Because of this, p53 mutations are extremely common in cancers, including hepatocellular carcinoma. However, in a recent article published in Cancer Research, a team of researchers at Osaka University observed that constant activation of p53 in liver cells of patients suffering from chronic liver disease (CLD) could actually promote the development of liver cancer.   

CLD can be brought on by different factors including viruses, alcohol use, and fat accumulation, all of which can induce p53 activation. Previous studies have shown that p53 is in a constant state of activation in the liver cells of CLD patients. Yet, it is not clear what role this plays in CLD pathophysiology.    

“Clinical data clearly show that p53 is activated in the hepatocytes of individuals with CLD,” says Yuki Makino, lead author of the study. “Because p53 is such a vital part of how the human body prevents tumor formation, its role in CLD became even more intriguing.”

To address their questions, the team generated a mouse model with p53 accumulation in hepatocytes. This was done by deleting Mdm2, the protein responsible for regulating p53 expression by targeting it for degradation. These mice developed liver inflammation with higher amounts of hepatocyte apoptosis and senescence-associated secretory phenotype (SASP), a phenomenon where cells produce signals within the microenvironment that can cause nearby cells to become cancerous. In fact, mice with p53 accumulation did have increased liver tumor development.

“We also observed an expanded population of hepatic progenitor cells (HPCs), which have stem cell-like characteristics,” explains senior author Tetsuo Takehara. “When the HPCs were isolated, grown in culture, and then injected under the skin of lab mice, these animals developed tumors. This suggested that HPCs played a key part in the liver tumor formation seen in the animals with p53 accumulation.”

Interestingly, acceleration of liver tumor development and the other observed phenotypes did not occur when p53 was deleted in addition to Mdm2 in the hepatocytes. These results demonstrated the significance of constant p53 activity in the tumorigenesis.

“We then compared samples from 182 CLD patients with 23 healthy liver samples,” says Dr. Makino. “The CLD liver biopsy samples showed activated p53 was positively correlated with apoptosis levels, SASP, HPC-associated gene expression, and later cancer development.”

The authors concluded that constitutively activated p53 in hepatocytes of CLD patients can create a microenvironment that is supportive of tumor formation from HPCs. Their work proposes a novel and paradoxical mechanism of liver tumorigenesis because p53 is one of the most well-known tumor suppressor genes. These data could highlight p53 as a potential cancer-prevention treatment target for CLD patients.

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The article, “Constitutive activation of the tumor suppressor p53 in hepatocytes paradoxically promotes non-cell autonomous liver carcinogenesis,” was published in Cancer Research at DOI: https://doi.org/10.1158/0008-5472.CAN-21-4390

Summary: Osaka University researchers identified a novel mechanism by which expression of the tumor suppressor p53 paradoxically promotes liver cancer development in patients with chronic liver disease. By generating a mouse model with constant p53 expression in its liver cells, the team observed increased numbers of hepatic progenitor cells (HPCs) and liver cancer incidence. These HPCs could induce cancer when injected into certain mice. This did not occur with p53 deleted, demonstrating its critical significance.

Tweet 1: Japanese researchers identify a paradoxical way that the “guardian of the genome” can actually cause liver cancer in certain patients
Tweet 2: The critical tumor suppressor protein p53 may in fact be a tumor promoter in patients suffering from chronic liver disease according to a new study from Japan

Primary Keyword: Health and medicine
Additional Keywords:Liver cancer, Tumor suppressors, Tumor microenvironments, Carcinogenesis, Cancer stem cells, Mouse models

Method of Research: Experimental study

Subject of Research: Animals

Figure 2. Increased liver carcinogenesis by p53 activation in hepatocyte-specific Kras-mutant mice and the tumor-suppressive effect of peretinoin (4 months of age).

Figure 3. Incidence of liver tumors based on p21 expression levels in 144 patients with hepatitis C virus (HCV).

Title: “Constitutive activation of the tumor suppressor p53 in hepatocytes paradoxically promotes non-cell autonomous liver carcinogenesis”
Journal: Cancer Research
Authors: Yuki Makino; Hayato Hikita; Kenji Fukumoto; Ji Hyun Sung; Yoshihiro Sakano; Kazuhiro Murai; Sadatsugu Sakane; Takahiro Kodama; Ryotaro Sakamori; Jumpei Kondo; Shogo Kobayashi; Tomohide Tatsumi; Tetsuo Takehara
DOI: 10.1158/0008-5472.CAN-21-4390

Funded by: Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, research grant from the Osaka Cancer Society.