p53 is one of the most important proteins in cancer biology, commonly referred to as “the genome of Guardians”, which are activated in response to various cellular stresses such as DNA damage. p53 activation induces different processes, such as controlled cell death, and if a cell becomes abnormal, it can prevent it from becoming cancerous and cancer progression. Because of this, mutations in p53 are extremely common in the development of cancer, including hepatocellular carcinoma.
Recently, an article was published in the international journal Cancer Research entitledIn the research report on “Constitutive activation of the tumor suppressor p53 in hepatocytes paradoxically promotes non-cell liver carcinogenesis” autonomous, scientists from Osaka University and other institutions in Japan have studied the It was observed that persistent activation of p53 in liver cells of patients suffering from chronic liver disease (CLD) actually promotes hepatocarcinogenesis.
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Chronic liver disease is driven by different factors, including viruses, alcohol use, and fat accumulation, all of which induce p53 activation. Previous studies have shown that p53 is persistently activated in liver cells of patients with chronic liver disease, however, it is currently unclear what role it plays in the pathophysiology of chronic liver disease.
Researcher Yuki Makino said, “The clinical data clearly show that p53 plays an important role in liver cells of patients with chronic liver disease. Because p53 is an important part of how the body prevents tumor formation, its critical role in chronic liver disease makes it very intriguing.
To address this issue, the researchers developed a mouse model of p53 accumulation in liver cells by Deletion of Mdm2, a specialized protein responsible for regulating p53 expression, resulted in targeted degradation. These mouse models often exhibit hepatic inflammation, high levels of hepatocyte apoptosis, and the senescence-associated secretory phenotype (SASP), a phenomenon in which cells signal in the microenvironment that trigger proximity The cells became cancerous and, in fact, the liver tumors in mice with accumulation of p53 in the body increased.
Researcher Tetsuo Takehara, we also observed an expansion of the population of liver progenitor cells (HPCs), which have Stem cell-like characteristics, when HPCs were isolated, cultured, and then injected into the subcutaneous tissue of laboratory mice, these animals developed tumors, which may suggest that HPCs accumulate in p53-accumulating animals in the liver tumor formation plays a key role in the process.
Interestingly, when p53 and Mdm2 were depleted in hepatocytes, the accelerated development of liver tumors and other The observed phenotype may not have occurred, and these findings reveal the significance of persistent p53 activity in tumorigenesis.
Dr. Makino said, we then compared 182 chronic liver disease patients with 23 healthy liver samples, Analysis of liver biopsy samples from patients with chronic liver disease showed that activated p53 was positively correlated with apoptosis levels, SASP, HPC-related gene expression, and later cancer development.
The researchers concluded that persistent p53 activation in hepatocytes from patients with chronic liver disease may create an energy In support of the tumor microenvironment in which HPCs form, this study proposes a novel, paradoxical mechanism of liver tumorigenesis, as p53 is one of the best-known tumor suppressor genes. Therefore, relevant research data highlight p53 as a novel target for developing potential cancer prevention strategies in patients with chronic liver disease.
In conclusion, our findings suggest that p53 activation in hepatocytes may create a tumor-promoting Optimizing the activity of p53 in hepatocytes is very important for preventing the occurrence of hepatocellular carcinoma in patients with chronic liver disease.
Original Source:
Yuki Makino , Hayato Hikita, Kenji Fukumoto, et al. Constitutive activation of the tumorsuppressor p53 in hepatocytes paradoxically promotes non-cell autonomous liver carcinogenesis., Cancer Research (2022). DOI: 10.1158/0008-5472.CAN-21-4390