P53 expression in hepatocellular carcinoma: influence on the radiotherapeutic response of the hepatocellular carcinoma.

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death with increasing incidence.1 The standard treatments of HCC consist of surgical resection, liver transplantation, radiofrequency ablation and transarterial chemoembolization. However, because a large proportion of HCC patients are diagnosed in advanced stage, long-term prognosis is disappointing with few available therapeutic modalities.23

Although Radiotherapy is not included in the Barcelona Clinic Liver Cancer (BCLC) algorithm, it has shown acceptable therapeutic efficacy as one of the therapeutic options for HCC patients.4 However, as HCC often acquires radioresistance which are correlated with treatment failure,5 only a small number of radionuclides, such as iodine-131, yttrium-90, rhenium-188 and holmium-166, have been used to the HCC treatment.67 The P53 protein is a transcription factor related to DNA damage repair, growth arrest and apoptosis leading to uncontrolled proliferation, associated with more than 50% of human cancers.8910 P53 normally exists in low steady level, but the expression and activation of P53 increases after radiation. The P53 is thought to be one of the key elements involved in the response to radiotherapy.8 Many studies have been conducted for elucidating relationship between P53 and effectiveness of radiotherapy in cancer and revealed that mutation or inactivation of P53 causes genetic instability, resulting in development of tumors and ineffectiveness of radiotherapy.91011

In this issue, Gomes et al. reported influence of P53 on the radiotherapeutic response of the HCC. In this study, investigation of the effect of iodine-131 radiotherapy in three human HCC cell lines with different degrees of P53 expression was conducted to assess the influence of P53 on the HCC cell survival after radiation therapy. As a result, Hep3B2.1-7 cell line, which has a homozygous deletion in the TP53 gene, did not express P53, HepG2 expresses its normal form, and HuH7, which has a mutated codon, overexpressed P53. For HepG2 and HuH7 cell lines, an increase in P53 expression was observed after both external and internal radiation with I-131, especially in HuH7. Level of phosphorylated P53 was higher after external irradiation than internal radiation with highest levels of phosphorylation in HepG2 cell line. The Hep3B2.1-7 cells were less radiosensitive than other two cell lines. More radiosensitive cell lines, which exhibit a great decrease in cell survival (HepG2, HbH7) showed a higher expression of P53. Thus, P53 protein, encoded by the TP 53 tumor suppressor gene, might be an important factor in radiotherapeutic response in HCC, which is consistent with previous studies.910

Although P53 triggered most apoptotic cell death, in this study, cells died by late apoptosis/necrosis and necrosis. We must consider the possibility of the aggressiveness of radiation to cells or observation of cell death in later stage. Moreover, HepG2 cell line is more sensitive to both external and internal radiation than HuH7 cell line. It might be related to the character of HepG2 cell line which expressed the normal and more functional form of P53.

Further studies are warranted about more detail signaling pathways. It would be an important target for HCC treatment.