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Della Porta et al. Comparison of p53 and prohibitin expression

followed the same profile of activated NFκB expression tumor gene, PHB, has been associated with an
by Southwestern histochemistry, as previously increase of p53 activity in the induction of apoptosis in
reported. [22] Thus, these data were discoursed together cancer. [29]
as activated NFκB expression. We observed a
crescent augmentation of activated NFκB expression The role of PHB, in particular, is not fully understood.
in HCV and CIR in relation to NL. NFκB activation There are controversies because both antitumorigenic
may be induced by TNFα secondarily to the increase and protumorigenic functions have been reported for
of proinflammatory status in HCV and CIR. Since PHB, depending on its subcellular localization. [30] In
TNFα-induced NFκB activation acts as an important addition to regulation of various cellular functions,
[9]
survival factor for hepatocytes, higher activated NFκB the mitochondrial location of PHB is mainly engaged
expression could explain the slight number of apoptotic in reducing damage caused by oxidative stress in
hepatocytes in HCV and CIR samples in comparison the chronic phase of various diseases. [31] In our HCV
to HCC. In addition, constant activation of NFκB during and CIR samples, we detected a high expression of
chronic liver disease performs as an early molecular cytoplasmic PHB, likely due to chronic inflammation
change during HCC progression. [11] Nevertheless, associated with these diseases. Moreover, in spite of
in the later stages of hepatocarcinogenesis, NFκB PHB reducing NFκB activation mediated by TNFα,
inhibition can accelerate development of HCC by which permits occurrence of apoptosis, high levels
cellular proliferation. [23] Thus, in spite of the reduction of TNFα can also inhibit tumour suppressor PHB
of activated NFκB expression in HCC patients which activity during chronic inflammation. [32] This regulatory
may be related to the significant increase of apoptosis, mechanism may explain increased NFκB activation
other mechanisms could be associated with this and higher hepatocytes survival in HCV and CIR in
phenomenon. comparison with HCC, despite high cytoplasmic PHB
expression in HCV and CIR. In addition, the failure of
TRAIL expression was increased and accompanied apoptosis of mutated hepatocytes may represent a
by decreased NFκB activation and frequent primary event in the hepatocarcinogenesis associated
apoptosis in the cases of HCC when compared to with chronic liver disease.
HCV and CIR. In addition to inducing apoptosis in
normal hepatocytes, [24] TRAIL can mediate NFκB Our data show that PHB expression was exclusively
inhibition with consequent apoptosis in transformed identified as nuclear labelling in HCC. It has been
hepatocytes. [11] This finding may be related to the reported that nuclear PHB appears to be essential for
attempt of preventing tumorigenesis during chronic regulation of cellular processes such as apoptosis,
inflammatory disease. Moreover, increase of TRAIL proliferation, and gene transcription. [30] PHB was also
expression in HCC with consequent reduction of NFκB detected in the nucleus associated with retinoblastoma
activation and augment of hepatocytes apoptosis may and p53, inducing changes in transcription factors,
occur by a p53-independent pathway. [25] resulting in cell cycle inhibition and induction of
apoptosis. [33] The tumour suppressor action of PHB
p53 has been widely considered as a tumor was associated with nuclear expression in cells of
suppressor gene associated with induction of several neoplasms. [29,34] In agreement, the HCC group
apoptosis in different types of neoplasms, including presented exclusively a PHB nuclear expression in
HCC. [26] Furthermore, p53 is usually less expressed contrast to CIR and HCV. Because NFκB may be
during HCV than in HCC. [27] Accordingly, we found p53 acting as an antiapoptotic mediator, and once inhibited
expression almost solely in HCC, without significant by the action of PHB in HCC, it may increase the rate
changes during chronic liver inflammation. Increased of apoptosis in these cases.
p53 expression was also followed by augmentation
of apoptosis in HCC. Moreover, the RelA/p65 subunit In conclusion, our results suggest that, in addition to
can inhibit p53 activation, as well as p53 also well-understood sequences of proinflammatory events
suppresses NFκB transcriptional effects. [28] Perhaps such as TNF-induced NFκB activation and NFκB/
during HCV and CIR, the inflammatory stimulus TRAIL pathway-mediated apoptosis, development
induces an increase of TNFα with consequent NFκB of human hepatic cancer may be influenced by
activation and p53 inhibition, which leaked from regulation of p53 and PHB tumour suppressor
hepatocytes from apoptosis. Concerning HCC, which function. Another possibility would be that expression
present a less evident inflammatory process, TNFα- of p53 and PHB may have been altered as a
induced NFκB activation is discrete and, in addition consequence of an already-established hepatocellular
to inhibition of NFκB activation by p53, augments carcinoma. Additional studies are necessary to
apoptosis. Furthermore, another possible suppressor explain the contradictory mechanisms of the tumour
40 Hepatoma Research ¦ Volume 3 ¦ February 28, 2017