PIN1 in hepatocellular carcinoma is associated with TP53 gene status

Abstract

Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.

Prolyl isomerase Pin1: a promoter of cancer and a target for therapy

“…Interestingly, a number of studies indicated that Pin1 increases p53-induced cell senescence and apoptosis 88 , 89 . However, Pin1 expression is higher in HCC cells with mutant p53 (p53M) compared to wild-type p53 (p53WT), and the deletion of Pin1 significantly reduces the proliferation of p53M HCC cells but not p53WT 90 . More research revealed that Pin1 facilitates the p53M-induced aggressiveness of cancers 33 , 91 , 92 , which contributes to a reasonable explanation for why p53 is aberrant in most cancers.…”

Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways

“…Furthermore, Pin1 is overexpressed in about 70% of human HCC patients and it promotes heptocarcinogenesis in cell line PLC/PRF/538394041. Pin1 might play different roles in HCC cells depending on status of TP53 gene mutation42. Pin1 single nucleotide promoter and exon polymorphisms are associated with the susceptibility of HBV-related HCC43.…”

Cellular stress modulates severity of the acute respiratory distress syndrome in COVID-19

“…We focused our attention in the ones whose levels changed upon LPS challenge and were then restored after 4-PBA treatment, and we identified 12 proteins that followed this pattern (Figure 5C-O). Levels of six of these proteins dropped with LPS and returned to normal values after 4-PBA treatment (Figure 5D-I): Pin1 (a peptidyl isomerase with a role in regulation of TP53, stress and cytokine signaling in immune system) 63 , Gpm6a, Ephx2, L2hgdh, Dhdh (general metabolic modulators) and Tmed5 (Transmembrane P24 Trafficking protein 5 involved in ER-Golgi trafficking and WNT signaling) 64 . The other six proteins had elevated levels upon LPS challenge and returned to low levels with 4-PBA (Fig.…”