Bae Jun Sang, Noh Sang Jae, Kim Kyoung Min, Jang Kyu Yun, Park Ho Sung, Chung Myoung Ja, Park Byung-Hyun, Moon Woo Sung
Department of Pathology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
Department of Forensic Medicine, Chonbuk National University Medical School, Jeonju 561‑756, Republic of Korea.
Oncol Rep. 2016 Oct;36(4):2405-11. doi: 10.3892/or.2016.5001. Epub 2016 Aug 4.
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.
脯氨酸之前的丝氨酸/苏氨酸残基上的蛋白质磷酸化（pSer/Thr-Pro）由肽基脯氨酰顺反异构酶PIN1特异性催化。PIN1介导的脯氨酰异构化通过调节包括TP53在内的靶蛋白诱导细胞周期停滞和生长抑制。我们研究了在肝细胞癌（HCC）中，PIN1是否根据TP53基因状态以不同方式发挥作用。我们调查了119例HCC组织样本中PIN1和TP53蛋白的表达。我们还结合TP53基因突变分析了PIN1表达及其与临床结局的相关性。此外，我们使用合成小干扰RNA使TP53野生型和TP53突变型HCC细胞系中的PIN1基因表达沉默，然后评估细胞增殖、迁移和侵袭。PIN1的表达与HCC样本中TP53蛋白的表达或TP53突变密切相关。TP53突变型HCC细胞系中PIN1和TP53的表达高于TP53野生型HCC细胞系。在含有突变型TP53的HLE细胞中沉默PIN1可显著降低细胞增殖、迁移和侵袭。与在HLE细胞中沉默PIN1相反，在含有功能性野生型TP53的HepG2细胞中沉默PIN1导致肿瘤细胞增殖增强。预测携带野生型TP53且有PIN1表达的HCC患者无复发生存良好。我们的结果表明，在HCC中，PIN1根据TP53基因突变状态以不同方式在癌细胞增殖、迁移和侵袭中发挥作用。特别是，PIN1与突变型TP53的相互作用可作为肿瘤促进剂并增加其在HCC中的致癌活性。
