Top

Published in:

01-12-2013 | Translational Research and Biomarkers

Clinical Significance of PICT1 in Patients of Hepatocellular Carcinoma with Wild-Type TP53

Authors: Masahisa Ishibashi, MD, PhD, Ryunosuke Kogo, MD, PhD, Kohei Shibata, MD, PhD, Hiroki Ueo, MD, Ryutaro Uchi, MD, Tae Matsumura, MD, Yuki Takano, MD, Genta Sawada, MD, Yusuke Takahashi, MD, Kousuke Mima, MD, PhD, Junji Kurashige, MD, PhD, Sayuri Akiyoshi, MD, PhD, Takeshi Iwaya, MD, PhD, Hidetoshi Eguchi, MD, PhD, Tomoya Sudo, MD, PhD, Keishi Sugimachi, MD, PhD, Akira Suzuki, MD, PhD, Go Wakabayashi, MD, PhD, Masaki Mori, MD, PhD, Koshi Mimori, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 3/2013

Abstract

Background

TP53 is one of the most widely known cancer suppressor genes. Mutations in TP53 are ubiquitously observed in almost all cancers. Incidences of mutations range from ~15–70 % in patients with hepatocellular carcinoma (HCC). Moreover, patients with mutated TP53 have poorer prognoses than those with wild-type TP53; therefore, it would be beneficial to predict the prognosis of HCC patients with wild-type TP53. We previously reported that PICT1, coding a nucleolus protein, regulates TP53 through indirect association.

Methods

In this study, we examined PICT1 expression levels and the status of TP53 in 51 primary HCC tissues in order to determine the clinical significance of PICT1 expression and the function of PICT1 in HCC cells.

Results

We detected 6 mutations in the 51 samples. In 45 patients with wild-type TP53, those with high PICT1 expression (n = 11) had poorer prognoses than those with low PICT1 expression (n = 34), and there were no significant associations with other clinicopathological factors. According to gene set enrichment analysis, PICT1 expression was inversely correlated with the gene set of TP53. In vitro assays indicated that suppression of PICT1 expression caused an increase in TP53 expression, reduction in cell proliferation, and arrest at the G₁ phase of the cell cycle in HCC cells expressing wild-type TP53.

Conclusions

PICT1 should be a useful prognostic marker in HCC patients having wild-type TP53. Furthermore, PICT1 may become a promising therapeutic target because of its ability to increase the expression and activation of TP53.

Available only for authorised users

Weinberg RA. Tumor suppressor genes. Science. 1991;254:1138–46.PubMedCrossRef

Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458:1127–30.PubMedCrossRef

Soussi T, Beroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. 2001;1:233–40.PubMedCrossRef

Baker L, Quinlan PR, Patten N, Ashfield A, Birse-Stewart-Bell LJ, McCowan C et al. p53 mutation, deprivation and poor prognosis in primary breast cancer. Br J Cancer. 2010;102:719–26.PubMedCrossRef

Campling BG, El-Deiry WS. Clinical implication of p53 mutation in lung cancer. Mol Biotechnol. 2003;24:141–56.PubMedCrossRef

Honda K, Sbisa E, Tullo A, Papeo PA, Saccone C, Poole S, et al. p53 mutation is a poor prognostic indicator for survival in patients with hepatocellular carcinoma undergoing surgical tumour ablation. Br J Cancer. 1998;77:776–82.PubMedCrossRef

Okubo R, Masuda H, Nemoto N. p53 mutation found to be a significant prognostic indicator in distal colorectal cancer. Oncol Rep. 2001;8:509–14.PubMed

Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387:299–303.PubMedCrossRef

Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9.PubMedCrossRef

10.

Moller MB, Nielsen O, Pedersen NT. Oncoprotein MDM2 overexpression is associated with poor prognosis in distinct non-Hodgkin’s lymphoma entities. Mod Pathol. 1999;12:1010–6.PubMed

11.

Haitel A, Wiener HG, Baethge U, Marberger M, Susani M. mdm2 expression as a prognostic indicator in clear cell renal cell carcinoma: comparison with p53 overexpression and clinicopathological parameters. Clin Cancer Res. 2000;6:1840–4.PubMed

12.

Zhou M, Gu L, Abshire TC, Homans A, Billett AL, Yeager AM, et al. Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia. Leukemia. 2000;14:61–7.PubMedCrossRef

13.

Dogan E, Saygili U, Tuna B, Gol M, Gurel D, Acar B, et al. p53 and mdm2 as prognostic indicators in patients with epithelial ovarian cancer: a multivariate analysis. Gynecol Oncol. 2005;97:46–52.PubMedCrossRef

14.

Zhu Y, Poyurovsky MV, Li Y, Biderman L, Stahl J, Jacq X, et al. Ribosomal protein S7 is both a regulator and a substrate of MDM2. Mol Cell. 2009;35:316–26.PubMedCrossRef

15.

Dai MS, Shi D, Jin Y, Sun XX, Zhang Y, Grossman SR, et al. Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism. J Biol Chem. 2006;281:24304–13.PubMedCrossRef

16.

Lindstrom MS, Deisenroth C, Zhang Y. Putting a finger on growth surveillance: insight into MDM2 zinc finger-ribosomal protein interactions. Cell Cycle. 2007;6:434–7.PubMedCrossRef

17.

Sasaki M, Kawahara K, Nishio M, Mimori K, Kogo R, Hamada K, et al. Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nat Med. 2011;17:944–51.PubMedCrossRef

18.

von Deimling A, Nagel J, Bender B, Lenartz D, Schramm J, Louis DN, et al. Deletion mapping of chromosome 19 in human gliomas. Int J Cancer. 1994;57:676–80.CrossRef

19.

Michotte A, Chaskis C, Sadones J, Veld PI, Neyns B. Primary leptomeningeal anaplastic oligodendroglioma with a 1p36-19q13 deletion: report of a unique case successfully treated with Temozolomide. J Neurol Sci. 2009;287:267–70.PubMedCrossRef

20.

Yim JH, Kim YJ, Ko JH, Cho YE, Kim SM, Kim JY, et al. The putative tumor suppressor gene GLTSCR2 induces PTEN-modulated cell death. Cell Death Differ. 2007;14:1872–9.PubMedCrossRef

21.

Okahara F, Itoh K, Nakagawara A, Murakami M, Kanaho Y, Maehama T. Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation. Mol Biol Cell. 2006;17:4888–95.PubMedCrossRef

22.

Okahara F, Ikawa H, Kanaho Y, Maehama T. Regulation of PTEN phosphorylation and stability by a tumor suppressor candidate protein. J Biol Chem. 2004;279:45300–3.PubMedCrossRef

23.

Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell. 2004;119:847–60.PubMedCrossRef

24.

Craanen ME, Blok P, Dekker W, Offerhaus GJ, Tytgat GN. Chronology of p53 protein accumulation in gastric carcinogenesis. Gut. 1995;36:848–52.PubMedCrossRef

25.

Bian YS, Osterheld MC, Bosman FT, Benhattar J, Fontolliet C. p53 gene mutation and protein accumulation during neoplastic progression in Barrett’s esophagus. Mod Pathol. 2001;14:397–403.PubMedCrossRef

26.

Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K. Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol. 2009;44 Suppl 19:102–7.PubMedCrossRef

27.

Buendia MA. Genetics of hepatocellular carcinoma. Semin Cancer Biol. 2000;10:185–200.PubMedCrossRef

28.

Montesano R, Hainaut P, Wild CP. Hepatocellular carcinoma: from gene to public health. J Natl Cancer Inst. 1997;89:1844–51.PubMedCrossRef

29.

Villanueva A, Hoshida Y. Depicting the role of TP53 in hepatocellular carcinoma progression. J Hepatol. 2011;55:724–5.PubMedCrossRef

30.

Liu J, Ma Q, Zhang M, Wang X, Zhang D, Li W, et al. Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer. 2012;48:2328–38.PubMedCrossRef

31.

Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53.PubMedCrossRef

32.

Yokobori T, Mimori K, Iwatsuki M, Ishii H, Onoyama I, Fukagawa T, et al. p53-Altered FBXW7 expression determines poor prognosis in gastric cancer cases. Cancer Res. 2009;69:3788–94.PubMedCrossRef

33.

Inoue H, Mori M, Honda M, Li J, Shibuta K, Mimori K, et al. The expression of tumor-rejection antigen “MAGE” genes in human gastric carcinoma. Gastroenterology. 1995;109:1522–5.PubMedCrossRef

34.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.PubMedCrossRef

35.

Inoue-Narita T, Hamada K, Sasaki T, Hatakeyama S, Fujita S, Kawahara K, et al. Pten deficiency in melanocytes results in resistance to hair graying and susceptibility to carcinogen-induced melanomagenesis. Cancer Res. 2008;68:5760–8.PubMedCrossRef

36.

Okahara F, Itoh K, Ebihara M, Kobayashi M, Maruyama H, Kanaho Y, et al. Production of research-grade antibody by in vivo electroporation of DNA-encoding target protein. Anal Biochem. 2005;336:138–40.PubMedCrossRef

37.

Boulon S, Westman BJ, Hutten S, Boisvert FM, Lamond AI. The nucleolus under stress. Mol Cell. 2010;40:216–27.PubMedCrossRef

Title: Clinical Significance of PICT1 in Patients of Hepatocellular Carcinoma with Wild-Type TP53
Authors: Masahisa Ishibashi, MD, PhD
Ryunosuke Kogo, MD, PhD
Kohei Shibata, MD, PhD
Hiroki Ueo, MD
Ryutaro Uchi, MD
Tae Matsumura, MD
Yuki Takano, MD
Genta Sawada, MD
Yusuke Takahashi, MD
Kousuke Mima, MD, PhD
Junji Kurashige, MD, PhD
Sayuri Akiyoshi, MD, PhD
Takeshi Iwaya, MD, PhD
Hidetoshi Eguchi, MD, PhD
Tomoya Sudo, MD, PhD
Keishi Sugimachi, MD, PhD
Akira Suzuki, MD, PhD
Go Wakabayashi, MD, PhD
Masaki Mori, MD, PhD
Koshi Mimori, MD, PhD
Publication date: 01-12-2013
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue Special Issue 3/2013
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-013-2958-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clinical Significance of PICT1 in Patients of Hepatocellular Carcinoma with Wild-Type TP53

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Special Issue 3/2013

Elevated SHOX2 Expression is Associated with Tumor Recurrence of Hepatocellular Carcinoma

Identification of the NEDD4L Gene as a Prognostic Marker by Integrated Microarray Analysis of Copy Number and Gene Expression Profiling in Non-small Cell Lung Cancer

In Vivo Fluorescence Imaging of Gastrointestinal Stromal Tumors Using Fluorophore-Conjugated Anti-KIT Antibody

Enhancer of Zeste Homolog 2 (EZH2) Promotes Progression of Cholangiocarcinoma Cells by Regulating Cell Cycle and Apoptosis

Expression of Brachyury Gene Is a Significant Prognostic Factor for Primary Lung Carcinoma

Diagnostic and Prognostic Relevance of MMP-11 Expression in the Stromal Fibroblast-Like Cells Adjacent to Invasive Ductal Carcinoma of the Breast