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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

邮发代号 80-967

2019 Impact Factor: 3.421

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Frontiers of Medicine  2016, Vol. 10 Issue (1): 52-60   https://doi.org/10.1007/s11684-016-0433-3
  本期目录
Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma
Zhi Xu1,*(),Chunxiang Cao1,Haiyan Xia1,Shujing Shi1,Lingzhi Hong1,Xiaowei Wei1,Dongying Gu1,Jianmin Bian2,Zijun Liu2,Wenbin Huang3,Yixin Zhang4,Song He5,Nikki Pui-Yue Lee6,Jinfei Chen1,*()
1. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
2. Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
3. Department of Pathology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
4. Department of General Surgery, Nantong Tumor Hospital, Nantong 226361, China
5. Department of Pathology, Nantong Tumor Hospital, Nantong 226361, China
6. Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Abstract：

Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P= 0.044). Kaplan-Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCC-specific overall survival (HR, 2.799; 95% CI, 1.346–5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.
Key words： PPM1D    hepatocellular carcinoma    prognosis    target therapy
收稿日期: 2015-05-01      出版日期: 2016-03-31
Corresponding Author(s): Zhi Xu,Jinfei Chen   
 引用本文:   
. [J]. Frontiers of Medicine, 2016, 10(1): 52-60.
Zhi Xu,Chunxiang Cao,Haiyan Xia,Shujing Shi,Lingzhi Hong,Xiaowei Wei,Dongying Gu,Jianmin Bian,Zijun Liu,Wenbin Huang,Yixin Zhang,Song He,Nikki Pui-Yue Lee,Jinfei Chen. Protein phosphatase magnesium-dependent 1δ is a novel tumor marker and target in hepatocellular carcinoma. Front. Med., 2016, 10(1): 52-60.
 链接本文:  
https://academic.hep.com.cn/fmd/CN/10.1007/s11684-016-0433-3
https://academic.hep.com.cn/fmd/CN/Y2016/V10/I1/52
Clinicopathological features Total patients PPM1D expression P value
N = 81 (%) Low (n = 33) High (n = 48)
Age
Year [(mean±SD)] 48.9±9.9 48.8±9.5 49.0±9.8 0.938
Gender
Male 70 (86.4) 28 38
Female 16 (13.6) 5 10 0.574
Tumor sizea
≤5 cm 49 (60.5) 23 26
>5 cm 32 (39.5) 10 22 0.175
Hepatitis
Negative 19 (23.5) 8 11
HBV 62 (76.5) 25 37 1.000
Tumor nodules
Single 59 (72.8) 24 35
Multiple 22 (27.2) 9 13 1.000
Capsule
No 53 (65.4) 23 30
Yes 27 (34.6) 9 18 0.472
Vascular invasionb
No 67 (82.7) 28 39
Yes 14 (17.3) 5 9 0.771
Tumor stage (AJCC 7th)
Stage I 12 (14.8) 6 6
Stage II 33 (40.7) 14 19
Stage III 36 (44.4) 13 23 0.676
Tumor differentiation
Well to moderately 43 (53.1) 18 25
Poorly 38 (46.9) 15 23 1.000
Serum AFP level
≤400 ng/ml 58 (71.6) 28 30
>400 ng/ml 23 (29.4) 5 18 0.044c
Tab.1  
Fig.1  
Clinicopathological features Univariate analysis Multivariate analysis
Median OS (month) P value HR P value HR 95% CI
Age NA 0.509 1.010 0.450 1.012 0.981–1.044
Gender 0.536 0.505
Male 44.0 1 1
Female 64.0 0.774 0.728 0.286–1.852
Tumor size <0.001b 0.146
≤5 cm 63.8a 1 1
>5 cm 20.0 2.786 3.459 0.648–18.468
Tumor differentiation 0.029b 0.111
Well to moderately 61.7a 1 1
Poorly 26.0 1.986 1.756 0.879–3.509
Tumor staging (AJCC) 0.008b 0.194
Stage I 68.4a 1 1
Stage II 36.0 0.111 2.341 0.091 2.675 0.854–8.384
Stage III 20.0 0.002b 3.010 0.865 0.865 0.144–5.105
PPM1D expression 0.013b 0.006b
Low 66.0a 1 1
High 32.0 2.350 2.799 1.346–5.818
Tab.2  
Fig.2  
Fig.3  
Fig.4  
1 Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65(2): 87–108
https://doi.org/10.3322/caac.21262 pmid: 25651787
2 Giannelli G, Antonaci S. Novel concepts in hepatocellular carcinoma: from molecular research to clinical practice. J Clin Gastroenterol 2006; 40(9): 842–846
https://doi.org/10.1097/01.mcg.0000225543.11503.17 pmid: 17016142
3 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012; 379(9822): 1245–1255
https://doi.org/10.1016/S0140-6736(11)61347-0 pmid: 22353262
4 Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O’Connor PM, Appella E. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA 1997; 94(12): 6048–6053
https://doi.org/10.1073/pnas.94.12.6048 pmid: 9177166
5 Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven WG, Nguyen KC, Gabriele T, McCurrach ME, Marks JR, Hoey T, Lowe SW, Powers S. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet 2002; 31(2): 133–134
https://doi.org/10.1038/ng888 pmid: 12021784
6 Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, Ambrosino C, Sauter G, Nebreda AR, Anderson CW, Kallioniemi A, Fornace AJ Jr, Appella E. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 2002; 31(2): 210–215
https://doi.org/10.1038/ng894 pmid: 12021785
7 Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T, Nozawa S, Inazawa J, Imoto I. Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 2003; 9(6): 1995–2004
pmid: 12796361
8 Loukopoulos P, Shibata T, Katoh H, Kokubu A, Sakamoto M, Yamazaki K, Kosuge T, Kanai Y, Hosoda F, Imoto I, Ohki M, Inazawa J, Hirohashi S. Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: identification of genetic indicators that predict patient outcome. Cancer Sci 2007; 98(3): 392–400
https://doi.org/10.1111/j.1349-7006.2007.00395.x pmid: 17233815
9 Saito-Ohara F, Imoto I, Inoue J, Hosoi H, Nakagawara A, Sugimoto T, Inazawa J. PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res 2003; 63(8): 1876–1883
pmid: 12702577
10 Castellino RC, De Bortoli M, Lu X, Moon SH, Nguyen TA, Shepard MA, Rao PH, Donehower LA, Kim JY. Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. J Neurooncol 2008; 86(3): 245–256
https://doi.org/10.1007/s11060-007-9470-8 pmid: 17932621
11 Rauta J, Alarmo EL, Kauraniemi P, Karhu R, Kuukasjärvi T, Kallioniemi A. The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Res Treat 2006; 95(3): 257–263
https://doi.org/10.1007/s10549-005-9017-7 pmid: 16254685
12 Mendrzyk F, Radlwimmer B, Joos S, Kokocinski F, Benner A, Stange DE, Neben K, Fiegler H, Carter NP, Reifenberger G, Korshunov A, Lichter P. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol 2005; 23(34): 8853–8862
https://doi.org/10.1200/JCO.2005.02.8589 pmid: 16314645
13 Peng TS, He YH, Nie T, Hu XD, Lu HY, Yi J, Shuai YF, Luo M. PPM1D is a prognostic marker and therapeutic target in colorectal cancer. Exp Ther Med 2014; 8(2): 430–434
pmid: 25009596
14 Ma D, Zhang CJ, Chen ZL, Yang H. Prognostic value of PPM1D in 800 gastric cancer patients. Mol Med Rep 2014; 10(1): 191–194
pmid: 24788664
15 Yang H, Gao XY, Li P, Jiang TS. PPM1D overexpression predicts poor prognosis in non-small cell lung cancer. Tumour Biol 2015; 36(3): 2179–2184
https://doi.org/10.1007/s13277-014-2828-6 pmid: 25412952
16 Li GB, Zhang XL, Yuan L, Jiao QQ, Liu DJ, Liu J. Protein phosphatase magnesium-dependent 1d (PPM1D) mRNA expression is a prognosis marker for hepatocellular carcinoma. PLoS ONE 2013; 8(3): e60775
https://doi.org/10.1371/journal.pone.0060775 pmid: 23556002
17 Xu MZ, Chan SW, Liu AM, Wong KF, Fan ST, Chen J, Poon RT, Zender L, Lowe SW, Hong W, Luk JM. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene 2011; 30(10): 1229–1240
https://doi.org/10.1038/onc.2010.504 pmid: 21076472
18 Liu LX, Lee NP, Chan VW, Xue W, Zender L, Zhang C, Mao M, Dai H, Wang XL, Xu MZ, Lee TK, Ng IO, Chen Y, Kung HF, Lowe SW, Poon RT, Wang JH, Luk JM. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology 2009; 50(5): 1453–1463
https://doi.org/10.1002/hep.23143 pmid: 19676131
19 Xu MZ, Yao TJ, Lee NP, Ng IO, Chan YT, Zender L, Lowe SW, Poon RT, Luk JM. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009; 115(19): 4576–4585
https://doi.org/10.1002/cncr.24495 pmid: 19551889
20 Zhang T, Zhang J, You X, Liu Q, Du Y, Gao Y, Shan C, Kong G, Wang Y, Yang X, Ye L, Zhang X. Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology 2012; 56(6): 2051–2059
https://doi.org/10.1002/hep.25899 pmid: 22707013
21 Lu X, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA. The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 2008; 27(2): 123–135
https://doi.org/10.1007/s10555-008-9127-x pmid: 18265945
22 Lowe J, Cha H, Lee MO, Mazur SJ, Appella E, Fornace AJ Jr. Regulation of the Wip1 phosphatase and its effects on the stress response. Front Biosci (Landmark Ed) 2012; 17(1): 1480–1498
https://doi.org/10.2741/3999 pmid: 22201816
23 Pärssinen J, Alarmo EL, Karhu R, Kallioniemi A. PPM1D silencing by RNA interference inhibits proliferation and induces apoptosis in breast cancer cell lines with wild-type p53. Cancer Genet Cytogenet 2008; 182(1): 33–39
https://doi.org/10.1016/j.cancergencyto.2007.12.013 pmid: 18328948
24 Wang P, Rao J, Yang H, Zhao H, Yang L. PPM1D silencing by lentiviral-mediated RNA interference inhibits proliferation and invasion of human glioma cells. J Huazhong Univ Sci Technolog Med Sci 2011; 31(1): 94–99
https://doi.org/10.1007/s11596-011-0157-1 pmid: 21336731
25 Yin H, Yan Z, Liang Y, Liu B, Su Q. Knockdown of protein phosphatase magnesium-dependent 1 (PPM1D) through lentivirus-mediated RNA silencing inhibits colorectal carcinoma cell proliferation. Technol Cancer Res Treat 2013; 12(6): 537–543
pmid: 23745790
26 Wang W, Zhu H, Zhang H, Zhang L, Ding Q, Jiang H. Targeting PPM1D by lentivirus-mediated RNA interference inhibits the tumorigenicity of bladder cancer cells. Braz J Med Biol Res 2014; 47(12): 1044–1049
https://doi.org/10.1590/1414-431X20143645 pmid: 25387670
27 Zhang C, Chen Y, Wang M, Chen X, Li Y, Song E, Liu X, Kim S, Peng H. PPM1D silencing by RNA interference inhibits the proliferation of lung cancer cells. World J Surg Oncol 2014; 12(1): 258
https://doi.org/10.1186/1477-7819-12-258 pmid: 25123458
28 Levine AJ. p53, the cellular gatekeeper for growth and division. Cell 1997; 88(3): 323–331
https://doi.org/10.1016/S0092-8674(00)81871-1 pmid: 9039259
29 Yu E, Ahn YS, Jang SJ, Kim MJ, Yoon HS, Gong G, Choi J. Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. Breast Cancer Res Treat 2007; 101(3): 269–278
https://doi.org/10.1007/s10549-006-9304-y pmid: 16897432
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