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JAB1 and phospho-Ser10 p27 expression profile determine human hepatocellular carcinoma prognosis

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

To elucidate the clinicopathological significance and the role of Jun Activation Domain-Binding Protein 1 (JAB1), Ser10-phosphorylated p27 (p27S10), and total p27 in human hepatocellular carcinoma (HCC) prognosis.

Methods

We evaluated the expression of JAB1 and p27S10 in tissues by immunohistochemical and immunoblot analyses. p27 Ser10 phosphorylation and Ser10 phosphorylation-dependent p27–JAB1 interaction were demonstrated in proliferating Huh7 cells following transfection of pEGFP-p27WT/p27S10A/p27S10D plasmids and pcDNA3.1-p27WT/p27S10A/p27S10D-Myc plasmids. Univariate and multivariate analysis were used to determine their role in HCC prognosis.

Results

JAB1 and p27S10 are overexpressed in HCC samples compared with paired normal tissues. There was a strong correlation between JAB1 and p27S10 expression (P < 0.001), and expression of both inversely correlated with total p27 levels (P < 0.001). High JAB1 and p27S10 expression correlated with histological grade, vascular invasion, and serum α-fetoprotein (AFP) level (all P < 0.01). Total p27 expression also correlated with histological tumor grade (P = 0.048) and AFP level (P = 0.015). The p27S10(high)/JAB1(high)/p27(1ow) profile was the most reliable indication of poor prognostic. Ser10 phosphorylation increased and total p27 levels decreased in a time-dependent manner in serum-starved Huh7 cells following addition of serum. Immunoprecipitation analysis revealed that p27 Ser-to-Asp substitution at position 10 (S10D) markedly enhanced the interaction between JAB1 and p27, but replacement of S10A reduced binding.

Conclusions

This study revealed that combined JAB1, p27S10, and total p27 expression may serve as a prognostic marker for HCC.

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Abbreviations

JAB1:

Jun Activation Domain-Binding Protein 1

p27S10:

Ser10-phosphorylated p27

HCC:

Hepatocellular carcinoma

AFP:

α-Fetoprotein

p27Kip1 :

Cyclin-dependent kinase inhibitor p27

S10A:

Ser-to-Ala substitution at position 10

S10D:

Ser-to-Asp substitution at position 10

WT:

Wild type

DMEM:

Dulbecco’s modified Eagle medium

SDS:

Sodium dodecyl sulfate

RR:

Risk ratio

CI:

Confidence interval

AP-1:

Activator protein-1

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Acknowledgments

This study was supported by grants from National Natural Science Foundation of China (nos. 81001160), Science Foundation of Shanghai Municipal Health Bureau (no. 2009060), Foundation from The Bureau of Science and Technology of Wuxi City (CSE00948), Key Disciplines and Specialties Foundation, Shanghai Education Commission Key Disciplines Foundation, Key Discipline Project of Renji Hospital, Shanghai Jiatong University School of Medicine.

Conflict of interest

All authors have no conflict of interests.

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Authors and Affiliations

  1. Shanghai Key Laboratory of Gynecologic Oncology, Focus Construction Subject of Shanghai Education Department, Shanghai, 200127, China

    You Wang & Fang Ji

  2. Department of Obstetrics and Gynecology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China

    You Wang & Fang Ji

  3. Department of Gastroenterology and Hepatology, Affiliated Hospital of Qingdao University School of Medicine, Qingdao, China

    Ya-nan Yu

  4. Department of Pathology, Affiliated Yancheng First People’s Hospital of Nantong University, Yancheng, China

    Shu Song

  5. Biomics Biotechnologies Co., Ltd., Nantong, China

    Tie-jun Li

  6. Department of Obstetrics and Gynecology, Affiliated Wuxi Maternal and Child Health Hospital, Affiliated Wuxi Maternal and Child Health Hospital of Nanjing Medical University, 48 Huaishu Rd, Wuxi, 214002, China

    You Wang, Jing-ying Xiang, Hong Zhang, Mu-dan Lu & Ling-qing Hu

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  1. You Wang
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  2. Ya-nan Yu
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Correspondence to Fang Ji or Ling-qing Hu.

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You Wang, Ya-nan Yu and Shu Song have contributed equally to this work.

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Wang, Y., Yu, Yn., Song, S. et al. JAB1 and phospho-Ser10 p27 expression profile determine human hepatocellular carcinoma prognosis. J Cancer Res Clin Oncol 140, 969–978 (2014). https://doi.org/10.1007/s00432-014-1646-y

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  • DOI: https://doi.org/10.1007/s00432-014-1646-y

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