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Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery.

Methods

Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line.

Results

Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan–Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p < 0.0001) than in the low-risk group (26.9 months for TTR, 95% CI 22.4–31.5) than in the high-risk group (14.5 months for TTR, 95% CI 10.6–18.4). Similar results were observed in two validation cohorts. In addition, a nomogram to predict recurrence was developed. Moreover, Knockdown of TPI1 by shRNA inhibited ICC cell growth, colony information, migration, invasion in vitro.

Conclusions

Current prognostic models were accurate in predicting recurrence for ICC patients after surgical resection.

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Abbreviations

ICC:

Intrahepatic cholangiocarcinoma

AUC:

Area under the curve

OS:

Overall survival

TTR:

Time to recurrence

TNM:

Tumor–node–metastasis

AJCC:

American Joint Committee on Cancer

iTRAQ:

Isobaric tag for relative and absolute quantitation

PKM2:

Pyruvate kinase isozymes M1/M2

TPI1:

Triosephosphate isomerise

FFPE:

Formalin-fixed paraffin-embedded

IHBD:

Intrahepatic bile duct

TMA:

Tissue microarray

EHBH:

Eastern Hepatobiliary Surgery Hospital

ZSH:

Zhongshan Hospital

IOD:

Integrated optical density

TKT:

Tansketolase

ALDOA:

Fructose-bisphosphate aldolase A

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Acknowledgements

We thank Lu Xin Yuan (Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University) for review of HE stained sections in the initial stage of the study.

Funding

This work was supported by grants from the National Natural Science Foundation of China; 81972574, 81472769 (Guang-Zhi Jin), 81572856 (Guanzhen Yu), 81472278 (Wen-Ming Cong). National S&T Major Project of China, 2017ZX10203205 (Guang-Shun Yang). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Wen-Long Yu, Guanzhen Yu, Hui Dong, Ke Chen and Jun Xie authors contributed equally to this work.

  2. Ai-Jun Li, Wen-Ming Cong and Guang-Zhi Jin senior authors contributed equally to this work.

Authors and Affiliations

  1. Department II of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China

    Wen-Long Yu

  2. Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, NO.725, South Wanping RoadShanghai, Shanghai, 200032, China

    Guanzhen Yu

  3. Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China

    Hui Dong, Hua Yu & Wen-Ming Cong

  4. Department of Pathology, Zhong Shan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

    Ke Chen & Yuan Ji

  5. The School of Life Science, Fudan University, 2005 Songhu Road, 200438, Shanghai, China

    Jun Xie

  6. Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China

    Guang-Shun Yang

  7. Department of Special Treatment II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China

    Ai-Jun Li

  8. Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111, Xianxia Road, Shanghai, 200336, China

    Guang-Zhi Jin

Authors
  1. Wen-Long Yu
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  2. Guanzhen Yu
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  10. Wen-Ming Cong
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Contributions

Study concept and design: G-ZJ, W-LY. Drafting of the manuscript: G-ZJ, W-LY. Acquisition of data, analysis and interpretation of data: G-ZJ, W-LY, GY, HD, KC, JX, HY. Critical revision of the manuscript: W-MC, A-JL. Statistical analysis: G-ZJ, JX. Study supervision: G-SY. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ai-Jun Li, Wen-Ming Cong or Guang-Zhi Jin.

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Conflict of interest

The authors declare that they have no conflict of interests.

Ethics approval and consent to participate

Each patient or their guardians provided informed consent and the Ethics Committee of Eastern Hepatobiliary Surgery Hospital and Zhongshan Hospital Research Ethics Committee approved the study.

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Yu, WL., Yu, G., Dong, H. et al. Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma. J Gastroenterol 55, 1171–1182 (2020). https://doi.org/10.1007/s00535-020-01729-0

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  • DOI: https://doi.org/10.1007/s00535-020-01729-0

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