Skip to main content

Advertisement

SpringerLink
Log in

S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background

Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear.

Methods

We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies.

Results

The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI.

Conclusions

Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. Vogel A, Cervantes A, Chau I, Daniele B, Llovet J, Meyer T, Nault JC, Neumann U, Ricke J, Sangro B, Schirmacher P, Verslype C, Zech CJ, Arnold D, Martinelli E. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv238–55. https://doi.org/10.1093/annonc/mdy308.

    Article  CAS  PubMed  Google Scholar 

  3. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53. https://doi.org/10.1053/j.gastro.2015.12.041.

    Article  PubMed  Google Scholar 

  4. Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, Kadoya M, Kudo M, Ku Y, Sakamoto M, Nakashima O, Kaneko S, Kokudo N, Liver Cancer Study Group of J (2016) Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 65(5):938–943. https://doi.org/10.1016/j.jhep.2016.05.044

  5. Pote N, Cauchy F, Albuquerque M, Voitot H, Belghiti J, Castera L, Puy H, Bedossa P, Paradis V. Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol. 2015;62(4):848–54. https://doi.org/10.1016/j.jhep.2014.11.005.

    Article  CAS  PubMed  Google Scholar 

  6. Huang J, Deng Q, Wang Q, Li KY, Dai JH, Li N, Zhu ZD, Zhou B, Liu XY, Liu RF, Fei QL, Chen H, Cai B, Xiao HS, Qin LX, Han ZG. Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012;44(10):1117–21. https://doi.org/10.1038/ng.2391.

    Article  CAS  PubMed  Google Scholar 

  7. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY, Wang XW. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111. https://doi.org/10.1016/j.ccr.2006.06.016.

    Article  CAS  PubMed  Google Scholar 

  8. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118(3):277–9. https://doi.org/10.1016/j.cell.2004.07.011.

    Article  CAS  PubMed  Google Scholar 

  9. Becker T, Gerke V, Kube E, Weber K. S100P, a novel Ca(2+)-binding protein from human placenta. cDNA cloning, recombinant protein expression and Ca2+ binding properties. Eur J Biochem. 1992;207(2):541–7. https://doi.org/10.1111/j.1432-1033.1992.tb17080.x.

    Article  CAS  PubMed  Google Scholar 

  10. Kypriotou M, Huber M, Hohl D. The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the “fused genes” family. Exp Dermatol. 2012;21(9):643–9. https://doi.org/10.1111/j.1600-0625.2012.01472.x.

    Article  CAS  PubMed  Google Scholar 

  11. Arumugam T, Ramachandran V, Gomez SB, Schmidt AM, Logsdon CD. S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. Clin Cancer Res. 2012;18(16):4356–64. https://doi.org/10.1158/1078-0432.CCR-12-0221.

    Article  CAS  PubMed  Google Scholar 

  12. Austermann J, Nazmi AR, Muller-Tidow C, Gerke V. Characterization of the Ca2+ -regulated ezrin-S100P interaction and its role in tumor cell migration. J Biol Chem. 2008;283(43):29331–40. https://doi.org/10.1074/jbc.M806145200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bresnick AR, Weber DJ, Zimmer DB. S100 proteins in cancer. Nat Rev Cancer. 2015;15(2):96–109. https://doi.org/10.1038/nrc3893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim JK, Jung KH, Noh JH, Eun JW, Bae HJ, Xie HJ, Ahn YM, Ryu JC, Park WS, Lee JY, Nam SW. Targeted disruption of S100P suppresses tumor cell growth by down-regulation of cyclin D1 and CDK2 in human hepatocellular carcinoma. Int J Oncol. 2009;35(6):1257–64.

    Article  CAS  PubMed  Google Scholar 

  15. Yuan RH, Chang KT, Chen YL, Hsu HC, Lee PH, Lai PL, Jeng YM. S100P expression is a novel prognostic factor in hepatocellular carcinoma and predicts survival in patients with high tumor stage or early recurrent tumors. PLoS ONE. 2013;8(6):e65501. https://doi.org/10.1371/journal.pone.0065501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ye X, Li C, Zu X, Lin M, Liu Q, Liu J, Xu G, Chen Z, Xu Y, Liu L, Luo D, Cao Z, Shi G, Feng Z, Deng H, Liao Q, Cai C, Liao DF, Wang J, Jin J, Cao D. A large-scale multicenter study validates Aldo-Keto reductase family 1 member B10 as a prevalent serum marker for detection of hepatocellular carcinoma. Hepatology. 2019;69(6):2489–501. https://doi.org/10.1002/hep.30519.

    Article  CAS  PubMed  Google Scholar 

  17. Tsai TJ, Chau GY, Lui WY, Tsay SH, King KL, Loong CC, Hsia CY, Wu CW. Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma. Surgery. 2000;127(6):603–8. https://doi.org/10.1067/msy.2000.105498.

    Article  CAS  PubMed  Google Scholar 

  18. Lim KC, Chow PK, Allen JC, Chia GS, Lim M, Cheow PC, Chung AY, Ooi LL, Tan SB. Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria. Ann Surg. 2011;254(1):108–13. https://doi.org/10.1097/SLA.0b013e31821ad884.

    Article  PubMed  Google Scholar 

  19. Shen Z, Deng H, Fang Y, Zhu X, Ye GT, Yan L, Liu H, Li G. Identification of the interplay between SOX9 and S100P in the metastasis and invasion of colon carcinoma. Oncotarget. 2015;6(24):20672–84. https://doi.org/10.18632/oncotarget.3967.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shen ZY, Fang Y, Zhen L, Zhu XJ, Chen H, Liu H, Jiang B, Li GX, Deng HJ. Analysis of the predictive efficiency of S100P on adverse prognosis and the pathogenesis of S100P-mediated invasion and metastasis of colon adenocarcinoma. Cancer Genet. 2016;209(4):143–53. https://doi.org/10.1016/j.cancergen.2016.02.002.

    Article  CAS  PubMed  Google Scholar 

  21. Al-Othman N, Alhendi A, Ihbaisha M, Barahmeh M, Alqaraleh M, Al-Momany BZ. Role of CD44 in breast cancer. Breast Dis. 2020;39(1):1–13. https://doi.org/10.3233/BD-190409.

    Article  CAS  PubMed  Google Scholar 

  22. Jiang H, Hu H, Lin F, Lim YP, Hua Y, Tong X, Zhang S. S100P is overexpressed in squamous cell and adenosquamous carcinoma subtypes of endometrial cancer and promotes cancer cell proliferation and invasion. Cancer Invest. 2016;34(10):477–88. https://doi.org/10.1080/07357907.2016.1212206.

    Article  CAS  PubMed  Google Scholar 

  23. Kim J, Jiang J, Badawi M, Schmittgen TD. miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway. Biochem Biophys Res Commun. 2017;487(3):709–15. https://doi.org/10.1016/j.bbrc.2017.04.121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wu Z, Boonmars T, Nagano I, Boonjaraspinyo S, Srinontong P, Ratasuwan P, Narong K, Nielsen PS, Maekawa Y. Significance of S100P as a biomarker in diagnosis, prognosis and therapy of opisthorchiasis-associated cholangiocarcinoma. Int J Cancer. 2016;138(2):396–408. https://doi.org/10.1002/ijc.29721.

    Article  CAS  PubMed  Google Scholar 

  25. Arumugam T, Logsdon CD. S100P: a novel therapeutic target for cancer. Amino Acids. 2011;41(4):893–9. https://doi.org/10.1007/s00726-010-0496-4.

    Article  CAS  PubMed  Google Scholar 

  26. Arumugam T, Ramachandran V, Logsdon CD. Effect of cromolyn on S100P interactions with RAGE and pancreatic cancer growth and invasion in mouse models. J Natl Cancer Inst. 2006;98(24):1806–18. https://doi.org/10.1093/jnci/djj498.

    Article  CAS  PubMed  Google Scholar 

  27. Sato N, Fukushima N, Matsubayashi H, Goggins M. Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling. Oncogene. 2004;23(8):1531–8. https://doi.org/10.1038/sj.onc.1207269.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Nature Science Foundation of China (NSFC 81972306, 81960450, 81860502, 81502533), and Guangxi Nature Sciences Grants (2018GXNSFAA138028, 2018GXNSFAA050124, Gui Ke AB16380242). This work was also supported in part by the Guangxi BaGui Scholars Special Fund and the Guangxi Medical University Training Program for Distinguished Young Scholars.

Author information

Author notes

  1. Lu-Nan Qi, Liang Ma and Fei-Xiang Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, No. 71 Hedi Road, Nanning, 530021, Guangxi, China

    Lu-Nan Qi, Liang Ma, Fei-Xiang Wu, Wan-Ting Xing, Zhi-Jun Jiang, Jian-Hong Zhong, Zu-Shun Chen, Wen-Feng Gong, Jia-Zhou Ye, Bang-De Xiang & Le-Qun Li

  2. Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, 530021, Guangxi, China

    Lu-Nan Qi, Liang Ma, Fei-Xiang Wu, Bang-De Xiang & Le-Qun Li

  3. Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, 530021, Guangxi, China

    Lu-Nan Qi, Liang Ma, Fei-Xiang Wu, Wan-Ting Xing, Zhi-Jun Jiang, Hong-Hao Li, Bang-De Xiang & Le-Qun Li

  4. Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China

    Yuan-Yuan Chen

  5. Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, 210000, Jiangsu, China

    Jin-Jie Shang

Authors
  1. Lu-Nan Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fei-Xiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan-Yuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wan-Ting Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi-Jun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-Hong Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zu-Shun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wen-Feng Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jia-Zhou Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hong-Hao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin-Jie Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bang-De Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Le-Qun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: L-NQ, B-DX, L-QL, W-TX, Z-JJ, and Z-SC. Methodology: L-NQ, LM, F-XW, J-ZY, W-FG, and H-HL. Validation: L-NQ and F-XW. Formal analysis: L-NQ, J-JS, and Y-YC. Investigation: L-NQ and Y-YC. Resources: J-HZ, Z-SC, W-FG, and J-ZY. Data curation: L-NQ and J-HZ. Writing—original draft preparation: L-NQ, LM, and B-DX. Writing—review and editing: L-QL. Visualization: W-TX, Z-JJ, H-HL, and J-JS. Supervision: L-NQ, B-DX, and L-QL. Project administration: L-NQ. Funding acquisition: L-NQ.

Corresponding authors

Correspondence to Lu-Nan Qi, Bang-De Xiang or Le-Qun Li.

Ethics declarations

Conflict of interest

Lu-Nan Qi declares that he has no conflict of interest. Liang Ma declares that he has no conflict of interest. Fei-Xiang Wu declares that he has no conflict of interest. Yuan-Yuan Chen declares that he has no conflict of interest. Wan-Ting Xing declares that he has no conflict of interest. Zhi-Jun Jiang declares that he has no conflict of interest. Jian-Hong Zhong declares that he has no conflict of interest. Zu-Shun Chen declares that he has no conflict of interest. Wen-Feng Gong declares that he has no conflict of interest. Jia-Zhou Ye declares that he has no conflict of interest. Hong-Hao Li declares that he has no conflict of interest. Jin-Jie Shang declares that he has no conflict of interest. Bang-De Xiang declares that he has no conflict of interest. Le-Qun Li declares that he has no conflict of interest.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Tumor Hospital of Guangxi Medical University No. LW2018035) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent in studies with human subjects

Informed consent was obtained from all patients for being included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1960 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, LN., Ma, L., Wu, FX. et al. S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma. Hepatol Int 15, 114–126 (2021). https://doi.org/10.1007/s12072-020-10130-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-020-10130-1

Keywords

Search

Navigation