Skip to main content

Advertisement

SpringerLink
Log in

Tumor suppressor LHPP suppresses cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma cell lines

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer in the world with high mortality due to its high potential of metastasis. Epithelial-mesenchymal transition (EMT) plays a key role in the pathogenesis of HCC occurrence and metastasis. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. There is little study about LHPP in human HCC development. In the present study, we aimed to investigate the role of LHPP in human HCC cell metastasis. We analyzed the LHPP expression level in human HCC tissues compared with normal tissues in the public database. We detected the mRNA level and protein level of LHPP in transformed liver cell line (LO2) and human HCC cell lines (MHCC-97 H, MHCC-97L, and HepG2). We performed genetic gain and loss of function experiments with LHPP using small interfering RNA (siRNA) and lentivirus infection. Then, we detected that LHPP suppressed proliferation and promoted apoptosis in hepatocellular carcinoma cell lines. Also, we investigated the role of LHPP in the EMT process. Finally, we examined the effect of LHPP on TGF-β-induced EMT. Interestingly, we also found that LHPP expression is positively regulated tumor suppressor p53. Our data showed that LHPP is significantly decreased in the human HCC tissues and human HCC cell lines compared with normal liver tissues and transformed liver cells. Knockdown of LHPP promotes HCC cell proliferation and metastasis, and LHPP expression levels negatively correlate with EMT-related genes. Furthermore, LHPP inhibits TGF-β-induced EMT in HCC cell lines. These studies validate LHPP as a tumor suppressor in liver cancer and provide a new genetic target for HCC diagnosis and treatment.

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
Fig. 6
Fig. 7
Fig. 8
Scheme 1

Similar content being viewed by others

References

  1. Alqahtani, A., Z. Khan, A. Alloghbi, T. S. Said Ahmed, M. Ashraf & D. M. Hammouda (2019) Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina (Kaunas), 55.

  2. Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK (2020) EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol 30:764–776

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM (2013) The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 45(10):1113–1120

    Article  PubMed Central  Google Scholar 

  4. Consortium C (2015) Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523:588–591

    Article  Google Scholar 

  5. Craig AJJAO, von Felden T, Garcia-Lezana S, Sarcognato AAO (2020) Villanueva Tumour evolution in hepatocellular carcinoma.

  6. Cui L, Gong X, Tang Y, Kong L, Chang M, Geng H, Xu K, Wang F (2016) Relationship between the LHPP gene polymorphism and resting-state brain activity in major depressive disorder. Neural Plast 2016:9162590

    Article  PubMed  PubMed Central  Google Scholar 

  7. Giannelli G, Koudelkova P, Dituri F, Mikulits W (2016) Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 65:798–808

    Article  CAS  PubMed  Google Scholar 

  8. Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299

    Article  CAS  PubMed  Google Scholar 

  9. Hindupur SK, Colombi M, Fuhs SR, Matter MS, Guri Y, Adam K, Cornu M, Piscuoglio S, Ng CKY, Betz C, Liko D, Quagliata L, Moes S, Jenoe P, Terracciano LM, Heim MH, Hunter T, Hall MN (2018) The protein histidine phosphatase LHPP is a tumour suppressor. Nature 555:678–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hiraishi H, Yokoi F, Kumon A (1998) 3-phosphohistidine and 6-phospholysine are substrates of a 56-kDa inorganic pyrophosphatase from bovine liver. Arch Biochem Biophys 349:381–387

    Article  CAS  PubMed  Google Scholar 

  11. Hou B, Li W, Li J, Ma J, Xia P, Liu Z, Zeng Q, Zhang X, Chang D (2020) Tumor suppressor LHPP regulates the proliferation of colorectal cancer cells via the PI3K/AKT pathway. Oncol Rep 43:536–548

    CAS  PubMed  Google Scholar 

  12. Klutstein M, Nejman D, Greenfield R, Cedar H (2016) DNA methylation in cancer and aging. Cancer Res 76:3446–3450

    Article  CAS  PubMed  Google Scholar 

  13. Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56

    Article  PubMed  Google Scholar 

  14. Lee GA, Hwang KA, Choi KC (2016) Roles of dietary phytoestrogens on the regulation of epithelial-mesenchymal transition in diverse cancer metastasis. Toxins (Basel), 8.

  15. Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, Lacko M, Eluf-Neto J, Franceschi S, Lagiou P, Macfarlane GJ, Richiardi L, Boccia S, Polesel J, Kjaerheim K, Zaridze D, Johansson M, Menezes AM, Curado MP, Robinson M, Ahrens W, Canova C, Znaor A, Castellsagué X, Conway DI, Holcátová I, Mates D, Vilensky M, Healy CM, Szeszenia-Dąbrowska N, Fabiánová E, Lissowska J, Grandis JR, Weissler MC, Tajara EH, Nunes FD, de Carvalho MB, Thomas S, Hung RJ, Peters WH, Herrero R, Cadoni G, Bueno-de-Mesquita HB, Steffen A, Agudo A, Shangina O, Xiao X, Gaborieau V, Chabrier A, Anantharaman D, Boffetta P, Amos CI, McKay JD, Brennan P (2016) Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet 48:1544–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Y, Zhang X, Zhou X (2019) LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway. Biosci Rep, 39.

  17. Li Z, Zhou X, Zhu H, Song X, Gao H, Niu Z, Lu J (2021) Purpurin binding interacts with LHPP protein that inhibits PI3K/AKT phosphorylation and induces apoptosis in colon cancer cells HCT-116. J Biochem Mol Toxicol 35:e22665

    Article  CAS  PubMed  Google Scholar 

  18. Liao L, Duan D, Liu Y, Chen L (2020) LHPP inhibits hepatocellular carcinoma cell growth and metastasis. Cell Cycle 19:1846–1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu M, Jiang L, Guan XY (2014) The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update. Protein Cell 5:673–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liver EAFTSOT, Cancer EOFRATO (2012) EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56:908–943

    Article  Google Scholar 

  21. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS (2021) Hepatocellular carcinoma Nat Rev Dis Primers 7:6

    Article  PubMed  Google Scholar 

  22. Polimanti R, Wang Q, Meda SA, Patel KT, Pearlson GD, Zhao H, Farrer LA, Kranzler HR, Gelernter J (2017) The interplay between risky sexual behaviors and alcohol dependence: genome-wide association and neuroimaging support for LHPP as a risk gene. Neuropsychopharmacology 42:598–605

    Article  CAS  PubMed  Google Scholar 

  23. Roessler S, Jia HL, Budhu A, Forgues M, Ye QH, Lee JS, Thorgeirsson SS, Sun Z, Tang ZY, Qin LX, Wang XW (2010) A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res 70(24):10202–10212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sun W, Qian K, Guo K, Chen L, Xiang J, Li D, Wu Y, Ji Q, Sun T, Wang Z (2020) LHPP inhibits cell growth and migration and triggers autophagy in papillary thyroid cancer by regulating the AKT/AMPK/mTOR signaling pathway. Acta Biochim Biophys Sin (Shanghai) 52:382–389

    Article  CAS  PubMed  Google Scholar 

  25. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  PubMed  Google Scholar 

  26. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F (2015) Proteomics Tissue-based map of the human proteome. Science 347(6220):1260419

    Article  PubMed  Google Scholar 

  27. Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380:1450–1462

    Article  CAS  PubMed  Google Scholar 

  28. Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 201020(5):299–309

    Article  Google Scholar 

  29. Wang D, Ning Z, Zhu Z, Zhang C, Wang P, Meng Z (2021) LHPP suppresses tumorigenesis of intrahepatic cholangiocarcinoma by inhibiting the TGFβ/smad signaling pathway. Int J Biochem Cell Biol 132:105845

    Article  CAS  PubMed  Google Scholar 

  30. Wu, F., Y. Chen & J. Zhu (2020) LHPP suppresses proliferation, migration, and invasion and promotes apoptosis in pancreatic cancer. Biosci Rep, 40.

  31. Xu MY, Chen R, Yu JX, Liu T, Qu Y, Lu LG (2016) AZGP1 suppresses epithelial-to-mesenchymal transition and hepatic carcinogenesis by blocking TGFβ1-ERK2 pathways. Cancer Lett 374:241–249

    Article  CAS  PubMed  Google Scholar 

  32. Yokoi F, Hiraishi H, Izuhara K (2003) Molecular cloning of a cDNA for the human phospholysine phosphohistidine inorganic pyrophosphate phosphatase. J Biochem 133:607–614

    Article  CAS  PubMed  Google Scholar 

  33. Zhang X, Kang H, Xiao J, Shi B, Li X, Chen G (2020) LHPP inhibits the proliferation and metastasis of renal cell carcinoma. Biomed Res Int 2020:7020924

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zheng J, Dai X, Chen H, Fang C, Chen J, Sun L (2018) Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT. Biochem Biophys Res Commun 503:1108–1114

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Guanbin Song (Chongqing University, Chongqing, China) for sharing the MHCC97H and MHCC97L cell lines.

Funding

This work was supported by the Natural Science Foundation of Chongqing (2021ycjh-bgzxm0169; cstc2021jcyj-cxttX0002cstc), Chongqing Graduate Scientific Research and Innovation Foundation of China (No. CYB19043), the National Natural Science Foundation of China (No. 82002909), Visiting Scholar Foundation of Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education (CQKLBST-2021-002) and Sichuan Science and Technology Program (2022NSFSC1318).

Author information

Author notes

  1. Lunkun Ma and Huifang Sun contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Lunkun Ma, Huifang Sun, Xichao Xu, Ying Chen, Lu Zhang, Shun Li & Liling Tang

  2. Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, 610500, China

    Shun Li

  3. Non-Coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, 610500, China

    Shun Li

Authors
  1. Lunkun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huifang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xichao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liling Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.M. and S.F. executed this study; L.M. wrote the manuscript; X.X. assisted with the cell culture experiments; Y.C. and L.Z. assisted with the Western blots experiments; S.L. proofread the manuscript; L.T. supervised the study and edited the manuscript. The authors declare that all data was generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Shun Li or Liling Tang.

Ethics declarations

Conflicts of interest

The authors declare no competing interests.

Additional information

Publisher's note

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

Key points

1. LHPP acts as a tumor suppressor in HCC and LHPP expression is lower in HCC compared with in normal conditions.

2. LHPP suppresses cell proliferation and migration in HCC cell lines.

3. LHPP suppresses the EMT process in HCC.

4. p53 protein expression is positively regulated by LHPP in HCC.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, L., Sun, H., Xu, X. et al. Tumor suppressor LHPP suppresses cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma cell lines. J Physiol Biochem 78, 807–817 (2022). https://doi.org/10.1007/s13105-022-00903-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-022-00903-7

Keywords

Search

Navigation