Tumor Biology

, Volume 37, Issue 10, pp 14173–14181 | Cite as

Depletion of STYK1 inhibits intrahepatic cholangiocarcinoma development both in vitro and in vivo

  • Mei-yuan Chen
  • Hao Zhang
  • Jian-xin Jiang
  • Cheng-yi Sun
  • Chao Yu
  • She Tian
Original Article


Intrahepatic cholangiocarcinoma (ICC) has been reported to be the second most common primary hepatic carcinoma worldwide, and very limited therapies are currently available. Serine threonine tyrosine kinase (STYK1), a member of the receptor tyrosine kinase family, exhibits tumorigenicity in many types of cancers and is a potential therapeutic target for ICC. In this study, STYK1 was knocked down in the ICC cell lines HCCC-9810 and RBE via a lentivirus-mediated system using short hairpin RNA (shRNA). Next, cell proliferation, colony formation, cell cycle progression, tumor formation in nude mice, migration and invasion, and the expression levels of cell cycle proteins in Lv-sh STYK1- or Lv-sh Con-infected cells were analyzed by CCK-8 assay, colony formation evaluation, flow cytometry, tumor formation evaluation, wound scratch assay, transwell assay, and western blotting. The results indicated that depletion of STYK1 inhibits ICC development both in vitro and in vivo.


Intrahepatic cholangiocarcinoma (ICC) STYK1 Biomarker Gene therapy Molecular mechanism 



This work was supported by the International Science and Technology Cooperation Program of China (No. 2014DFA31420) and the National Natural Science Foundation of China (No. 81160311).

Compliance with ethical standards

All animal experiments were approved by the Animal Care Committee of the Affiliated Hospital of Guiyang Medical College.


  1. 1.
    Suzuki H, Komuta M, Bolog A, Yokobori T, Wada S, Araki K, Kubo N, Watanabe A, Tsukagoshi M, Kuwano H. Relationship between 18-f-fluoro-deoxy-d-glucose uptake and expression of glucose transporter 1 and pyruvate kinase m2 in intrahepatic cholangiocarcinoma. Dig Liver Dis. 2015;47:590–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000;69:373–98.CrossRefPubMedGoogle Scholar
  3. 3.
    Robinson DR, YM W, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–57.CrossRefPubMedGoogle Scholar
  4. 4.
    Zwick E, Bange J, Ullrich A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer. 2001;8:161–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen P, Li WM, Lu Q, Wang J, Yan XL, Zhang ZP, Li XF. Clinicopathologic features and prognostic implications of NOK/STYK1 protein expression in non-small cell lung cancer. BMC Cancer. 2014;14:402.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Liu L, XZ Y, Li TS, Song LX, Chen PL, Suo TL, Li YH, Wang SD, Chen Y, Ren YM, Zhang SP, Chang ZJ, Fu XY. A novel protein tyrosine kinase NOK that shares homology with platelet- derived growth factor/fibroblast growth factor receptors induces tumorigenesis and metastasis in nude mice. Cancer Res. 2004;64:3491–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Fambrough D, McClure K, Kazlauskas A, Lander ES. Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell. 1999;97:727–41.CrossRefPubMedGoogle Scholar
  8. 8.
    Chen Y, Li YH, Chen XP, Gong LM, Zhang SP, Chang ZJ, Zhang XF, XY F, Liu L. Point mutation at single tyrosine residue of novel oncogene NOK abrogates tumorigenesis in nude mice. Cancer Res. 2005;65:10838–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Li YH, Wang YY, Zhong S, Rong ZL, Ren YM, Li ZY, Zhang SP, Chang ZJ, Liu L. Transmembrane helix of novel oncogene with kinase-domain (NOK) influences its oligomerization and limits the activation of RAS/MPAK signaling. Mol Cell. 2009;27:39–45.CrossRefGoogle Scholar
  10. 10.
    Ding X, Jiang QB, Li R, Chen S, Zhang S. NOK/STYK1 has a strong tendency towards forming aggregates and colocalises with epidermal growth factor receptor in endosomes. Biochem Biophys Res Commun. 2012;421:468–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Orang AV, Safaralizadeh R, Hosseinpour Feizi MA, Somi MH. Diagnostic relevance of overexpressed serine threonine tyrosine kinase/novel oncogene with kinase domain (STYK1/NOK) mRNA in colorectal cancer. Asian Pac J Cancer Prev. 2014;15:6685–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Amachika T, Kobayashi D, Moriai R, Tsuji N, Watanabe N. Diagnostic relevance of overexpressed mRNA of novel oncogene with kinase-domain (NOK) in lung cancers. Lung Cancer. 2007;56:337–40.CrossRefPubMedGoogle Scholar
  13. 13.
    Kimbro KS, Duschene K, Willard M, Moore JA, Freeman S. A novel gene STYK1/NOK is upregulated in estrogen receptor-alpha negative estrogen receptor-beta positive breast cancer cells following estrogen treatment. Mol Biol Rep. 2008;35:23–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Jackson KA, Oprea G, Handy J, Kimbro KS. Aberrant STYK1 expression in ovarian cancer tissues and cell lines. J Ovarian Res. 2009;2:15.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    BL Y, Peng XH, Zhao FP, Liu X, Lu J, Wang L, Li G, Chen HH, Li XP. MicroRNA-378 functions as an onco-miR in nasopharyngeal carcinoma by repressing TOB2 expression. Int J Oncol. 2014;44:1215–22.Google Scholar
  16. 16.
    Lee MM, Chen YY, Liu PY, Hsu S, Sheu MJ. Pipoxolan inhibits CL1-5 lung cancer cells migration and invasion through inhibition of MMP-9 and MMP-2. Chem Biol Interact. 2015;236:19–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang Z, Tang X, Zhang Y, Qi R, Li Z, Zhang K, Liu Z, Yang X. Lobaplatin induces apoptosis and arrests cell cycle progression in human cholangiocarcinoma cell line RBE. Biomedicine Pharmacother. 2012;66:161–6.CrossRefGoogle Scholar
  18. 18.
    Shi RY, Yang XR, Shen QJ, Yang LX, Xu Y, Qiu SJ, Sun YF, Zhang X, Wang Z, Zhu K, Qin WX, Tang ZY, Fan J, Zhou J. High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery. Cancer. 2013;119:993–1003.CrossRefPubMedGoogle Scholar
  19. 19.
    Eriksson JE, Dechat T, Grin B, Helfand B, Mendez M, Pallari HM, Goldman RD. Introducing intermediate filaments: from discovery to disease. J Clin Invest. 2009;119:1763–71.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cabeen MT, Jacobs-Wagner C. The bacterial cytoskeleton. Annu Rev Genet. 2010;44:365–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Goldman RD, Khuon S, Chou YH, Opal P, Steinert PM. The function of intermediate filaments in cell shape and cytoskeletal integrity. J Cell Biol. 1996;134:971–83.CrossRefPubMedGoogle Scholar
  22. 22.
    Leader M, Collins M, Patel J, Henry K. Vimentin: an evaluation of its role as a tumour marker. Histopathology. 1987;11:63–72.CrossRefPubMedGoogle Scholar
  23. 23.
    Ramis-Conde I, Chaplain MA, Anderson AR, Drasdo D. Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis. Phys Biol. 2009;6:016008.CrossRefPubMedGoogle Scholar
  24. 24.
    Yuan J, Yan R, Kramer A, Eckerdt F, Roller M, Kaufmann M, Strebhardt K. Cyclin b1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene. 2004;23:5843–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang F, Liu B, Wang Z, XJ Y, Ni QX, Yang WT, Mukaida N, Li YY. A novel regulatory mechanism of Pim-3 kinase stability and its involvement in pancreatic cancer progression. Mol Cancer Res. 2013;11:1508–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Lee MG, Nurse P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature. 1987;327:31–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Kristjansdottir K, Rudolph J. Cdc25 phosphatases and cancer. Chem Biol. 2004;11:1043–51.CrossRefPubMedGoogle Scholar
  28. 28.
    Canel M, Serrels A, Frame MC, Brunton VG. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci. 2013;126:393–401.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical CollegeGuiyangChina

Personalised recommendations