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Caveolin-1 promotes Rfng expression via Erk-Jnk-p38 signaling pathway in mouse hepatocarcinoma cells

  • Cheng Zhang
  • Qiong Wu
  • Huang Huang
  • Xixi Chen
  • Tianmiao Huang
  • Wenli Li
  • Yubo LiuEmail author
  • Jianing ZhangEmail author
Original Article
  • 148 Downloads

Abstract

Caveolin-1 (Cav-1) is a critical structural protein of caveolae and plays an oncogene-like role by participating in abnormal protein glycosylation in hepatocellular carcinoma (HCC). However, the mechanism by which Cav-1 regulates glycosylation and glycosyltransferase expression has not been completely defined. Here, we show that Cav-1 promotes the expression of Rfng, which is a β-1,3-N-acetylglucosaminyltransferase included in the Fringe family. In this study, we showed that the mouse HCC cell line, Hepa1–6, with low Rfng transcription and protein levels, lacked Cav-1 expression, whereas strong Rfng expression was found in the mouse HCC cell line Hca-F, with high transcription and protein levels for Cav-1. Subsequently Cav-1 overexpression in Hepa1–6 was found to activate mitogen-activated protein kinase (MAPK) signaling and induce phosphorylation of the transcription factors Hnf4a and Sp1, which bind to the Rfng promoter region to promote its transcription. On the contrary, when knocking down Cav-1 expression in Hca-F, the activity of the MAPK pathway was significantly inhibited, and phosphorylation of Hnf4a, Sp1 and the expression of Rfng were attenuated. These data reveal that Cav-1 promotes phosphorylation of transcription factors Hnf4a and Sp1, which bind to the Rfng promoter region, via the MAPK signaling pathway, to induce the transcription of Rfng. Our current findings provide molecular genetic evidence that Cav-1 plays an important role in regulating glycosyltransferase expression and may participate in the abnormal glycosylation that mediates the invasion and metastasis of HCC.

Keywords

Caveolin-1 Rfng MAPK Hnf4a Sp1 HCC 

Notes

Supplementary material

13105_2019_703_MOESM1_ESM.xlsx (575 kb)
ESM 1 (XLSX 574 kb)

References

  1. 1.
    Aster JC, Pear WS, Blacklow SC (2017) The Varied Roles of Notch in Cancer. Annu Rev Pathol 12:245–275CrossRefPubMedGoogle Scholar
  2. 2.
    Dennis JW, Granovsky M, Warren CE (1999) Protein glycosylation in development and disease. Bioessays 21:412–421CrossRefPubMedGoogle Scholar
  3. 3.
    Fernandez-Rojo MA, Ramm GA (2016) Caveolin-1 function in liver physiology and disease. Trends Mol Med 22:889–904CrossRefPubMedGoogle Scholar
  4. 4.
    Haines N, Irvine KD (2003) Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 4:786–797CrossRefPubMedGoogle Scholar
  5. 5.
    Hoseth EZ, Krull F, Dieset I, Morch RH, Hope S, Gardsjord ES, Steen NE, Melle I, Brattbakk HR, Steen VM, Aukrust P, Djurovic S, Andreassen OA, Ueland T (2018) Attenuated Notch signaling in schizophrenia and bipolar disorder. Sci Rep 8:5349CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hu H, Han T, Zhuo M, Wu LL, Yuan C, Wu L, Lei W, Jiao F, Wang LW (2017) Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent signalling in pancreatic cancer. Sci Rep 7:470CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Huang H, Liu Y, Yu P, Qu J, Guo Y, Li W, Wang S, Zhang J (2018) MiR-23a transcriptional activated by Runx2 increases metastatic potential of mouse hepatoma cell via directly targeting Mgat3. Sci Rep 8:7366CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jia L, Wang S, Zhou H, Cao J, Hu Y, Zhang J (2006) Caveolin-1 up-regulates CD147 glycosylation and the invasive capability of murine hepatocarcinoma cell lines. Int J Biochem Cell Biol 38:1584–1593CrossRefPubMedGoogle Scholar
  9. 9.
    Jiang Y, Lin X, Tang Z, Lee C, Tian G, Du Y, Yin X, Ren X, Huang L, Ye Z, Chen W, Zhang F, Mi J, Gao Z, Wang S, Chen Q, Xing L, Wang B, Cao Y, Sessa WC, Ju R, Liu Y, Li X (2017) Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK. Proc Natl Acad Sci USA 114:10737–10742CrossRefPubMedGoogle Scholar
  10. 10.
    Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF (1997) A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 124:2245–2254PubMedGoogle Scholar
  11. 11.
    Kadur Lakshminarasimha Murthy P, Srinivasan T, Bochter MS, Xi R, Varanko AK, Tung KL, Semerci F, Xu K, Maletic-Savatic M, Cole SE, Shen X (2018) Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis. Elife 7:e35710CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kakuda S, Haltiwanger RS (2017) Deciphering the Fringe-mediated Notch code: identification of activating and inhibiting sites allowing discrimination between ligands. Dev Cell 40:193–201CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kaushik DK, Hahn JN, Yong VW (2015) EMMPRIN, an upstream regulator of MMPs, in CNS biology. Matrix Biol 44-46:138–146CrossRefPubMedGoogle Scholar
  14. 14.
    Khan A, Fornes O, Stigliani A, Gheorghe M, Castro-Mondragon JA, van der Lee R, Bessy A, Cheneby J, Kulkarni SR, Tan G, Baranasic D, Arenillas DJ, Sandelin A, Vandepoele K, Lenhard B, Ballester B, Wasserman WW, Parcy F, Mathelier A (2018) JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res 46:D260–d266CrossRefPubMedGoogle Scholar
  15. 15.
    Lamaze C, Tardif N, Dewulf M, Vassilopoulos S, Blouin CM (2017) The caveolae dress code: structure and signaling. Curr Opin Cell Biol 47:117–125CrossRefPubMedGoogle Scholar
  16. 16.
    Lee SH, Lee YJ, Park SW, Kim HS, Han HJ (2011) Caveolin-1 and integrin beta1 regulate embryonic stem cell proliferation via p38 MAPK and FAK in high glucose. J Cell Physiol 226:1850–1859CrossRefPubMedGoogle Scholar
  17. 17.
    Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12:323CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Luo Y, Nita-Lazar A, Haltiwanger RS (2006) Two distinct pathways for O-fucosylation of epidermal growth factor-like or thrombospondin type 1 repeats. J Biol Chem 281:9385–9392CrossRefPubMedGoogle Scholar
  19. 19.
    Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2015) Caveolae and signalling in cancer. Nat Rev Cancer 15:225–237CrossRefPubMedGoogle Scholar
  20. 20.
    Parton RG, del Pozo MA (2013) Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol 14:98–112CrossRefPubMedGoogle Scholar
  21. 21.
    Pinho SS, Reis CA (2015) Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer 15:540–555CrossRefPubMedGoogle Scholar
  22. 22.
    Ryu BK, Lee MG, Kim NH, Lee KY, Oh SJ, Moon JR, Kim HJ, Chi SG (2017) Bidirectional alteration of Cav-1 expression is associated with mitogenic conversion of its function in gastric tumor progression. BMC Cancer 17:766CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Simo R, Barbosa-Desongles A, Hernandez C, Selva DM (2012) IL1beta down-regulation of sex hormone-binding globulin production by decreasing HNF-4alpha via MEK-1/2 and JNK MAPK pathways. Mol Endocrinol 26:1917–1927CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Song B, Tang JW, Wang B, Cui XN, Zhou CH, Hou L (2005) Screening for lymphatic metastasis-associated genes in mouse hepatocarcinoma cell lines Hca-F and Hca-P using gene chip (in Chinese). Ai Zheng 24:774–780Google Scholar
  25. 25.
    Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP (2012) Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 7:423–467CrossRefPubMedGoogle Scholar
  26. 26.
    Wang DX, Pan YQ, Liu B, Dai L (2018) Cav-1 promotes atherosclerosis by activating JNK-associated signaling. Biochem Biophys Res Commun 503:513–520CrossRefPubMedGoogle Scholar
  27. 27.
    Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol Biol Cell 16:927–942CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yin H, Liu T, Zhang Y, Yang B (2016) Caveolin proteins: a molecular insight into disease. Front Med 10:397–404CrossRefPubMedGoogle Scholar
  29. 29.
    Yu S, Fan J, Liu L, Zhang L, Wang S, Zhang J (2013) Caveolin-1 up-regulates integrin alpha2,6-sialylation to promote integrin alpha5beta1-dependent hepatocarcinoma cell adhesion. FEBS Lett 587:782–787CrossRefPubMedGoogle Scholar

Copyright information

© University of Navarra 2019

Authors and Affiliations

  1. 1.School of Life Science and MedicineDalian University of TechnologyPanjinChina
  2. 2.School of Life Science and BiotechnologyDalian University of TechnologyDalianChina

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