FXYD6: a novel therapeutic target toward hepatocellular carcinoma

Abstract

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na⁺/K⁺-ATPase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma (HCC) and enhances the migration and proliferation of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na⁺/K⁺-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

Keywords

FXYD6 / hepatocellular carcinoma (HCC) / tumor progression / therapeutic target / Na⁺/K⁺-ATPase / Src-ERK signaling pathway

References

[1] Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, Krasucki R, Lawrence J, Bass NJ, Quested D (2007) A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am J Hum Genet80: 664-672

[2] Delprat B, Puel JL, Geering K (2007a) Dynamic expression of FXYD6 in the inner ear suggests a role of the protein in endolymph homeostasis and neuronal activity. Dev Dyn236: 2534-2540

[3] Delprat B, Schaert D, Roy S, Wang J, Puel JL, Geering K (2007b) FXYD6 is a novel regulator of Na, K-ATPase expressed in the inner ear. J Biol Chem282: 7450-7456

[4] Garty H, Karlish SJD (2006) Role of FXYD proteins in ion transport. Annu Rev Physiol68: 431-459

[5] Gaut JP, Crimmins DL, Lockwood CM, McQuillan JJ, Ladenson JH (2013) Expression of the Na+/K+ -transporting ATPase gamma subunit FXYD2 in renal tumors. Mod Pathol26: 716-724

[6] Geering K (2006) FXYD proteins: new regulators of Na-k-ATPase. Am J Physiol Renal290: F241-F250

[7] Grzmil M, Voigt S, Thelen P, Hemmerlein B, Helmke K, Burfeind P (2004) Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells. Int J Oncol24: 97-105

[8] Han CP, Kok LF, Wang PH, Wu TS, Tyan YS, Cheng YW, Lee MY, Yang SF (2009) Scoring of p16(INK4a) immunohistochemistry based on independent nuclear staining alone can sufficiently distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. Mod Pathol22: 797-806

[9] Ino Y, Gotoh M, Sakamoto M, Tsukagoshi K, Hirohashi S (2002) Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis. Proc Natl Acad Sci USA99: 365-370

[10] Kayed H, Kleeff J, Kolb A, Ketterer K, Keleg S, Felix K, Giese T, Penzel R, Zentgraf H, Buchler MW (2006) FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth. Int J Cancer118: 43-54

[11] Mijatovic T, Ingrassia L, Facchini V, Kiss R (2008) Na+/K+-ATPase alpha subunits as new targets in anticancer therapy. Expert Opin Ther Targets12: 1403-1417

[12] Mishra NK, Peleg Y, Cirri E, Belogus T, Lifshitz Y, Voelker DR, Apell HJ, Garty H, Karlish SJD (2011) FXYD proteins stabilize Na, K-ATPase amplification of specific phosphatidylserine-protein interactions. J Biol Chem286: 9699-9712

[13] Prassas I, Diamandis EP (2008) Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov7: 926-935

[14] Sato H, Ino Y, Miura A, Abe Y, Sakai H, Ito K, Hirohashi S (2003) Dysadherin: expression and clinical significance in thyroid carcinoma. J Clin Endocrinol Metab88: 4407-4412

[15] Shiina N, Yamaguchi K, Tokunaga M (2010) RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks. J Neurosci30: 12816-12830

[16] Sweadner KJ, Rael E (2000) The FXYD gene family of small ion transport regulators or channels: cDNA sequence, protein signature sequence, and expression. Genomics68: 41-56

[17] Widegren E, Onnesjo S, Arbman G, Kayed H, Zentgraf H, Kleeff J, Zhang H, Sun XF (2009) Expression of FXYD3 protein in relation to biological and clinicopathological variables in colorectal cancers. Chemotherapy55: 407-413

[18] Xu ZW, Wang FM, Gao MJ, Chen XY, Hu WL, Xu RC (2010) Targeting the Na+/K+-ATPase alpha 1 subunit of hepatoma HepG2 cell line to induce apoptosis and cell cycle arresting. Biol Pharm Bull33: 743-751

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.