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Recent advances in research on aspartate β-hydroxylase (ASPH) in pancreatic cancer: A brief update

Guofang Hou, Boran Xu, Yanghui Bi, Chuanlin Wu, Beibei Ru, Bei Sun, Xuewei Bai


Pancreatic cancer (PC) is a highly aggressive tumor, often difficult to diagnose and treat. Aspartate β-hydroxylase (ASPH) is a type II transmembrane protein and the member of α-ketoglutarate-dependent dioxygenase family, found to be overexpressed in different cancer types, including PC. ASPH appears to be involved in the regulation of proliferation, invasion and metastasis of PC cells through multiple signaling pathways, suggesting its role as a tumor biomarker and therapeutic target. In this review, we briefly summarize the possible mechanisms of action of ASPH in PC and recent progress in the therapeutic approaches targeting ASPH.


Aspartate β-hydroxylase; pancreatic cancer; Notch signaling pathway; Mitochondrial DNA; NK cell

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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11-30.

Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378(9791):607-20.

Lin QJ, Yang F, Jin C, Fu DL. Current status and progress of pancreatic cancer in China. World J Gastroenterol 2015;21(26):7988-8003.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7-30.

Tsai S, Evans DB. Therapeutic advances in localized pancreatic cancer. JAMA Surg 2016;151(9):862-8.

Rahib L, Smith BD, Izeberg R, Osenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74(11):2913-21.

Ronke RS, VanDusen WJ, Garsky VM, Jacobs JW, Sardana MK, Stern AM, et al. Aspartyl beta-hydroxylase: In vitro hydroxylation of a synthetic peptide based on the structure of the first growth factor-like domain of human factor IX. Proc Natl Acad Sci U S A 1989;86(10):3609-13.

Stenflo J, Holme E, Lindstedt S, Chandramouli N, Huang LH, Tam JP, et al. Hydroxylation of aspartic acid in domains homologous to the epidermal growth factor precursor is catalyzed by a 2-oxoglutarate-dependent dioxygenase. Proc Natl Acad Sci U S A 1989;86(2):444-7.

Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y, et al. Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods. J Biol Chem 1999;274(46):32961-9.

Zimrin AB, Pepper MS, McMahon GA, Nguyen F, Montesano R, Maciag T. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem 1996;271(51):32499-502.

McGinnis K, Ku GM, VanDusen WJ, Fu J, Garsky V, Stern AM, et al. Site-directed mutagenesis of residues in a conserved region of bovine aspartyl (asparaginyl) beta-hydroxylase: Evidence that histidine 675 has a role in binding Fe2+. Biochemistry 1996;35(13):3957-62.

Wands JR, Lavaissiere L, Moradpour D, de la Monte S, Mohr L, Nicolau C, et al. Immunological approach to hepatocellular carcinoma. J Viral Hepat 1997;4(Suppl2):60-74.

Ho SP, Scully MS, Krauthauser CM, Wexler EJ, Stow MD, Dinchuk JE, et al. Antisense oligonucleotides selectively regulate aspartyl beta-hydroxylase and its truncated protein isoform in vitro but distribute poorly into A549 tumors in vivo. J Pharmacol Exp Ther 2002;302(2):795-803.

Dinchuk JE, Henderson NL, Burn TC, Huber R, Ho SP, Link J, et al. Aspartyl beta-hydroxylase (Asph) and an evolutionarily conserved isoform of Asph missing the catalytic domain share exons with junctin. J Biol Chem 2000;275(50):39543-54.

Treves S, Feriotto G, Moccagatta L, Gambari R, Zorzato F. Molecular cloning, expression, functional characterization, chromosomal localization, and gene structure of junctate, a novel integral calcium binding protein of sarco(endo)plasmic reticulum membrane. J Biol Chem 2000;275(50):39555-68.

Tomimaru Y, Koga H, Yano H, de la Monte SM, Wands JR, Kim M. Up-regulation of TCF-4 isoform responsive target genes in hepatocellular carcinoma. Liver Int 2013;33(7):1100-12.

Cantarini MC, de la Monte SM, Pang M, Tong M, D'Errico A, Trevisani F, et al. Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology 2006;44(2):446-57.

Chung W, Kim M, de la Monte S, Longato L, Carlson R, Slagle BL, et al. Activation of signal transduction pathways during hepatic oncogenesis. Cancer Lett 2016;370(1):1-9.

Bommer GT, Feng Y, Iura A, Giordano TJ, Kuick R, Kadikoy H, et al. IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. J Biol Chem 2010;285(3):1928-38.

Saltiel AR, Pessin JE. Insulin signaling pathways in time and space. Trends Cell Biol 2002;12(2):65-71.

Mohr L, Tanaka S, Wands JR. Ethanol inhibits hepatocyte proliferation in insulin receptor substrate 1 transgenic mice. Gastroenterology 1998;115(6):1558-65.

de la Monte S, Tamaki S, Cantarini MC, Ince N, Wiedmann M, Cater J, et al. Aspartyl-(asparaginyl)-b-bydroxylase regulates hepatocellular carcinoma invasiveness. J Hepatol 2006;44(5):971-83.

Patel N, Khan AO, Mansour A, Mohamed JY, Al-Assiri A, Haddad R, et al. Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome. Am J Hum Genet 2014;94(5):755-9.

Wang Z, Li Y, Kong D, Sarkar FH. The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr Drug Targets 2010;11(6):745-51.

Wang K, Liu J, Yan ZL, Li J, Shi LH, Cong WM, et al. Overexpression of aspartyl-(asparaginyl)-beta-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome. Hepatology 2010;52(1):164-73.

Ince N, de la Monte SM, Wands JR. Overexpression of human aspartyl (asparaginyl) beta-hydroxylase is associated with malignant transformation. Cancer Res 2000;60(5):1261-6.

Dong X, Lin Q, Aihara A, Li Y, Huang CK, Chung W, et al. Aspartate beta-hydroxylase expression promotes a malignant pancreatic cellular phenotype. Oncotarget 2015;6(2):1231-48.

Avila JL, Kissil JL. Notch signaling in pancreatic cancer: Oncogene or tumor suppressor? Trends Mol Med 2013;19(5):320-7.

Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B, et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res 2015;21(9):2084-95.

Hu H, Zhou L, Awadallah A, Xin W. Significance of Notch1-signaling pathway in human pancreatic development and carcinogenesis. Appl Immunohistochem Mol Morphol 2013;21(3):242-7.

Vo K, Amarasinghe B, Washington K, Gonzalez A, Berlin J, Dang TP. Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation. Mol Cancer 2011;10:138.

Chiorean EG, Coveler AL. Pancreatic cancer: Optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015;9:3529-45.

Gao J, Lang B, Wang ZW. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 2017;7(2):173-86.

Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: Targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 2013;6:1249-59.

Espinoza I, Miele L. Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett 2013;341(1):41-5.

Wang J, Han F, Wu J, Lee SW, Chan CH, Wu CY, et al. The role of Skp2 in hematopoietic stem cell quiescence, pool size, and self-renewal. Blood 2011;118(20):5429-38.

Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: A little bit of everything but not all the time. Nat Rev Cancer 2011;11(5):338-51.

Tang C, Hou Y, Wang H, Wang K, Xiang H, Wan X, et al. Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma. Oncogenesis 2017;6(7):e362.

Kassauei K, Habbe N, Mullendore ME, Karikari CA, Maitra A, Feldmann G. Mitochondrial DNA mutations in pancreatic cancer. Int J Gastrointest Cancer 2006;37(2-3):57-64.

Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE. Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations. Cancer Res 2001;61(4):1299-304.

Navaglia F, Basso D, Fogar P, Sperti C, Greco E, Zambon CF, et al. Mitochondrial DNA D-loop in pancreatic cancer: Somatic mutations are epiphenomena while the germline 16519 T variant worsens metabolism and outcome. Am J Clin Pathol 2006;126(4):593-601.

Kang D, Kim SH, Hamasaki N. Mitochondrial transcription factor A (TFAM): Roles in maintenance of mtDNA and cellular functions. Mitochondrion 2007;7(1-2):39-44.

Campbell CT, Kolesar JE, Kaufman BA. Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim Biophys Acta 2012;1819(9-10):921-9.

Choi YS, Hoon Jeong J, Min HK, Jung HJ, Hwang D, Lee SW, et al. Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: Identification of mitochondrial histones. Mol Biosyst 2011;7(5):1523-36.

Wallace DC. Mitochondria and cancer. Nat Rev Cancer 2012;12(10):685-98.

Lawton M, Tong M, Gundogan F, Wands JR, de la Monte SM. Aspartyl-(asparaginyl) beta-hydroxylase, hypoxia-inducible factor-alpha and Notch cross-talk in regulating neuronal motility. Oxid Med Cell Longev 2010;3(5):347-56.

Garcea G, Dennison AR, Steward WP, Berry DP. Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology 2005;5(6):514-29.

Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol 2005;42(4):501-10.

Lieberman LA, Hunter CA. Regulatory pathways involved in the infection-induced production of IFN-gamma by NK cells. Microbes Infect 2002;4(15):1531-8.

Zwirner NW, Fuertes MB, Girart MV, Domaica CI, Rossi LE. Cytokine-driven regulation of NK cell functions in tumor immunity: Role of the MICA-NKG2D system. Cytokine Growth Factor Rev 2007;18(1-2):159-70.

Fiala M. Curcumin and omega-3 fatty acids enhance NK cell-induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-γ production: Benefits of omega-3 with curcumin against cancer. Molecules 2015;20(2):3020-6.

Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 2015;15(4):243-54.

Sun C, Sun H, Zhang C, Tian Z. NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. Cell Mol Immunol 2015;12(3):292-302.

Fang F, Xiao W, Tian Z. NK cell-based immunotherapy for cancer. Semin Immunol 2017;31:37-54.

Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol 2017;8:1124.

Huyan T, Li Q, Ye LJ, Yang H, Xue XP, Zhang MJ, et al. Inhibition of human natural killer cell functional activity by human aspartyl β-hydroxylase. Int Immunopharmacol 2014;23(2):452-9.

Chiossone L, Vitale C, Cottalasso F, Moretti S, Azzarone B, Moretta L, et al. Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: Evidence for different susceptibility of IL-2- versus IL-15-activated NK cells. Blood 2007;109(9):3767-75.

Ogbomo H, Michaelis M, Kreuter J, Doerr HW, Cinatl Jr J. Histone deacetylase inhibitors suppress natural killer cell cytolytic activity. FEBS Lett 2007;581(7):1317-22.

Shimoda M, Tomimaru Y, Charpentier K.P, Safran H, Carlson RI, Wands J. Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma. J Hepatol 2012;56(5):1129-35.

Solar P, Sytkowski AJ. Differentially expressed genes associated with cisplatin resistance in human ovarian adenocarcinoma cell line A2780. Cancer Lett 2011;309(1):11-8.

Tomimaru Y, Mishra S, Safran H, Charpentier KP, Martin W, De Groot AS, et al. Aspartate-β-hydroxylase induces epitope-specific T cell responses in hepatocellular carcinoma. Vaccine 2015;33(10):1256-66.

Noda T, Shimoda M, Ortiz V, Sirica AE, Wands JR. Immunization with aspartate-β-hydroxylase-loaded dendritic cells produces antitumor effects in a rat model of intrahepatic cholangiocarcinoma. Hepatology 2012;55(1):86-97.

Sturla LM, Tong M, Hebda N, Gao J, Thomas JM, Olsen M, et al. Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas. Heliyon 2016;2(12):2-31.

Revskaya E, Jiang Z, Morgenstern A, Bruchertseifer F, Sesay M, Walker S, et al. A radiolabeled fully human antibody to human aspartyl (asparaginyl) β-hydroxylase is a promising agent for imaging and therapy of metastatic breast cancer. Cancer Biother Radiopharm 2017;32(2):57-65.

Maeda T, Sepe P, Lahousse S, Tamaki S, Enjoji M, Wands JR, et al. Antisense oligodeoxynucleotides directed against aspartyl (asparaginyl) beta-hydroxylase suppress migration of cholangiocarcinoma cells. J Hepatol 2003;38(5):615-22.

Huyan T, Li Q, Dong DD, Yang H, Xue XP, Huang QS. Development of a novel anti-human aspartyl-(asparaginyl) β-hydroxylase monoclonal antibody with diagnostic and therapeutic potential. Oncol Lett 2017;13(3):1539-46.


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