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Current Protein & Peptide Science

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ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

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Research Article

Aspartate β-hydroxylase (ASPH) Accelerates Intrahepatic Cholangiocarcinoma Metastasis via Upregulating SHH Signaling Pathway

Author(s): Yiran Zou, Jianbo Lin, Jian Liu, Fabiao Zhang, Tingsong Yang, Jian Gong, Tao Jiang, Jieliang Zuo, Ruimei Song, Hao Shen, Feng Shen* and Jun Li*

Volume 24, Issue 5, 2023

Published on: 12 May, 2023

Page: [436 - 446] Pages: 11

DOI: 10.2174/1389203724666230502110404

Price: $65

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Abstract

Background: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with a poor prognosis. Aspartate β-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase involved in the post-translational hydroxylation of target proteins. ASPH has been demonstrated to be upregulated in ICC, yet its role remains to be elucidated. This study aimed to investigate the potential function of ASPH in ICC metastasis.

Methods: Survival curves for the overall survival of pan-cancer data from The Cancer Genome Atlas (TCGA) database was depicted using the Kaplan-Meier method and compared using the log-rank test. The expression of ASPH, glycogen synthase kinase (GSK)-3β, phosphorylation GSK-3β (p-GSK-3β), epithelial-mesenchymal transition (EMT) biomarkers, and sonic hedgehog (SHH) signaling elements in ICC cell lines was analyzed by western blot. Wound healing and transwell assays were conducted to examine the effects of ASPH knockdown and overexpression on cell migration and invasion. An immunofluorescence assay was conducted to evaluate the expression of glioma-associated oncogene 2 (GLI2), GSK-3β and ASPH. The effect of ASPH on tumor in vivo was analyzed using a nude mouse xenograft model.

Results: Pan-cancer data showed that expressed ASPH was significantly correlated with a poor prognosis in patients. ASPH knockdown inhibited the migration and invasion of human ICC cells lines QBC939 and RBE. ASPH overexpression contributed to an increase in the N-cadherin and Vimentin, resulting in the promotion of the EMT process. The p-GSK-3β levels decreased in the presence of ASPH overexpression. The overexpression of ASPH led to an upregulation of the expression of SHH signaling elements GLI2 and SUFU. The results of in vivo experiments with a lung metastasis model in nude mice with ICC cell line RBE are consistent with these results.

Conclusion: ASPH accelerated metastasis of ICC cells by facilitating EMT via a GSK-3β/SHH/GLI2 axis-dependent manner, in which phosphorylation of GSK-3β was downregulated and the SHH signaling pathway was activated.

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[1]
El-Diwany, R.; Pawlik, T.M.; Ejaz, A. Intrahepatic Cholangiocarcinoma. Surg. Oncol. Clin. N. Am., 2019, 28(4), 587-599.
[http://dx.doi.org/10.1016/j.soc.2019.06.002] [PMID: 31472907]
[2]
Huang, C.K.; Iwagami, Y.; Aihara, A.; Chung, W.; de la Monte, S.; Thomas, J.M.; Olsen, M.; Carlson, R.; Yu, T.; Dong, X.; Wands, J. Anti-tumor effects of second generation β-hydroxylase inhibitors on cholangiocarcinoma development and progression. PLoS One, 2016, 11(3), e0150336.
[http://dx.doi.org/10.1371/journal.pone.0150336] [PMID: 26954680]
[3]
Kelley, R.K.; Bridgewater, J.; Gores, G.J.; Zhu, A.X. Systemic therapies for intrahepatic cholangiocarcinoma. J. Hepatol., 2020, 72(2), 353-363.
[http://dx.doi.org/10.1016/j.jhep.2019.10.009] [PMID: 31954497]
[4]
Lee, A.J.; Chun, Y.S. Intrahepatic cholangiocarcinoma: The AJCC/UICC 8th edition updates. Chin. Clin. Oncol., 2018, 7(5), 52.
[http://dx.doi.org/10.21037/cco.2018.07.03]
[5]
Massarweh, N.N.; El-Serag, H.B. Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Contr., 2017, 24(3)
[http://dx.doi.org/10.1177/1073274817729245] [PMID: 28975830]
[6]
Korioth, F.; Gieffers, C.; Frey, J. Cloning and characterization of the human gene encoding aspartyl β-hydroxylase. Gene, 1994, 150(2), 395-399.
[http://dx.doi.org/10.1016/0378-1119(94)90460-X] [PMID: 7821814]
[7]
Barboro, P.; Benelli, R.; Tosetti, F.; Costa, D.; Capaia, M.; Astigiano, S.; Venè, R.; Poggi, A.; Ferrari, N. Aspartate β-hydroxylase targeting in castration-resistant prostate cancer modulates the NOTCH/HIF1α/GSK3β crosstalk. Carcinogenesis, 2020, 41(9), 1246-1252.
[http://dx.doi.org/10.1093/carcin/bgaa053] [PMID: 32525968]
[8]
Dong, X.; Lin, Q.; Aihara, A.; Li, Y.; Huang, C.K.; Chung, W.; Tang, Q.; Chen, X.; Carlson, R.; Nadolny, C.; Gabriel, G.; Olsen, M.; Wands, J.R. Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype. Oncotarget, 2015, 6(2), 1231-1248.
[http://dx.doi.org/10.18632/oncotarget.2840] [PMID: 25483102]
[9]
Sturla, L.M.; Tong, M.; Hebda, N.; Gao, J.; Thomas, J.M.; Olsen, M.; de la Monte, S.M. Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas. Heliyon, 2016, 2(12), e00203.
[http://dx.doi.org/10.1016/j.heliyon.2016.e00203] [PMID: 27981247]
[10]
Yao, W.F.; Liu, J.W.; Huang, D.S. MiR-200a inhibits cell proliferation and EMT by down-regulating the ASPH expression levels and affecting ERK and PI3K/Akt pathways in human hepatoma cells. Am. J. Transl. Res., 2018, 10(4), 1117-1130.
[PMID: 29736205]
[11]
Greve, J.M.; Pinkham, A.M.; Cowan, J.A. Human aspartyl (asparaginyl) hydroxylase. A multifaceted enzyme with broad intra- and extra-cellular activity. Metallomics, 2021, 13(8), mfab044.
[http://dx.doi.org/10.1093/mtomcs/mfab044] [PMID: 34283245]
[12]
Lin, Q.; Chen, X.; Meng, F.; Ogawa, K.; Li, M.; Song, R.; Zhang, S.; Zhang, Z.; Kong, X.; Xu, Q.; He, F.; Bai, X.; Sun, B.; Hung, M.C.; Liu, L.; Wands, J.; Dong, X. ASPH-notch axis guided exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis. Mol. Cancer, 2019, 18(1), 156.
[http://dx.doi.org/10.1186/s12943-019-1077-0] [PMID: 31694640]
[13]
Ogawa, K.; Lin, Q.; Li, L.; Bai, X.; Chen, X.; Chen, H.; Kong, R.; Wang, Y.; Zhu, H.; He, F.; Xu, Q.; Liu, L.; Li, M.; Zhang, S.; Nagaoka, K.; Carlson, R.; Safran, H.; Charpentier, K.; Sun, B.; Wands, J.; Dong, X. Aspartate β-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway. J. Hematol. Oncol., 2019, 12(1), 144.
[http://dx.doi.org/10.1186/s13045-019-0837-z] [PMID: 31888763]
[14]
Peng, H.; Guo, Q.; Xiao, Y.; Su, T.; Jiang, T.J.; Guo, L.J.; Wang, M. ASPH regulates osteogenic differentiation and cellular senescence of BMSCs. Front. Cell Dev. Biol., 2020, 8, 872.
[http://dx.doi.org/10.3389/fcell.2020.00872] [PMID: 33015050]
[15]
Zou, Q.; Hou, Y.; Wang, H.; Wang, K.; Xing, X.; Xia, Y.; Wan, X.; Li, J.; Jiao, B.; Liu, J.; Huang, A.; Wu, D.; Xiang, H.; Pawlik, T.M.; Wang, H.; Lau, W.Y.; Wang, Y.; Shen, F. Hydroxylase activity of ASPH promotes hepatocellular carcinoma metastasis through epithelial-to-mesenchymal transition pathway. EBioMedicine, 2018, 31, 287-298.
[http://dx.doi.org/10.1016/j.ebiom.2018.05.004] [PMID: 29764768]
[16]
Aihara, A.; Huang, C.K.; Olsen, M.J.; Lin, Q.; Chung, W.; Tang, Q.; Dong, X.; Wands, J.R. A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma. Hepatology, 2014, 60(4), 1302-1313.
[http://dx.doi.org/10.1002/hep.27275] [PMID: 24954865]
[17]
Tang, C.; Hou, Y.; Wang, H.; Wang, K.; Xiang, H.; Wan, X.; Xia, Y.; Li, J.; Wei, W.; Xu, S.; Lei, Z.; Pawlik, T.M.; Wang, H.; Wu, M.; Shen, F. Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma. Oncogenesis, 2017, 6(7), e362.
[http://dx.doi.org/10.1038/oncsis.2017.64] [PMID: 28714949]
[18]
Wang, K.; Liu, J.; Yan, Z.L.; Li, J.; Shi, L.H.; Cong, W.M.; Xia, Y.; Zou, Q.F.; Xi, T.; Shen, F.; Wang, H.Y.; Wu, M.C. Overexpression of aspartyl-(asparaginyl)-β-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome. Hepatology, 2010, 52(1), 164-173.
[http://dx.doi.org/10.1002/hep.23650] [PMID: 20578260]
[19]
Huang, C.K.; Iwagami, Y.; Zou, J.; Casulli, S.; Lu, S.; Nagaoka, K.; Ji, C.; Ogawa, K.; Cao, K.Y.; Gao, J.S.; Carlson, R.I.; Wands, J.R. Aspartate beta-hydroxylase promotes cholangiocarcinoma progression by modulating RB1 phosphorylation. Cancer Lett., 2018, 429, 1-10.
[http://dx.doi.org/10.1016/j.canlet.2018.04.041] [PMID: 29733964]
[20]
Xu, Y.; Kang, P.; Leng, K.; Yao, Y.; Liao, G.; Han, Y.; Shi, G.; Zhong, X.; Cui, Y. Circ_ASPH promotes cholangiocarcinoma growth and metastasis through the miR-581/ATP-binding cassette transporter G1 signaling pathway. Cancer Commun., 2020, 40(10), 545-550.
[http://dx.doi.org/10.1002/cac2.12083] [PMID: 32735059]
[21]
Tang, Z.; Kang, B.; Li, C.; Chen, T.; Zhang, Z. GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res., 2019, 47(W1), W556-W560.
[http://dx.doi.org/10.1093/nar/gkz430] [PMID: 31114875]
[22]
Martinotti, S.; Ranzato, E. Scratch wound healing assay. Methods Mol. Biol., 2019, 2109, 225-229.
[http://dx.doi.org/10.1007/7651_2019_259] [PMID: 31414347]
[23]
Wang, Y.; Zhu, Y.; Gu, Y.; Ma, M.; Wang, Y.; Qi, S.; Zeng, Y.; Zhu, R.; Wang, X.; Yu, P.; Xu, J.; Shu, Y.; Yu, F.X. Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis. Cell Rep., 2021, 36(8), 109596.
[http://dx.doi.org/10.1016/j.celrep.2021.109596] [PMID: 34433060]
[24]
Diepenbruck, M.; Christofori, G. Epithelial–mesenchymal transition (EMT) and metastasis: Yes, no, maybe? Curr. Opin. Cell Biol., 2016, 43, 7-13.
[http://dx.doi.org/10.1016/j.ceb.2016.06.002] [PMID: 27371787]
[25]
Du, B.; Shim, J. Targeting Epithelial–Mesenchymal Transition (EMT) to overcome drug resistance in cancer. Molecules, 2016, 21(7), 965.
[http://dx.doi.org/10.3390/molecules21070965] [PMID: 27455225]
[26]
Pastushenko, I.; Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol., 2019, 29(3), 212-226.
[http://dx.doi.org/10.1016/j.tcb.2018.12.001] [PMID: 30594349]
[27]
Saitoh, M. Involvement of partial EMT in cancer progression. J. Biochem., 2018, 164(4), 257-264.
[http://dx.doi.org/10.1093/jb/mvy047] [PMID: 29726955]
[28]
Zhang, J.; Tian, X.J.; Xing, J. Signal transduction pathways of EMT induced by TGF-β SHH, and WNT and their crosstalks. J. Clin. Med., 2016, 5(4), 41.
[http://dx.doi.org/10.3390/jcm5040041] [PMID: 27043642]
[29]
Skoda, A.M.; Simovic, D.; Karin, V.; Kardum, V.; Vranic, S.; Serman, L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn. J. Basic Med. Sci., 2018, 18(1), 8-20.
[http://dx.doi.org/10.17305/bjbms.2018.2756] [PMID: 29274272]
[30]
Carballo, G.B.; Honorato, J.R.; de Lopes, G.P.F.; Spohr, T.C.L.S. A highlight on Sonic hedgehog pathway. Cell Commun. Signal., 2018, 16(1), 11.
[http://dx.doi.org/10.1186/s12964-018-0220-7] [PMID: 29558958]
[31]
Zhou, C.; Zheng, Y.; Li, L.; Zhai, W.; Li, R.; Liang, Z.; Zhao, L. Adrenomedullin promotes intrahepatic cholangiocellular carcinoma metastasis and invasion by inducing epithelial-mesenchymal transition. Oncol. Rep., 2015, 34(2), 610-616.
[http://dx.doi.org/10.3892/or.2015.4034] [PMID: 26043778]
[32]
Zhu, Z.; Chen, W.; Yin, X.; Lai, J.; Wang, Q.; Liang, L.; Wang, W.; Wang, A.; Zheng, C. WAVE3 induces EMT and promotes migration and invasion in intrahepatic cholangiocarcinoma. Dig. Dis. Sci., 2016, 61(7), 1950-1960.
[http://dx.doi.org/10.1007/s10620-016-4102-9] [PMID: 26971088]
[33]
Liu, L.Z.; He, Y.Z.; Dong, P.P.; Ma, L.J.; Wang, Z.C.; Liu, X.Y.; Duan, M.; Yang, L.X.; Shi, J.Y.; Zhou, J.; Fan, J.; Gao, Q.; Wang, X.Y. Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway. Oncotarget, 2016, 7(46), 75210-75220.
[http://dx.doi.org/10.18632/oncotarget.12116] [PMID: 27655691]
[34]
Jeng, K.S.; Chang, C.F.; Lin, S.S. Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int. J. Mol. Sci., 2020, 21(3), 758.
[http://dx.doi.org/10.3390/ijms21030758] [PMID: 31979397]
[35]
Martin, J.; Donnelly, J.M.; Houghton, J.; Zavros, Y. The role of sonic hedgehog reemergence during gastric cancer. Dig. Dis. Sci., 2010, 55(6), 1516-1524.
[http://dx.doi.org/10.1007/s10620-010-1252-z] [PMID: 20437100]
[36]
Rosow, D.E.; Liss, A.S.; Strobel, O.; Fritz, S.; Bausch, D.; Valsangkar, N.P.; Alsina, J.; Kulemann, B.; Park, J.K.; Yamaguchi, J.; LaFemina, J.; Thayer, S.P. Sonic Hedgehog in pancreatic cancer: From bench to bedside, then back to the bench. Surgery, 2012, 152(3)(Suppl. 1), S19-S32.
[http://dx.doi.org/10.1016/j.surg.2012.05.030] [PMID: 22770959]
[37]
El Khatib, M.; Kalnytska, A.; Palagani, V.; Kossatz, U.; Manns, M.P.; Malek, N.P.; Wilkens, L.; Plentz, R.R. Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma. Hepatology, 2013, 57(3), 1035-1045.
[http://dx.doi.org/10.1002/hep.26147] [PMID: 23172661]
[38]
Cho, K.; Moon, H.; Seo, S.H.; Ro, S.W.; Kim, B.K. Pharmacological inhibition of sonic hedgehog signaling suppresses tumor development in a murine model of intrahepatic cholangiocarcinoma. Int. J. Mol. Sci., 2021, 22(24), 13214.
[http://dx.doi.org/10.3390/ijms222413214] [PMID: 34948011]
[39]
Fan, Y-H.; Ding, J.; Nguyen, S.; Liu, X-J.; Xu, G.; Zhou, H-Y.; Duan, N-N.; Yang, S-M.; Zern, M.A.; Wu, J. Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells. Oncogene, 2016, 35(1), 116-124.
[http://dx.doi.org/10.1038/onc.2015.67] [PMID: 25772244]
[40]
Bijlsma, M.F.; Spek, C.A.; Peppelenbosch, M.P. Hedgehog: An unusual signal transducer. BioEssays, 2004, 26(4), 387-394.
[http://dx.doi.org/10.1002/bies.20007] [PMID: 15057936]
[41]
Takenaka, K.; Kise, Y.; Miki, H. GSK3β positively regulates Hedgehog signaling through Sufu in mammalian cells. Biochem. Biophys. Res. Commun., 2007, 353(2), 501-508.
[http://dx.doi.org/10.1016/j.bbrc.2006.12.058] [PMID: 17182001]
[42]
Kanwal, M.; Smahel, M.; Olsen, M.; Smahelova, J.; Tachezy, R. Aspartate β-hydroxylase as a target for cancer therapy. J. Exp. Clin. Cancer Res., 2020, 39(1), 163.
[http://dx.doi.org/10.1186/s13046-020-01669-w] [PMID: 32811566]
[43]
Iwagami, Y.; Huang, C.K.; Olsen, M.J.; Thomas, J.M.; Jang, G.; Kim, M.; Lin, Q.; Carlson, R.I.; Wagner, C.E.; Dong, X.; Wands, J.R. Aspartate β-hydroxylase modulates cellular senescence through glycogen synthase kinase 3β in hepatocellular carcinoma. Hepatology, 2016, 63(4), 1213-1226.
[http://dx.doi.org/10.1002/hep.28411] [PMID: 26683595]

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