Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Paeoniflorin Affects Hepatocellular Carcinoma Progression by Inhibiting Wnt/β-Catenin Pathway through Downregulation of 5-HT1D

Author(s): Yang Zhou, Xun Liu, Yahan Gao, Rulan Tan, Zhiyuan Wu, Qixin Zhong and Feng Zeng*

Volume 22, Issue 9, 2021

Published on: 09 October, 2020

Page: [1246 - 1253] Pages: 8

DOI: 10.2174/1389201021666201009153808

Price: $65

Abstract

Background: Hepatocellular Carcinoma (HCC) is a primary liver cancer with high mortality. Paeoniflorin is a pinane monoterpene picroside with anti-tumor effect isolated from Chinese peony root and white peony root.

Objective: The study was conducted to investigate the underlying mechanism of Paeoniflorin (PF) regulating Hepatocellular Carcinoma (HCC) progression via 5-hydroxytryptamine receptor 1D (5-HT1D).

Methods: HepG2 and SMMC-7721 hepatoma cells were treated with different concentrations of PF (0, 5, 10, 20 μM). Cell proliferation, apoptosis, migration, and invasion were examined by CCK-8 and colony formation assays, flow cytometry, wound healing assay, and transwell assay, respectively. RTqPCR assay was used to detect the expression level of 5-HT1D, and Western blot assay was used to detect the expressions of 5-HT1D and Wnt/β-catenin pathway-related proteins.

Results: With the increase in PF concentration, the mRNA levels of 5-HT1D in HepG2 and SMMC- 7721 hepatoma cells were decreased in a dose-dependent manner, and the proliferation, colony formation, migration and invasion ability of cells were gradually weakened, while the apoptosis rate was gradually increased. Overexpression of 5-HT1D significantly promoted the proliferation, colony formation, migration and invasion of HepG2 and SMMC-7721 cells, and increased the expression of Wnt/β-catenin pathway-related proteins, β -actenin, survivin, C-myc, and Cyclin D1. Furthermore, 5-HT1D overexpression could reverse the effect of PF on hepatoma cells and inhibit the expressions of Wnt/β-catenin pathway-related proteins.

Conclusion: PF may inhibit the progression of HCC by blocking Wnt/β-catenin pathway expression through downregulating 5-HT1D.

Keywords: Hepatocellular carcinoma, paeoniflorin, 5-HT1D, Wnt/β-catenin pathway, proliferation, migration.

« Previous Next »
Graphical Abstract

[1]
Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: A systematic analysis for the global burden of disease study 2015. Lancet, 2016, 388(10053), 1459-1544.
[http://dx.doi.org/10.1016/S0140-6736(16)31012-1] [PMID: 27733281]
[2]
Yu, J.; Xu, Q.G.; Wang, Z.G.; Yang, Y.; Zhang, L.; Ma, J.Z.; Sun, S.H.; Yang, F.; Zhou, W.P. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J. Hepatol., 2018, 68(6), 1214-1227.
[http://dx.doi.org/10.1016/j.jhep.2018.01.012] [PMID: 29378234]
[3]
Flores, A.; Marrero, J.A. Emerging trends in hepatocellular carcinoma: Focus on diagnosis and therapeutics. Clin. Med. Insights Oncol., 2014, 8, 71-76.
[http://dx.doi.org/10.4137/CMO.S9926] [PMID: 24899827]
[4]
Bruix, J.; Gores, G.J.; Mazzaferro, V. Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut, 2014, 63(5), 844-855.
[http://dx.doi.org/10.1136/gutjnl-2013-306627] [PMID: 24531850]
[5]
Page, A.J.; Cosgrove, D.C.; Philosophe, B.; Pawlik, T.M. Hepatocellular carcinoma: diagnosis, management, and prognosis. Surg. Oncol. Clin. N. Am., 2014, 23(2), 289-311.
[http://dx.doi.org/10.1016/j.soc.2013.10.006] [PMID: 24560111]
[6]
Zhao, N.; Wang, R.; Zhou, L.; Zhu, Y.; Gong, J.; Zhuang, S.M. MicroRNA-26b suppresses the NF-κB signaling and enhances the chemosensitivity of hepatocellular carcinoma cells by targeting TAK1 and TAB3. Mol. Cancer, 2014, 13, 35.
[http://dx.doi.org/10.1186/1476-4598-13-35] [PMID: 24565101]
[7]
Iwata, H.; Shibamoto, Y.; Hashizume, C.; Mori, Y.; Kobayashi, T.; Hayashi, N.; Kosaki, K.; Ishikawa, T.; Kuzuya, T.; Utsunomiya, S. Hypofractionated stereotactic body radiotherapy for primary and metastatic liver tumors using the novalis image-guided system: preliminary results regarding efficacy and toxicity. Technol. Cancer Res. Treat., 2010, 9(6), 619-627.
[http://dx.doi.org/10.1177/153303461000900610] [PMID: 21070084]
[8]
Ma, S.; Jiao, B.; Liu, X.; Yi, H.; Kong, D.; Gao, L.; Zhao, G.; Yang, Y.; Liu, X. Approach to radiation therapy in hepatocellular carcinoma. Cancer Treat. Rev., 2010, 36(2), 157-163.
[http://dx.doi.org/10.1016/j.ctrv.2009.11.008] [PMID: 20031332]
[9]
Madkhali, A.A.; Fadel, Z.T.; Aljiffry, M.M.; Hassanain, M.M. Surgical treatment for hepatocellular carcinoma. Saudi J. Gastroenterol., 2015, 21(1), 11-17.
[http://dx.doi.org/10.4103/1319-3767.151216] [PMID: 25672233]
[10]
Zakharia, K.; Luther, C.A.; Alsabbak, H.; Roberts, L.R. Hepatocellular carcinoma: Epidemiology, pathogenesis and surveillance - implications for sub-Saharan Africa. S. Afr. Med. J., 2018, 108(8b), 35-40.
[PMID: 30182911]
[11]
Khalaf, A.M.; Fuentes, D.; Morshid, A.I.; Burke, M.R.; Kaseb, A.O.; Hassan, M.; Hazle, J.D.; Elsayes, K.M. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J. Hepatocell. Carcinoma, 2018, 5, 61-73.
[http://dx.doi.org/10.2147/JHC.S156701] [PMID: 29984212]
[12]
Waisberg, J.; Saba, G.T. Wnt-/-β-catenin pathway signaling in human hepatocellular carcinoma. World J. Hepatol., 2015, 7(26), 2631-2635.
[http://dx.doi.org/10.4254/wjh.v7.i26.2631] [PMID: 26609340]
[13]
Lee, J.M.; Yang, J.; Newell, P.; Singh, S.; Monga, S.P. β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation. Cancer Lett., 2014, 343(1), 90-97.
[PMID: 24071572]
[14]
Wang, W.; Xu, L.; Liu, P.; Jairam, K.; Yin, Y.; Chen, K.; Sprengers, D.; Peppelenbosch, M.P.; Pan, Q.; Smits, R. Blocking Wnt secretion reduces growth of hepatocellular carcinoma cell lines mostly independent of β-catenin signaling. Neoplasia, 2016, 18(12), 711-723.
[http://dx.doi.org/10.1016/j.neo.2016.10.004] [PMID: 27851986]
[15]
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.; Meyer, T.; Kang, Y.K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet, 2017, 389(10088), 2492-2502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[16]
Kim, K.; Jha, R.; Prins, P.A.; Wang, H.; Chacha, M.; Hartley, M.L.; He, A.R. Regorafenib in advanced hepatocellular carcinoma (HCC): Considerations for treatment. Cancer Chemother. Pharmacol., 2017, 80(5), 945-954.
[http://dx.doi.org/10.1007/s00280-017-3431-5] [PMID: 28932966]
[17]
Vilchez, V.; Turcios, L.; Marti, F.; Gedaly, R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J. Gastroenterol., 2016, 22(2), 823-832.
[http://dx.doi.org/10.3748/wjg.v22.i2.823] [PMID: 26811628]
[18]
Zhang, L.; Wei, W. Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol. Ther., 2020, 207, 107452.
[http://dx.doi.org/10.1016/j.pharmthera.2019.107452] [PMID: 31836457]
[19]
Xiang, Y.; Zhang, Q.; Wei, S.; Huang, C.; Li, Z.; Gao, Y. Paeoniflorin: A monoterpene glycoside from plants of Paeoniaceae family with diverse anticancer activities. J. Pharm. Pharmacol., 2020, 72(4), 483-495.
[http://dx.doi.org/10.1111/jphp.13204] [PMID: 31858611]
[20]
Liao, F.; Yu, A.; Yu, J.; Wang, D.; Wu, Y.; Zheng, H.; Meng, Y.; He, D.; Shen, X.; Wang, L. Identification of active ingredients mediating anti-platelet aggregation effects of Buyang Huanwu decoction using a platelet binding assay, solid phase extraction, and HPLC-MS/MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2018, 1092, 320-327.
[http://dx.doi.org/10.1016/j.jchromb.2018.06.027] [PMID: 29936367]
[21]
Ma, X.; Zhang, W.; Jiang, Y.; Wen, J.; Wei, S.; Zhao, Y. Paeoniflorin, a natural product with multiple targets in liver diseases-a mini review. Front. Pharmacol., 2020, 11, 531.
[http://dx.doi.org/10.3389/fphar.2020.00531] [PMID: 32410996]
[22]
Su, J.; Zhang, P.; Zhang, J.J.; Qi, X.M.; Wu, Y.G.; Shen, J.J. Effects of total glucosides of paeony on oxidative stress in the kidney from diabetic rats. Phytomedicine, 2010, 17(3-4), 254-260.
[http://dx.doi.org/10.1016/j.phymed.2009.07.005] [PMID: 19758795]
[23]
Hung, J.Y.; Yang, C.J.; Tsai, Y.M.; Huang, H.W.; Huang, M.S. Antiproliferative activity of paeoniflorin is through cell cycle arrest and the Fas/Fas ligand-mediated apoptotic pathway in human non-small cell lung cancer A549 cells. Clin. Exp. Pharmacol. Physiol., 2008, 35(2), 141-147.
[PMID: 17941899]
[24]
Fang, S.; Zhu, W.; Zhang, Y.; Shu, Y.; Liu, P. Paeoniflorin modulates multidrug resistance of a human gastric cancer cell line via the inhibition of NF-κB activation. Mol. Med. Rep., 2012, 5(2), 351-356.
[PMID: 22051979]
[25]
Lu, J.T.; He, W.; Song, S.S.; Wei, W. Paeoniflorin inhibited the tumor invasion and metastasis in human hepatocellular carcinoma cells. Bratisl. Lek Listy, 2014, 115(7), 427-433.
[http://dx.doi.org/10.4149/BLL_2014_084] [PMID: 25077366]
[26]
Liu, D.F.; Wei, W.; Song, L.H. Protective effect of paeoniflorin on immunological liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide: Modulation of tumour necrosis factor-alpha and interleukin-6 MRNA. Clin. Exp. Pharmacol. Physiol., 2006, 33(4), 332-339.
[http://dx.doi.org/10.1111/j.1440-1681.2006.04371.x] [PMID: 16620297]
[27]
Chu, D.; Du, M.; Hu, X.; Wu, Q.; Shen, J. Paeoniflorin attenuates schistosomiasis japonica-associated liver fibrosis through inhibiting alternative activation of macrophages. Parasitology, 2011, 138(10), 1259-1271.
[http://dx.doi.org/10.1017/S0031182011001065] [PMID: 21810309]
[28]
Chen, J.; Rajasekaran, M.; Xia, H.; Zhang, X.; Kong, S.N.; Sekar, K.; Seshachalam, V.P.; Deivasigamani, A.; Goh, B.K.P.; Ooi, L.L.; Hong, W.; Hui, K.M. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway. Gut, 2016, 65(9), 1522-1534.
[http://dx.doi.org/10.1136/gutjnl-2015-310625] [PMID: 26941395]
[29]
Marrero, J.A.; Pelletier, S.; Bruix, J. Hepatocellular carcinoma. Clin. Liver Dis., 2006, 10(2), 339-351. ix.
[http://dx.doi.org/10.1016/j.cld.2006.05.012] [PMID: 16971265]
[30]
Maluccio, M.; Covey, A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J. Clin., 2012, 62(6), 394-399.
[http://dx.doi.org/10.3322/caac.21161] [PMID: 23070690]
[31]
Liu, H.; Zang, L.; Zhao, J.; Wang, Z.; Li, L. Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2. Oncol. Lett., 2020, 19(4), 3165-3172.
[http://dx.doi.org/10.3892/ol.2020.11424] [PMID: 32256812]
[32]
Sui, H.; Xu, H.; Ji, Q.; Liu, X.; Zhou, L.; Song, H.; Zhou, X.; Xu, Y.; Chen, Z.; Cai, J.; Ji, G.; Li, Q. 5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway. Oncotarget, 2015, 6(28), 25975-25987.
[http://dx.doi.org/10.18632/oncotarget.4543] [PMID: 26214021]
[33]
Gurbuz, N.; Ashour, A.A.; Alpay, S.N.; Ozpolat, B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One, 2014, 9(9), e110067.
[http://dx.doi.org/10.1371/journal.pone.0110067] [PMID: 25268648]
[34]
Fatima, S.; Shi, X.; Lin, Z.; Chen, G.Q.; Pan, X.H.; Wu, J.C.; Ho, J.W.; Lee, N.P.; Gao, H.; Zhang, G.; Lu, A.; Bian, Z.X. 5-Hydroxytryptamine promotes hepatocellular carcinoma proliferation by influencing β-catenin. Mol. Oncol., 2016, 10(2), 195-212.
[http://dx.doi.org/10.1016/j.molonc.2015.09.008] [PMID: 26474915]
[35]
Zuo, X.; Chen, Z.; Cai, J.; Gao, W.; Zhang, Y.; Han, G.; Pu, L.; Wu, Z.; You, W.; Qin, J.; Dai, X.; Shen, H.; Wu, J.; Wang, X. 5-Hydroxytryptamine receptor 1D aggravates hepatocellular carcinoma progression through FoxO6 in AKT-dependent and independent manners. Hepatology, 2019, 69(5), 2031-2047.
[http://dx.doi.org/10.1002/hep.30430] [PMID: 30561038]
[36]
Clevers, H.; Nusse, R. Wnt/β-catenin signaling and disease. Cell, 2012, 149(6), 1192-1205.
[http://dx.doi.org/10.1016/j.cell.2012.05.012] [PMID: 22682243]
[37]
Huge, N.; Sandbothe, M.; Schröder, A.K.; Stalke, A.; Eilers, M.; Schäffer, V.; Schlegelberger, B.; Illig, T.; Vajen, B.; Skawran, B. Wnt status-dependent oncogenic role of BCL9 and BCL9L in hepatocellular carcinoma. Hepatol. Int., 2020, 14(3), 373-384.
[http://dx.doi.org/10.1007/s12072-019-09977-w] [PMID: 31440992]
[38]
Qu, B.; Liu, B.R.; Du, Y.J.; Chen, J.; Cheng, Y.Q.; Xu, W.; Wang, X.H. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol. Lett., 2014, 7(4), 1175-1178.
[http://dx.doi.org/10.3892/ol.2014.1828] [PMID: 24944688]
[39]
Klaus, A.; Birchmeier, W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer, 2008, 8(5), 387-398.
[http://dx.doi.org/10.1038/nrc2389] [PMID: 18432252]
[40]
Zhao, G.; Song, Y.; Dong, L.; Shi, H.; Li, H.; Yang, L.; Wang, J. Silencing of lemur tyrosine kinase 2 restricts the proliferation and invasion of hepatocellular carcinoma through modulation of GSK-3β/Wnt/β-catenin signaling. Biochem. Biophys. Res. Commun., 2019, 517(4), 722-728.
[http://dx.doi.org/10.1016/j.bbrc.2019.07.122] [PMID: 31395338]
[41]
Zhang, R.; Lin, H.M.; Broering, R.; Shi, X.D.; Yu, X.H.; Xu, L.B.; Wu, W.R.; Liu, C. Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway. Signal Transduct. Target. Ther., 2019, 4, 54.
[http://dx.doi.org/10.1038/s41392-019-0082-5] [PMID: 31839998]

Rights & Permissions Print Cite
Article Metrics
43
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy