Asparagus Polysaccharide Inhibits the Hypoxia-induced Migration, Invasion and Angiogenesis of Hepatocellular Carcinoma Cells Partly Through Regulating HIF1α/VEGF Expression Via MAPK and PI3K Signaling Pathway

Overview

Journal J Cancer

Specialty Oncology

Date 2021 Jun 7

PMID 34093799

Citations 10

Authors

Wei Cheng

Ziwei Cheng

Lingling Weng

Dongwei Xing

Minguang Zhang

Affiliations

Soon will be listed here.

Abstract

Although there are so many treatment strategies used for hepatocellular carcinoma (HCC), the overall survival (OS) of HCC patients still remains very low. In our previous studies, asparagus polysaccharide (ASP) has been demonstrated to suppress proliferation, migration, invasion and angiogenesis of HCC cells under normoxic conditions . However, the inhibitory effects of ASP on the hypoxia-induced migration, invasion and angiogenesis of HCC cells still remain largely unexplored. Cell Counting Kit-8 (CCK-8) assay, transwell assay, and tube formation assay were used to determine the effects of ASP on hypoxia-induced proliferation, migration, invasion and angiogenesis of HCC cells. ELISA, Western blotting analysis and immunofluorescence assay were used to confirm the effects of ASP on the expressions of HIF-1α and VEGF at the protein level. Moreover, effects of ASP on signaling pathway-related proteins were investigated by Western blotting analysis. Immunohistochemistry (IHC) assay was applied to test the effects of ASP on angiogenesis-associated proteins of tumor cells. We showed that ASP effectively suppressed hypoxia-induced proliferation, migration, invasion and angiogenesis of SK-Hep1 and Hep-3B cells in a dose-dependent manner. In addition, the inhibitory effect of ASP might be partly attributed to down-regulation of HIF1α and VEGF proteins in SK-Hep1 and Hep-3B cells under hypoxic conditions. Moreover, signaling pathway study indicated that ASP significantly down-regulated the hypoxia-induced expressions of p-AKT, p-mTOR and p-ERK, while it had little effects on AKT, mTOR and ERK. Besides, SK-Hep1 xenograft tumor models in nude mice further confirmed that the inhibitory effect of ASP on xenograft tumors might be exerted partly via down-regulation of HIF1α and VEGF through blocking MAPK and PI3K signaling pathways. Our findings suggested that ASP suppressed the hypoxia-induced migration, invasion and angiogenesis of HCC cells partly through regulating HIF-1α/VEGF expression via MAPK and PI3K signaling pathways.

Citing Articles

The Role of Chemokine (C-C Motif) Ligand 7 (CCL7) in Hepatocellular Carcinoma: Expression, Function, and Mechanisms.

Luo Y, Wan F, Zhang Z, Qin Z, Ren Y Cancer Med. 2025; 14(5):e70701.

PMID: 40062588 PMC: 11891931. DOI: 10.1002/cam4.70701.

Targeting the mTOR Pathway in Hepatocellular Carcinoma: The Therapeutic Potential of Natural Products.

Chen G, Zhang Y, Zhou Y, Luo H, Guan H, An B J Inflamm Res. 2024; 17:10421-10440.

PMID: 39659752 PMC: 11630751. DOI: 10.2147/JIR.S501270.

Therapeutic Effects of Natural Products on Liver Cancer and Their Potential Mechanisms.

Guo J, Yan W, Duan H, Wang D, Zhou Y, Feng D Nutrients. 2024; 16(11).

PMID: 38892575 PMC: 11174683. DOI: 10.3390/nu16111642.

Traditional Chinese Medicine in Regulating Tumor Microenvironment.

Wang Z, Li M, Bi L, Hu X, Wang Y Onco Targets Ther. 2024; 17:313-325.

PMID: 38617090 PMC: 11016250. DOI: 10.2147/OTT.S444214.

Research Progress on the Anticancer Activity of Plant Polysaccharides.

Liu Q, Song B, Tong S, Yang Q, Zhao H, Guo J Recent Pat Anticancer Drug Discov. 2023; 19(5):573-598.

PMID: 37724671 DOI: 10.2174/1574892819666230915103434.

References

Yang W, Sun T, Cao J, Fan S . Hypoxia-inducible factor-1α downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and enhances radiosensitivity in chemical hypoxic human hepatoma SMMC-7721 cells. Cancer Biother Radiopharm. 2011; 26(5):565-71. DOI: 10.1089/cbr.2011.0955. View

Guo Y, Xiao Z, Yang L, Gao Y, Zhu Q, Hu L . Hypoxia‑inducible factors in hepatocellular carcinoma (Review). Oncol Rep. 2019; 43(1):3-15. PMC: 6908932. DOI: 10.3892/or.2019.7397. View

Wang G, Jiang B, Rue E, Semenza G . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510-4. PMC: 41725. DOI: 10.1073/pnas.92.12.5510. View

Zhang W, He W, Shi X, Li X, Wang Y, Hu M . An Asparagus polysaccharide fraction inhibits MDSCs by inducing apoptosis through toll-like receptor 4. Phytother Res. 2018; 32(7):1297-1303. DOI: 10.1002/ptr.6058. View

Wang G, Semenza G . Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995; 270(3):1230-7. DOI: 10.1074/jbc.270.3.1230. View

Comerford K, Wallace T, Karhausen J, Louis N, Montalto M, Colgan S . Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002; 62(12):3387-94. View

Koshiji M, Kageyama Y, Pete E, Horikawa I, Barrett J, Huang L . HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004; 23(9):1949-56. PMC: 404317. DOI: 10.1038/sj.emboj.7600196. View

Cao Y, Eble J, Moon E, Yuan H, Weitzel D, Landon C . Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res. 2013; 73(20):6230-42. PMC: 3800255. DOI: 10.1158/0008-5472.CAN-12-1345. View

Zhu H, Luo S, Wang J, Li X, Wang H, Pu W . Effect of environmental factors on chemoresistance of HepG2 cells by regulating hypoxia-inducible factor-1α. Chin Med J (Engl). 2012; 125(6):1095-103. View

10.

Lin J, Cao S, Wang Y, Hu Y, Liu H, Li J . Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma. J Exp Clin Cancer Res. 2018; 37(1):113. PMC: 5987644. DOI: 10.1186/s13046-018-0727-1. View

11.

Volm M, Koomagi R . Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 2000; 20(3A):1527-33. View

12.

Peng W, Zhang S, Zhang Z, Xu P, Mao D, Huang S . Jianpi Jiedu decoction, a traditional Chinese medicine formula, inhibits tumorigenesis, metastasis, and angiogenesis through the mTOR/HIF-1α/VEGF pathway. J Ethnopharmacol. 2018; 224:140-148. DOI: 10.1016/j.jep.2018.05.039. View

13.

Lee S, Jeong D, Han Y, Baek M . Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Ann Surg Treat Res. 2015; 89(1):1-8. PMC: 4481026. DOI: 10.4174/astr.2015.89.1.1. View

14.

Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J . Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma. BMC Cancer. 2013; 13:108. PMC: 3614870. DOI: 10.1186/1471-2407-13-108. View

15.

Hicklin D, Ellis L . Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2004; 23(5):1011-27. DOI: 10.1200/JCO.2005.06.081. View

16.

Xiang J, Xiang Y, Lin S, Xin D, Liu X, Weng L . Anticancer effects of deproteinized asparagus polysaccharide on hepatocellular carcinoma in vitro and in vivo. Tumour Biol. 2013; 35(4):3517-24. DOI: 10.1007/s13277-013-1464-x. View

17.

Cheng W, Cheng Z, Yang Z, Xing D, Zhang M . Upregulation of hypoxia-inducible factor 1α mRNA expression was associated with poor prognosis in patients with hepatocellular carcinoma. Onco Targets Ther. 2019; 12:6285-6296. PMC: 6691942. DOI: 10.2147/OTT.S197077. View

18.

Meijer T, Kaanders J, Span P, Bussink J . Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 2012; 18(20):5585-94. DOI: 10.1158/1078-0432.CCR-12-0858. View

19.

Niizeki H, Kobayashi M, Horiuchi I, Akakura N, Chen J, Wang J . Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells. Br J Cancer. 2002; 86(12):1914-9. PMC: 2375441. DOI: 10.1038/sj.bjc.6600331. View

20.

Weng L, Xiang J, Lin J, Yi S, Yang L, Li Y . Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model. Asian Pac J Cancer Prev. 2015; 15(24):10949-55. DOI: 10.7314/apjcp.2014.15.24.10949. View