Ginsenoside Rh2 Inhibits Migration of Lung Cancer Cells under Hypoxia via mir-491

Author(s): Yingying Chen, Yuqiang Zhang, Wei Song, Ying Zhang, Xiu Dong, Mingqi Tan*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 13 , 2019

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Graphical Abstract:


Abstract:

Background: Ginsenoside Rh2 (Rh2), which is extracted from ginseng, exerts antitumor activity. Here we would like to study the role of Rh2 on hypoxia-induced migration in lung adenocarcinoma.

Methods: Lung adenocarcinoma A549 and H1299 cells were cultured in 1% O2 condition to mimic the hypoxic tumor microenvironment. The migrations of cancer cells were measured by transwell assay and scratch assay.

Results: Rh2 could inhibit hypoxia-induced A549 and H1299 cell migration via increase of mir-491 expression. Further, mir-491 antisense oligonucleotide could repress hypoxia-induced migration and the expression of matrix metalloproteinase (MMP)-9 expression in Rh2-treated A549 cells.

Conclusion: These findings suggest that Rh2 exerts anti-metastasis activity in the hypoxic tumor microenvironment in lung adenocarcinoma cells via mir-491.

Keywords: Ginsenoside Rh2, hypoxia, lung adenocarcinoma, migration, mir-491, antitumor activity.

[1]
Chen, W.; Zheng, R.; Zeng, H.; Zhang, S. Epidemiology of lung cancer in China. Thorac. Cancer, 2015, 6(2), 209-215.
[2]
Burstein, H.J.; Schwartz, R.S. Molecular origins of cancer. N. Engl. J. Med., 2008, 358(5), 527.
[3]
Friedl, P.; Wolf, K. Tumour-cell invasion and migration: Diversity and escape mechanisms. Nat. Rev. Cancer, 2003, 3(5), 362-374.
[4]
Gupta, G.P. Massagué, J. Cancer metastasis: Building a framework. Cell, 2006, 127(4), 679-695.
[5]
Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst., 1990, 82(1), 4-6.
[6]
Cho, W.K.; Seong, Y.R.; Lee, Y.H.; Kim, M.J.; Hwang, K.S.; Yoo, J.; Choi, S.; Jung, C.R.; Im, D.S. Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor. Mol. Ther., 2004, 10(5), 938-949.
[7]
Brown, J.M. The hypoxic cell: A target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res., 1999, 59(23), 5863-5870.
[8]
Höckel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst., 2001, 93(4), 266-276.
[9]
Salem, A.; Asselin, M.C.; Reymen, B.; Jackson, A.; Lambin, P.; West, C.M.L.; O’Connor, J.P.B.; Faivre-Finn, C. Targeting hypoxia to improve non-small cell lung cancer outcome. J. Natl. Cancer Inst., 2018, 110(1), 110.
[10]
Bryant, J.L.; Meredith, S.L.; Williams, K.J.; White, A. Targeting hypoxia in the treatment of small cell lung cancer. Lung Cancer, 2014, 86(2), 126-132.
[11]
Liu, T.; Zhao, L.; Zhang, Y.; Chen, W.; Liu, D.; Hou, H.; Ding, L.; Li, X. Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS One, 2014, 9(9)e103887
[12]
Zhang, C.; Yu, H.; Hou, J. Effects of 20 (S) -ginsenoside Rh2 and 20 (R) -ginsenoside Rh2 on proliferation and apoptosis of human lung adenocarcinoma A549 cells. Zhongguo Zhongyao Zazhi, 2011, 36(12), 1670-1674.
[13]
Oh, M.; Choi, Y.H.; Choi, S.; Chung, H.; Kim, K.; Kim, S.I.; Kim, D.K.; Kim, N.D. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int. J. Oncol., 1999, 14(5), 869-875.
[14]
Chen, Y.; Shang, H.; Zhang, S.; Zhang, X. Ginsenoside Rh2 inhibits proliferation and migration of medulloblastoma Daoy by down-regulation of microRNA-31. J. Cell. Biochem., 2018, 119(8), 6527-6534.
[15]
Tang, X.P.; Tang, G.D.; Fang, C.Y.; Liang, Z.H.; Zhang, L.Y. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J. Gastroenterol., 2013, 19(10), 1582-1592.
[16]
Li, H.; Huang, N.; Zhu, W.; Wu, J.; Yang, X.; Teng, W.; Tian, J.; Fang, Z.; Luo, Y.; Chen, M.; Li, Y. Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2. BMC Cancer, 2018, 18(1), 579.
[17]
Ambros, V. microRNAs: Tiny regulators with great potential. Cell, 2001, 107(7), 823-826.
[18]
Tian, W.; Liu, J.; Pei, B.; Wang, X.; Guo, Y.; Yuan, L. Identification of miRNAs and differentially expressed genes in early phase non-small cell lung cancer. Oncol. Rep., 2016, 35(4), 2171-2176.
[19]
Gong, F.; Ren, P.; Zhang, Y.; Jiang, J.; Zhang, H. MicroRNAs-491-5p suppresses cell proliferation and invasion by inhibiting IGF2BP1 in non-small cell lung cancer. Am. J. Transl. Res., 2016, 8(2), 485-495.
[20]
An, I.S.; An, S.; Kwon, K.J.; Kim, Y.J.; Bae, S. Ginsenoside Rh2 mediates changes in the microRNA expression profile of human non-small cell lung cancer A549 cells. Oncol. Rep., 2013, 29(2), 523-528.
[21]
Kataoka, Y.; Ohshio, Y.; Teramoto, K.; Igarashi, T.; Asai, T.; Hanaoka, J. Hypoxiainduced galectin3 enhances RhoA function to activate the motility of tumor cells in nonsmall cell lung cancer. Oncol. Rep., 2019, 41(2), 853-862.
[22]
Hanna, J.; Goldman-Wohl, D.; Hamani, Y.; Avraham, I.; Greenfield, C.; Natanson-Yaron, S.; Prus, D.; Cohen-Daniel, L.; Arnon, T.I.; Manaster, I.; Gazit, R.; Yutkin, V.; Benharroch, D.; Porgador, A.; Keshet, E.; Yagel, S.; Mandelboim, O. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med., 2006, 12(9), 1065-1074.
[23]
Nagelkerke, A.; Bussink, J.; Mujcic, H.; Wouters, B.G.; Lehmann, S.; Sweep, F.C.; Span, P.N. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res., 2013, 15(1), R2.
[24]
Qian, J.; Bai, H.; Gao, Z.; Dong, Y.U.; Pei, J.; Ma, M.; Han, B. Downregulation of HIF-1α inhibits the proliferation and invasion of non-small cell lung cancer NCI-H157 cells. Oncol. Lett., 2016, 11(3), 1738-1744.
[25]
Djagaeva, I.; Doronkin, S. Hypoxia response pathway in border cell migration. Cell Adhes. Migr., 2010, 4(3), 391-395.
[26]
Fujiwara, S.; Nakagawa, K.; Harada, H.; Nagato, S.; Furukawa, K.; Teraoka, M.; Seno, T.; Oka, K.; Iwata, S.; Ohnishi, T. Silencing hypoxia-inducible factor-1alpha inhibits cell migration and invasion under hypoxic environment in malignant gliomas. Int. J. Oncol., 2007, 30(4), 793-802.
[27]
Li, L.; Madu, C.O.; Lu, A.; Lu, Y. HIF-1α promotes a hypoxia-independent cell migration. Open Biol. J., 2010, 3, 8-14.
[28]
Choi, J.Y.; Jang, Y.S.; Min, S.Y.; Song, J.Y. Overexpression of MMP-9 and HIF-1α in breast cancer cells under hypoxic conditions. J. Breast Cancer, 2011, 14(2), 88-95.
[29]
Kim, S.J.; Rabbani, Z.N.; Dewhirst, M.W.; Vujaskovic, Z.; Vollmer, R.T.; Schreiber, E.G.; Oosterwijk, E.; Kelley, M.J. Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer, 2005, 49(3), 325-335.
[30]
Yan, W.; Zhang, W.; Sun, L.; Liu, Y.; You, G.; Wang, Y.; Kang, C.; You, Y.; Jiang, T. Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res., 2011, 1411, 108-115.
[31]
Kleinman, H.K.; Martin, G.R. Matrigel: Basement membrane matrix with biological activity. Semin. Cancer Biol., 2005, 15(5), 378-386.
[32]
Xu, F.Y.; Shang, W.Q.; Yu, J.J.; Sun, Q.; Li, M.Q.; Sun, J.S. The antitumor activity study of ginsenosides and metabolites in lung cancer cell. Am. J. Transl. Res., 2016, 8(4), 1708-1718.
[33]
Wang, M.; Yan, S.J.; Zhang, H.T.; Li, N.; Liu, T.; Zhang, Y.L.; Li, X.X.; Ma, Q.; Qiu, X.C.; Fan, Q.Y.; Ma, B.A. Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncol. Lett., 2017, 13(2), 681-685.
[34]
Zhou, Y.; Li, Y.; Ye, J.; Jiang, R.; Yan, H.; Yang, X.; Liu, Q.; Zhang, J. MicroRNA-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. Liver Int., 2013, 33(8), 1271-1280.
[35]
Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res., 2006, 69(3), 562-573.
[36]
El-Badrawy, M.K.; Yousef, A.M.; Shaalan, D.; Elsamanoudy, A.Z. Matrix metalloproteinase-9 expression in lung cancer patients and its relation to serum mmp-9 activity, pathologic type, and prognosis. J. Bronchol Interv. Pulmonol., 2014, 21(4), 327-334.
[37]
Merchant, N.; Nagaraju, G.P.; Rajitha, B.; Lammata, S.; Jella, K.K.; Buchwald, Z.S.; Lakka, S.S.; Ali, A.N. Matrix metalloproteinases: their functional role in lung cancer. Carcinogenesis, 2017, 38(8), 766-780.


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Article Details

VOLUME: 19
ISSUE: 13
Year: 2019
Page: [1633 - 1641]
Pages: 9
DOI: 10.2174/1871520619666190704165205
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