Dihydromyricetin-mediated Inhibition of the Notch1 Pathway Induces Apoptosis in QGY7701 and HepG2 Hepatoma Cells

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2017 Oct 5

PMID 28974890

Citations 8

Authors

Cai-Jie Lu

Yi-Feng He

Wei-Zhuang Yuan

Li-Jun Xiang

Jian Zhang

Yan-Rui Liang

Juan Duan

Yun-He He

Ming-Yi Li

Affiliations

Soon will be listed here.

Abstract

Aim: To investigate whether Dihydromyricetin (DHM) inhibits cell proliferation and promotes apoptosis by downregulating Notch1 expression.

Methods: The correlation between Notch1 and Hes1 (a Notch1 target molecule) expression in hepatoma samples was confirmed by qRT-PCR. In addition, MTT assays, flow cytometry and TUNEL analysis showed that DHM possessed strong anti-tumor properties, evidenced not only by reduced cell proliferation but also by enhanced apoptosis in QGY7701 and HepG2 hepatocellular carcinoma (HCC) cells. The expressions of Notch1, Hes1, Bcl-2 and Bax were determined by Western blot.

Results: Among the tested samples ( = 64), the expression levels of Notch1 (75% of patients) and Hes1 (79.7% of patients) mRNA in tumor tissues were higher than in the normal liver tissues. There was a negative correlation between the expression of Notch1 and the degree of differentiation and positively correlated with the Alpha Fetal Protein concentration. The viability of HCC cells treated with DHM was significantly inhibited in a dose and time-dependent manner. Apoptosis was induced in HepG2 and QGY7701 cell lines following 24 h of DHM treatment. After treatment with DHM, the protein expression of Notch1 was downregulated, the apoptosis-related protein Bax was upregulated and Bcl2 was downregulated. Notch1 siRNA further enhanced the anti-tumor properties of DHM.

Conclusion: Notch1 is involved in the development of HCC and DHM inhibits cell proliferation and promotes apoptosis by down-regulating the expression of Notch1.

Citing Articles

Dihydromyricetin Protects Against Hypoxia/Reoxygenation Injury in Cardiomyocytes by Activating miR-34a-Mediated Notch1 Pathway.

Li Y, Li M Cardiovasc Toxicol. 2025; 25(2):294-305.

PMID: 39864044 DOI: 10.1007/s12012-025-09959-5.

Multiple molecular and cellular mechanisms of the antitumour effect of dihydromyricetin (Review).

Xia T, Zhu R Biomed Rep. 2024; 20(5):82.

PMID: 38628627 PMC: 11019658. DOI: 10.3892/br.2024.1769.

Dietary Dihydromyricetin Zinc Chelate Supplementation Improves the Intestinal Health of Magang Geese.

Wang R, Ren Y, Javad H, Zhou Z, Jiang W, Shu X Biol Trace Elem Res. 2024; 202(11):5219-5234.

PMID: 38263355 DOI: 10.1007/s12011-024-04065-z.

Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental validation.

Zhang S, Shi Y, Gu J, He P, Ai Q, Zhou X Pharm Biol. 2023; 61(1):1108-1119.

PMID: 37462387 PMC: 10355694. DOI: 10.1080/13880209.2023.2234000.

HIF-2α regulates proliferation, invasion, and metastasis of hepatocellular carcinoma cells VEGF/Notch1 signaling axis after insufficient radiofrequency ablation.

Yang Y, Chen W, Mai W, Gao Y Front Oncol. 2022; 12:998295.

PMID: 36212390 PMC: 9539942. DOI: 10.3389/fonc.2022.998295.

References

Morise Z, Kawabe N, Tomishige H, Nagata H, Kawase J, Arakawa S . Recent advances in the surgical treatment of hepatocellular carcinoma. World J Gastroenterol. 2014; 20(39):14381-92. PMC: 4202367. DOI: 10.3748/wjg.v20.i39.14381. View

Huang H, Hu M, Zhao R, Li P, Li M . Dihydromyricetin suppresses the proliferation of hepatocellular carcinoma cells by inducing G2/M arrest through the Chk1/Chk2/Cdc25C pathway. Oncol Rep. 2013; 30(5):2467-75. DOI: 10.3892/or.2013.2705. View

Liu B, Zhou W, Chen X, Xu F, Chen Y, Liu J . Dihydromyricetin induces mouse hepatoma Hepal-6 cell apoptosis via the transforming growth factor-β pathway. Mol Med Rep. 2014; 11(3):1609-14. PMC: 4270327. DOI: 10.3892/mmr.2014.2891. View

Bagci E, Vodovotz Y, Billiar T, Ermentrout G, Bahar I . Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores. Biophys J. 2005; 90(5):1546-59. PMC: 1367306. DOI: 10.1529/biophysj.105.068122. View

Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre M . The Global Burden of Cancer 2013. JAMA Oncol. 2015; 1(4):505-27. PMC: 4500822. DOI: 10.1001/jamaoncol.2015.0735. View

Nguyen K, Willmore W, Tayabali A . Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. Toxicology. 2013; 306:114-23. DOI: 10.1016/j.tox.2013.02.010. View

Franko-Tobin L, Mackey L, Huang W, Song X, Jin B, Luo J . Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics. Oncologist. 2012; 17(2):220-32. PMC: 3286171. DOI: 10.1634/theoncologist.2011-0269. View

Artavanis-Tsakonas S, Rand M, Lake R . Notch signaling: cell fate control and signal integration in development. Science. 1999; 284(5415):770-6. DOI: 10.1126/science.284.5415.770. View

Kunnimalaiyaan S, Clark Gamblin T, Kunnimalaiyaan M . Glycogen synthase kinase-3 inhibitor AR-A014418 suppresses pancreatic cancer cell growth via inhibition of GSK-3-mediated Notch1 expression. HPB (Oxford). 2015; 17(9):770-6. PMC: 4557650. DOI: 10.1111/hpb.12442. View

10.

Ji F, Tian X, Liu X, Fu L, Wu Y, Fang X . Dihydromyricetin induces cell apoptosis via a p53-related pathway in AGS human gastric cancer cells. Genet Mol Res. 2015; 14(4):15564-71. DOI: 10.4238/2015.December.1.7. View

11.

Zhang Q, Lu C, Fang T, Wang Y, Hu W, Qiao J . Notch3 functions as a regulator of cell self-renewal by interacting with the β-catenin pathway in hepatocellular carcinoma. Oncotarget. 2015; 6(6):3669-79. PMC: 4414145. DOI: 10.18632/oncotarget.2898. View

12.

Yuan X, Wu H, Xu H, Han N, Chu Q, Yu S . Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep. 2015; 5:10338. PMC: 4440529. DOI: 10.1038/srep10338. View

13.

Zhang X, Du G, Xu Y, Li X, Fan W, Chen J . Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes. Lab Invest. 2015; 96(3):350-60. DOI: 10.1038/labinvest.2015.149. View

14.

Zhong Z, Qin J, Zhou G, Chen X . [Experimental studies of hypoglycemic action on total flavone of Ampelopsis grossedentata from Guangxi]. Zhongguo Zhong Yao Za Zhi. 2003; 27(9):687-9. View

15.

Zeng G, Liu J, Chen H, Liu B, Zhang Q, Li M . Dihydromyricetin induces cell cycle arrest and apoptosis in melanoma SK-MEL-28 cells. Oncol Rep. 2014; 31(6):2713-9. DOI: 10.3892/or.2014.3160. View

16.

Jiang L, Zhang Q, Ren H, Ma S, Lu C, Liu B . Dihydromyricetin Enhances the Chemo-Sensitivity of Nedaplatin via Regulation of the p53/Bcl-2 Pathway in Hepatocellular Carcinoma Cells. PLoS One. 2015; 10(4):e0124994. PMC: 4411137. DOI: 10.1371/journal.pone.0124994. View

17.

Matsuno K, Diederich R, Go M, Blaumueller C, Artavanis-Tsakonas S . Deltex acts as a positive regulator of Notch signaling through interactions with the Notch ankyrin repeats. Development. 1995; 121(8):2633-44. DOI: 10.1242/dev.121.8.2633. View

18.

Chen S, Zhao X, Wan J, Ran L, Qin Y, Wang X . Dihydromyricetin improves glucose and lipid metabolism and exerts anti-inflammatory effects in nonalcoholic fatty liver disease: A randomized controlled trial. Pharmacol Res. 2015; 99:74-81. DOI: 10.1016/j.phrs.2015.05.009. View

19.

Hou X, Tong Q, Wang W, Xiong W, Shi C, Fang J . Dihydromyricetin protects endothelial cells from hydrogen peroxide-induced oxidative stress damage by regulating mitochondrial pathways. Life Sci. 2015; 130:38-46. DOI: 10.1016/j.lfs.2015.03.007. View

20.

Zhang Q, Liu J, Liu B, Xia J, Chen N, Chen X . Dihydromyricetin promotes hepatocellular carcinoma regression via a p53 activation-dependent mechanism. Sci Rep. 2014; 4:4628. PMC: 3982169. DOI: 10.1038/srep04628. View