Dihydroartemisinin suppresses proliferation, migration, the Wnt/β‑catenin pathway and EMT via TNKS in gastric cancer Corrigendum in /10.3892/ol.2021.13152

Ma,Yanmei; Zhang,Peng; Zhang,Qilong; Wang,Xiaofei; Miao,Qiong; Lyu,Xiaolan; Cui,Bo; Ma,Honghong

doi:10.3892/ol.2021.12949

Dihydroartemisinin suppresses proliferation, migration, the Wnt/β‑catenin pathway and EMT via TNKS in gastric cancer

Corrigendum in: /10.3892/ol.2021.13152

Authors:
- Yanmei Ma
- Peng Zhang
- Qilong Zhang
- Xiaofei Wang
- Qiong Miao
- Xiaolan Lyu
- Bo Cui
- Honghong Ma
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Affiliations: Department of Pathology, The First Hospital of Yulin, Yulin, Shaanxi 719000, P.R. China, Department of Geriatrics, The First Hospital of Yulin, Yulin, Shaanxi 719000, P.R. China, Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China, Department of Orthopedics, The First Hospital of Yulin, Yulin, Shaanxi 719000, P.R. China
Published online on: July 29, 2021 https://doi.org/10.3892/ol.2021.12949
Article Number: 688
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gastric cancer is a common malignancy worldwide. However, the molecular mechanisms underlying this malignancy remain unclear and there are a lack of effective drugs. The present study aimed to investigate the antitumor effect of Dihydroartemisinin (DHA) or inhibition of Tankyrases (TNKS), and determine the underlying molecular mechanisms of gastric cancer. Immunohistochemistry and immunofluorescence analyses were performed to detect the expression levels of TNKS, epithelial‑to‑mesenchymal transition (EMT) and Wnt/β‑catenin pathway‑related proteins in gastric cancer tissues and adjacent normal tissues. The Cell Counting Kit‑8 assay was performed to assess the viability of HGC‑27 and AGS cells following treatment with different concentrations of HLY78 (a Wnt activator) or DHA. Following treatment with HLY78, DHA or small interfering (si)‑TNKS1/si‑TNKS2, colony formation and migratory abilities were assessed via the colony formation, wound healing and Transwell assays. Furthermore, western blot and immunofluorescence analyses were performed to detect the expression levels of TNKS, EMT‑ and Wnt/β‑catenin‑related proteins. The results demonstrated that the expression levels of TNKS, AXI2, β‑catenin, N‑cadherin and Vimentin were upregulated, whereas E‑cadherin expression was downregulated in gastric cancer tissues compared with normal tissues. Furthermore, HLY78 and DHA suppressed the viability of HGC‑27 and AGS cells, in a concentration‑independent manner. Notably, TNKS knockdown or treatment with DHA suppressed colony formation, migration, TNKS expression, EMT and the Wnt/β‑catenin pathway. Opposing effects were observed following treatment with HLY78, which were ameliorated following co‑treatment with DHA. Taken together, these results suggest that DHA or inhibition of TNKS can suppress the proliferation and migration of gastric cancer cells, which is partly associated with inactivation of the Wnt/β‑catenin pathway and EMT process.

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1	Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA and Bray F: Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 159:335–349.e15. 2020. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
3	Venerito M, Link A, Rokkas T and Malfertheiner P: Review: Gastric cancer-Clinical aspects. Helicobacter. 24 (Suppl 1):e126432019. View Article : Google Scholar : PubMed/NCBI
4	Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, et al: Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: An open-label, dose escalation and expansion study. Clin Cancer Res. 25:515–523. 2019. View Article : Google Scholar : PubMed/NCBI
5	Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, Shimizu C, Shimoi T, Kuboki Y, Matsubara N, et al: Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: A phase 1 dose-escalation study. Lancet Oncol. 18:1512–1522. 2017. View Article : Google Scholar : PubMed/NCBI
6	Bando H, Doi T, Muro K, Yasui H, Nishina T, Yamaguchi K, Takahashi S, Nomura S, Kuno H, Shitara K, et al: A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201). Eur J Cancer. 62:46–53. 2016. View Article : Google Scholar : PubMed/NCBI
7	Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, et al: Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 382:2419–2430. 2020. View Article : Google Scholar : PubMed/NCBI
8	Sun X, Yang S, Feng X, Zheng Y, Zhou J, Wang H, Zhang Y, Sun H and He C: The modification of ferroptosis and abnormal lipometabolism through overexpression and knockdown of potential prognostic biomarker perilipin2 in gastric carcinoma. Gastric Cancer. 23:241–259. 2020. View Article : Google Scholar : PubMed/NCBI
9	Wang Q, Lu P, Wang T, Zheng Q, Li Y, Leng SX, Meng X, Wang B, Xie J and Zhang H: Sitagliptin affects gastric cancer cells proliferation by suppressing Melanoma-associated antigen-A3 expression through Yes-associated protein inactivation. Cancer Med. 9:3816–3828. 2020. View Article : Google Scholar : PubMed/NCBI
10	Guo HL, Zhang C, Liu Q, Li Q, Lian G, Wu D, Li X, Zhang W, Shen Y, Ye Z, et al: The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation. Cell Res. 22:1246–1257. 2012. View Article : Google Scholar : PubMed/NCBI
11	Huang J, Qu Q, Guo Y, Xiang Y and Feng D: Tankyrases/β-catenin signaling pathway as an anti-proliferation and anti-metastatic target in hepatocarcinoma cell lines. J Cancer. 11:432–440. 2020. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud GA, Schirle M, Shi X, Hild M, Bauer A, et al: RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol. 13:623–629. 2011. View Article : Google Scholar : PubMed/NCBI
13	Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H, Yasunaga S, Takihara Y, Yamamoto T, Izumi S, et al: Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. Mol Cell. 47:694–706. 2012. View Article : Google Scholar : PubMed/NCBI
14	Chi NW and Lodish HF: Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J Biol Chem. 275:38437–38444. 2000. View Article : Google Scholar : PubMed/NCBI
15	Cook BD, Dynek JN, Chang W, Shostak G and Smith S: Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol. 22:332–342. 2002. View Article : Google Scholar : PubMed/NCBI
16	Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, Kaplan JB, Chae YK and Giles FJ: Wnt/beta-catenin pathway: Modulating anticancer immune response. J Hematol Oncol. 10:1012017. View Article : Google Scholar : PubMed/NCBI
17	Gao J, Zhang J, Long Y, Tian Y and Lu X: Expression of tankyrase 1 in gastric cancer and its correlation with telomerase activity. Pathol Oncol Res. 17:685–690. 2011. View Article : Google Scholar : PubMed/NCBI
18	Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z and Zhao G: METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 18:1422019. View Article : Google Scholar : PubMed/NCBI
19	Bure IV, Nemtsova MV and Zaletaev DV: Roles of E-cadherin and noncoding RNAs in the epithelial-mesenchymal transition and progression in gastric cancer. Int J Mol Sci. 20:2019. View Article : Google Scholar : PubMed/NCBI
20	Ji L, Zhang B and Zhao G: Liver X receptor α (LXRα) promoted invasion and EMT of gastric cancer cells by regulation of NF-κB activity. Hum Cell. 30:124–132. 2017. View Article : Google Scholar : PubMed/NCBI
21	Zhu X, Chen L, Liu L and Niu X: EMT-mediated acquired EGFR-TKI resistance in NSCLC: Mechanisms and strategies. Front Oncol. 9:10442019. View Article : Google Scholar : PubMed/NCBI
22	Li S, Cong X, Gao H, Lan X, Li Z, Wang W, Song S, Wang Y, Li C, Zhang H, et al: Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. J Exp Clin Cancer Res. 38:62019. View Article : Google Scholar : PubMed/NCBI
23	Wei Y, Zhang F, Zhang T, Zhang Y, Chen H, Wang F and Li Y: LDLRAD2 overexpression predicts poor prognosis and promotes metastasis by activating Wnt/β-catenin/EMT signaling cascade in gastric cancer. Aging (Albany NY). 11:8951–8968. 2019. View Article : Google Scholar : PubMed/NCBI
24	Li G, Su Q, Liu H, Wang D, Zhang W, Lu Z, Chen Y, Huang X, Li W, Zhang C, et al: Frizzled7 promotes epithelial-to-mesenchymal transition and stemness via activating canonical Wnt/β-catenin pathway in gastric cancer. Int J Biol Sci. 14:280–293. 2018. View Article : Google Scholar : PubMed/NCBI
25	Wang S, Yin J, Chen D, Nie F, Song X, Fei C, Miao H, Jing C, Ma W, Wang L, et al: Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction. Nat Chem Biol. 9:579–585. 2013. View Article : Google Scholar : PubMed/NCBI
26	Luo H, Vong CT, Chen H, Gao Y, Lyu P, Qiu L, Zhao M, Liu Q, Cheng Z, Zou J, et al: Naturally occurring anti-cancer compounds: Shining from Chinese herbal medicine. Chin Med. 14:482019. View Article : Google Scholar : PubMed/NCBI
27	Fan HN, Zhu MY, Peng SQ, Zhu JS, Zhang J and Qu GQ: Dihydroartemisinin inhibits the growth and invasion of gastric cancer cells by regulating cyclin D1-CDK4-Rb signaling. Pathol Res Pract. 216:1527952020. View Article : Google Scholar : PubMed/NCBI
28	Su T, Li F, Guan J, Liu L, Huang P, Wang Y, Qi X, Liu Z, Lu L and Wang D: Artemisinin and its derivatives prevent Helicobacter pylori-induced gastric carcinogenesis via inhibition of NF-κB signaling. Phytomedicine. 63:1529682019. View Article : Google Scholar : PubMed/NCBI
29	In H, Solsky I, Palis B, Langdon-Embry M, Ajani J and Sano T: Validation of the 8th edition of the AJCC TNM staging system for gastric cancer using the national cancer database. Ann Surg Oncol. 24:3683–3691. 2017. View Article : Google Scholar : PubMed/NCBI
30	Zhao W, Deng C, Han Q, Xu H and Chen Y: Carvacrol may alleviate vascular inflammation in diabetic db/db mice. Int J Mol Med. 46:977–988. 2020. View Article : Google Scholar : PubMed/NCBI
31	Liu J, Huang C, Peng C, Xu F, Li Y, Yutaka Y, Xiong B and Yang X: Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/β-catenin pathway. BMC Cancer. 18:10992018. View Article : Google Scholar : PubMed/NCBI
32	Guo X, Zhang L, Fan Y, Zhang D, Qin L, Dong S and Li G: Oxysterol-binding protein-related protein 8 inhibits gastric cancer growth through induction of er stress, inhibition of wnt signaling, and activation of apoptosis. Oncol Res. 25:799–808. 2017. View Article : Google Scholar : PubMed/NCBI
33	Mazzoni SM and Fearon ER: AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett. 355:1–8. 2014. View Article : Google Scholar : PubMed/NCBI
34	Liu AN, Zhu ZH, Chang SJ and Hang XS: Twist expression associated with the epithelial-mesenchymal transition in gastric cancer. Mol Cell Biochem. 367:195–203. 2012. View Article : Google Scholar : PubMed/NCBI
35	Wang T, Hou J, Jian S, Luo Q, Wei J, Li Z, Wang X, Bai P, Duan B, Xing J and Cai J: miR-29b negatively regulates MMP2 to impact gastric cancer development by suppress gastric cancer cell migration and tumor growth. J Cancer. 9:3776–3786. 2018. View Article : Google Scholar : PubMed/NCBI
36	Jiang XJ, Lin J, Cai QH, Zhao JF and Zhang HJ: CDH17 alters MMP-2 expression via canonical NF-κB signalling in human gastric cancer. Gene. 682:92–100. 2019. View Article : Google Scholar : PubMed/NCBI
37	Ni YJ, Lu J and Zhou HM: Propofol suppresses proliferation, migration and invasion of gastric cancer cells via regulating miR-29/MMP-2 axis. Eur Rev Med Pharmacol Sci. 23:8606–8615. 2019.PubMed/NCBI
38	Zhao L, Niu H, Liu Y, Wang L, Zhang N, Zhang G, Liu R and Han M: LOX inhibition downregulates MMP-2 and MMP-9 in gastric cancer tissues and cells. J Cancer. 10:6481–6490. 2019. View Article : Google Scholar : PubMed/NCBI
39	Ju RJ, Cheng L, Peng XM, Wang T, Li CQ, Song XL, Liu S, Chao JP and Li XT: Octreotide-modified liposomes containing daunorubicin and dihydroartemisinin for treatment of invasive breast cancer. Artif Cells Nanomed Biotechnol. 46 (Suppl 1):616–628. 2018. View Article : Google Scholar : PubMed/NCBI
40	Chen X, He LY, Lai S and He Y: Dihydroartemisinin inhibits the migration of esophageal cancer cells by inducing autophagy. Oncol Lett. 20:942020. View Article : Google Scholar : PubMed/NCBI
41	Hui HY, Wu N, Wu M, Liu Y, Xiao SX and Zhang MF: Dihydroartemisinin suppresses growth of squamous cell carcinoma A431 cells by targeting the Wnt/β-catenin pathway. Anticancer Drugs. 27:99–105. 2016. View Article : Google Scholar : PubMed/NCBI
42	Solberg NT, Waaler J, Lund K, Mygland L, Olsen PA and Krauss S: TANKYRASE inhibition enhances the antiproliferative effect of PI3K and EGFR inhibition, mutually affecting β-CATENIN and AKT signaling in colorectal cancer. Mol Cancer Res. 16:543–553. 2018. View Article : Google Scholar : PubMed/NCBI
43	Yang HY, Shen JX, Wang Y, Liu Y, Shen DY and Quan S: Tankyrase promotes aerobic glycolysis and proliferation of ovarian cancer through activation of Wnt/β-catenin signaling. Biomed Res Int. 2019:26863402019.PubMed/NCBI
44	Ma Z, Han C, Xia W, Wang S, Li X, Fang P, Yin R, Xu L and Yang L: circ5615 functions as a ceRNA to promote colorectal cancer progression by upregulating TNKS. Cell Death Dis. 11:3562020. View Article : Google Scholar : PubMed/NCBI