MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2020 Jul 16

PMID 32664703

Citations 28

Authors

Milad Ashrafizadeh

Hui Li Ang

Ebrahim Rahmani Moghadam

Shima Mohammadi

Vahideh Zarrin

Kiavash Hushmandi

Saeed Samarghandian

Ali Zarrabi

Masoud Najafi

Reza Mohammadinejad

Alan Prem Kumar

Affiliations

Soon will be listed here.

Abstract

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

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References

Hobo W, Maas F, Adisty N, de Witte T, Schaap N, van der Voort R . siRNA silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD8+ T cells. Blood. 2010; 116(22):4501-11. DOI: 10.1182/blood-2010-04-278739. View

Tian L, Wang Z, Hao J, Zhang X . miR-505 acts as a tumor suppressor in gastric cancer progression through targeting HMGB1. J Cell Biochem. 2018; 120(5):8044-8052. DOI: 10.1002/jcb.28082. View

Sun S, Hang T, Zhang B, Zhu L, Wu Y, Lv X . miRNA-708 functions as a tumor suppressor in colorectal cancer by targeting ZEB1 through Akt/mTOR signaling pathway. Am J Transl Res. 2019; 11(9):5338-5356. PMC: 6789274. View

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

Ong P, Wang L, Dai X, Tseng S, Loo S, Sethi G . Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives. Front Pharmacol. 2016; 7:395. PMC: 5079084. DOI: 10.3389/fphar.2016.00395. View

Pan Y, Zhang J, Fu H, Shen L . miR-144 functions as a tumor suppressor in breast cancer through inhibiting ZEB1/2-mediated epithelial mesenchymal transition process. Onco Targets Ther. 2016; 9:6247-6255. PMC: 5067005. DOI: 10.2147/OTT.S103650. View

Dai B, Zhou G, Hu Z, Zhu G, Mao B, Su H . MiR-205 suppresses epithelial-mesenchymal transition and inhibits tumor growth of human glioma through down-regulation of HOXD9. Biosci Rep. 2019; 39(5). PMC: 6522733. DOI: 10.1042/BSR20181989. View

Zhao L, Liu Y, Zhang J, Liu Y, Qi Q . LncRNA SNHG14/miR-5590-3p/ZEB1 positive feedback loop promoted diffuse large B cell lymphoma progression and immune evasion through regulating PD-1/PD-L1 checkpoint. Cell Death Dis. 2019; 10(10):731. PMC: 6769008. DOI: 10.1038/s41419-019-1886-5. View

Fu D, Huang Y, Gao M . Hsa_circ_0057481 promotes laryngeal cancer proliferation and migration by modulating the miR-200c/ZEB1 axis. Int J Clin Exp Pathol. 2020; 12(11):4066-4076. PMC: 6949780. View

10.

Miao Y, Wang L, Zhang X, Xing R, Zhou W, Liu C . miR-30a inhibits breast cancer progression through the Wnt/β-catenin pathway. Int J Clin Exp Pathol. 2020; 12(1):241-250. PMC: 6944008. View

11.

Chen L, Yao H, Wang K, Liu X . Long Non-Coding RNA MALAT1 Regulates ZEB1 Expression by Sponging miR-143-3p and Promotes Hepatocellular Carcinoma Progression. J Cell Biochem. 2017; 118(12):4836-4843. DOI: 10.1002/jcb.26158. View

12.

Brown C, Dayan S, Wong S, Kaczmarek A, Hope C, Pederson S . FOXP3 and miR-155 cooperate to control the invasive potential of human breast cancer cells by down regulating ZEB2 independently of ZEB1. Oncotarget. 2018; 9(45):27708-27727. PMC: 6021232. DOI: 10.18632/oncotarget.25523. View

13.

Abolghasemi M, Tehrani S, Yousefi T, Karimian A, Mahmoodpoor A, Ghamari A . MicroRNAs in breast cancer: Roles, functions, and mechanism of actions. J Cell Physiol. 2019; 235(6):5008-5029. DOI: 10.1002/jcp.29396. View

14.

Soung Y, Chung H, Yan C, Ju J, Chung J . Arrestin Domain Containing 3 Reverses Epithelial to Mesenchymal Transition and Chemo-Resistance of TNBC Cells by Up-Regulating Expression of miR-200b. Cells. 2019; 8(7). PMC: 6679179. DOI: 10.3390/cells8070692. View

15.

Singh S, Yap W, Arfuso F, Kar S, Wang C, Cai W . Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?. World J Gastroenterol. 2015; 21(43):12261-73. PMC: 4649111. DOI: 10.3748/wjg.v21.i43.12261. View

16.

Li Y, Lv M, Song Z, Lou Z, Wang R, Zhuang M . Long non-coding RNA NNT-AS1 affects progression of breast cancer through miR-142-3p/ZEB1 axis. Biomed Pharmacother. 2018; 103:939-946. DOI: 10.1016/j.biopha.2018.04.087. View

17.

Yue S, Wang L, Zhang H, Min Y, Lou Y, Sun H . miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM. Tumour Biol. 2015; 36(9):6741-9. DOI: 10.1007/s13277-015-3372-8. View

18.

Jin H, Jin X, Chai W, Yin Z, Li Y, Dong F . Long non-coding RNA MIAT competitively binds miR-150-5p to regulate ZEB1 expression in osteosarcoma. Oncol Lett. 2019; 17(1):1229-1236. PMC: 6312950. DOI: 10.3892/ol.2018.9671. View

19.

Truong H, Xiong J, Ghotra V, Nirmala E, Haazen L, Le Devedec S . β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer. Sci Signal. 2014; 7(312):ra15. DOI: 10.1126/scisignal.2004751. View

20.

Yang T, He X, Chen A, Tan K, Du X . RETRACTED: LncRNA HOTAIR contributes to the malignancy of hepatocellular carcinoma by enhancing epithelial-mesenchymal transition via sponging miR-23b-3p from ZEB1. Gene. 2018; 670:114-122. DOI: 10.1016/j.gene.2018.05.061. View