MiR-532-3p Suppresses Colorectal Cancer Progression by Disrupting the ETS1/TGM2 Axis-mediated Wnt/β-catenin Signaling

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2019 Oct 2

PMID 31570702

Citations 61

Authors

Chuncai Gu

Jianqun Cai

Zhijun Xu

Shiming Zhou

Liangying Ye

Qun Yan

Yue Zhang

Yuxin Fang

Yongfeng Liu

Chenge Tu

Xinke Wang

Juan He

Qingyuan Li

Lu Han

Xin Lin

Aimin Li

Side Liu

Affiliations

Soon will be listed here.

Abstract

The expression panel of plasma microRNA defined miR-532-3p as a valuable biomarker for colorectal adenoma (CRA). However, its expression pattern and function in colorectal cancer (CRC) have remained unclear. The present study investigated the expression levels of miR-532-3p and found that it was in situ downregulated both in CRA and CRC. Moreover, it functioned as a sensitizer for chemotherapy in CRC by inducing cell cycle arrest and early apoptosis via its activating effects on p53 and apoptotic signaling pathways. In addition, miR-532-3p was found to restrain cell growth, metastasis, and epithelial-mesenchymal transition (EMT) phenotype of CRC. A study on the mechanism behind these effects revealed that miR-532-3p directly binds to 3'UTR regions of ETS1 and TGM2, ultimately repressing the canonical Wnt/β-catenin signaling. Further investigation showed that TGM2 was transcriptionally regulated by ETS1 and ETS1/TGM2 axis served as a vital functional target of miR-532-3p in suppressing CRC progression. To conclude, miR-532-3p mimics could act as potential candidate for molecular therapy in CRC through inactivation of the canonical Wnt/β-catenin signaling and enhancement of chemosensitivity.

Citing Articles

Circulating miR-18a and miR-532 Levels in Extrahepatic Cholangiocarcinoma.

Orzan R, Tigu A, Nechita V, Nistor M, Agoston R, Gonciar D J Clin Med. 2024; 13(20).

PMID: 39458127 PMC: 11509052. DOI: 10.3390/jcm13206177.

MicroRNA-532-3p Modulates Colorectal Cancer Cell Proliferation and Invasion via Suppression of FOXM1.

Mahajan K, Das A, Alahari S, Pothuraju R, Nair S Cancers (Basel). 2024; 16(17).

PMID: 39272919 PMC: 11394065. DOI: 10.3390/cancers16173061.

Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop.

Yao G, Fu L, Dai J, Chen J, Liu K, Liang H J Transl Med. 2024; 22(1):596.

PMID: 38926764 PMC: 11209967. DOI: 10.1186/s12967-024-05290-9.

Transglutaminase 2 serves as a pathogenic hub gene of KRAS mutant colon cancer based on integrated analysis.

Peng W, Li Y, Zeng Y, Chen K World J Gastrointest Oncol. 2024; 16(5):2074-2090.

PMID: 38764826 PMC: 11099438. DOI: 10.4251/wjgo.v16.i5.2074.

The crosstalk between non-coding RNAs and cell-cycle events: A new frontier in cancer therapy.

Pathania A, Chava H, Balusu R, Pasupulati A, Coulter D, Challagundla K Mol Ther Oncol. 2024; 32(2):200785.

PMID: 38595981 PMC: 10973673. DOI: 10.1016/j.omton.2024.200785.

References

Stiegelbauer V, Vychytilova-Faltejskova P, Karbiener M, Pehserl A, Reicher A, Resel M . miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5. Clin Cancer Res. 2017; 23(17):5255-5266. DOI: 10.1158/1078-0432.CCR-17-0023. View

Hur K, Toiyama Y, Schetter A, Okugawa Y, Harris C, Boland C . Identification of a metastasis-specific MicroRNA signature in human colorectal cancer. J Natl Cancer Inst. 2015; 107(3). PMC: 4334826. DOI: 10.1093/jnci/dju492. View

Toiyama Y, Okugawa Y, Fleshman J, Boland C, Goel A . MicroRNAs as potential liquid biopsy biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta Rev Cancer. 2018; 1870(2):274-282. PMC: 7286572. DOI: 10.1016/j.bbcan.2018.05.006. View

Hur K, Toiyama Y, Okugawa Y, Ide S, Imaoka H, Boland C . Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer. Gut. 2015; 66(4):654-665. PMC: 4919275. DOI: 10.1136/gutjnl-2014-308737. View

Kumar R, Coronel L, Somalanka B, Raju A, Aning O, An O . Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat Commun. 2018; 9(1):3931. PMC: 6158291. DOI: 10.1038/s41467-018-05805-1. View

Xu X, Zhang Y, Liu Z, Zhang X, Jia J . miRNA-532-5p functions as an oncogenic microRNA in human gastric cancer by directly targeting RUNX3. J Cell Mol Med. 2015; 20(1):95-103. PMC: 4717862. DOI: 10.1111/jcmm.12706. View

Park Y, Kim H, Cho Y, Min D, Cheon S, Lim Y . Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations. Int J Cancer. 2018; 144(2):389-401. PMC: 6587482. DOI: 10.1002/ijc.31662. View

Gu D, Li S, Du M, Tang C, Chu H, Tong N . A genetic variant located in the miR-532-5p-binding site of TGFBR1 is associated with the colorectal cancer risk. J Gastroenterol. 2018; 54(2):141-148. DOI: 10.1007/s00535-018-1490-y. View

Cheng J, Dwyer M, Okolotowicz K, Mercola M, Cashman J . A Novel Inhibitor Targets Both Wnt Signaling and ATM/p53 in Colorectal Cancer. Cancer Res. 2018; 78(17):5072-5083. DOI: 10.1158/0008-5472.CAN-17-2642. View

10.

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

11.

Zhou Y, Zheng X, Lu J, Chen W, Li X, Zhao L . Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells. Cell Physiol Biochem. 2018; 45(6):2548-2559. DOI: 10.1159/000488273. View

12.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

13.

Rodgers J, McClure R, Epis M, Cohen R, Leedman P, Harvey J . ETS1 induces transforming growth factor β signaling and promotes epithelial-to-mesenchymal transition in prostate cancer cells. J Cell Biochem. 2018; 120(1):848-860. DOI: 10.1002/jcb.27446. View

14.

Condello S, Cao L, Matei D . Tissue transglutaminase regulates β-catenin signaling through a c-Src-dependent mechanism. FASEB J. 2013; 27(8):3100-12. PMC: 4050431. DOI: 10.1096/fj.12-222620. View

15.

Pedersen E, Menon R, Bailey K, Thomas D, Van Noord R, Tran J . Activation of Wnt/β-Catenin in Ewing Sarcoma Cells Antagonizes EWS/ETS Function and Promotes Phenotypic Transition to More Metastatic Cell States. Cancer Res. 2016; 76(17):5040-53. PMC: 5010452. DOI: 10.1158/0008-5472.CAN-15-3422. View

16.

Hermeking H . MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer. 2012; 12(9):613-26. DOI: 10.1038/nrc3318. View

17.

Damalas A, Kahan S, Shtutman M, Ben-Zeev A, Oren M . Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBO J. 2001; 20(17):4912-22. PMC: 125598. DOI: 10.1093/emboj/20.17.4912. View

18.

Zhai W, Ma J, Zhu R, Xu C, Zhang J, Chen Y . MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1-mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis. Br J Cancer. 2018; 119(5):591-604. PMC: 6162242. DOI: 10.1038/s41416-018-0196-5. View

19.

Wu C, Luo K, Zhao F, Yin P, Song Y, Deng M . USP20 positively regulates tumorigenesis and chemoresistance through β-catenin stabilization. Cell Death Differ. 2018; 25(10):1855-1869. PMC: 6180113. DOI: 10.1038/s41418-018-0138-z. View

20.

Karni R, Gus Y, Dor Y, Meyuhas O, Levitzki A . Active Src elevates the expression of beta-catenin by enhancement of cap-dependent translation. Mol Cell Biol. 2005; 25(12):5031-9. PMC: 1140589. DOI: 10.1128/MCB.25.12.5031-5039.2005. View