MiR-21 Suppresses Anoikis through Targeting PDCD4 and PTEN in Human Esophageal Adenocarcinoma

Abstract

Anoikis is a form of apoptosis induced upon cell detachment from extracellular matrix. It has been determined that acquisition of resistance to anoikis is a critical step for tumor cell metastasis. MiR-21, the most prominent oncomiR, plays an important role in tumor progression. In this study, we revealed that up-regulation of miR-21 in human esophageal adenocarcinoma (EA) is associated with lymph node metastasis and poor survival rate. Because of the established anti-apoptosis effect of miR-21, it is tempting to speculate that miR-21 might contribute to tumor metastasis by regulating anoikis. qRT-PCR analysis demonstrated that miR-21 expression in OE33/AR cells (subpopulation of human EA OE33 cells that acquired resistance to anoikis) was significantly increased. Also, transfection of miR-21 mimics provided OE33 cells resisting to anoikis. By luciferase assays, we verified that PDCD4 and PTEN were the functional targets of miR-21. In mouse model, via tail vein injection experiment, we showed that the metastasis formation of OE33 cells in vivo could be mediated by changing the miR-21 expression pattern. Taken together, our findings suggested that miR-21 was involved in the regulation of anoikis in human EA cells. Targeting miR-21 may provide a novel strategy to prevent metastasis.

Keywords

miR-21 / anoikis resistance / PDCD4 / PTEN / esophageal adenocarcinoma

References

[1] PaoliP, GiannoniE, ChiarugiP. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta, 2013, 1833(12): 3481-3498

[2] MalagobadanS, NagoorNH. Evaluation of MicroRNAs Regulating Anoikis Pathways and Its Therapeutic Potential. Biomed Res Int, 2015, 2015: 716816

[3] YangJ, ZhengZ, YanX, et al.. Integration of autophagy and anoikis resistance in solid tumors. Anat Rec (Hoboken), 2013, 296(10): 1501-1508

[4] PachmayrE, TreeseC, SteinU. Underlying Mechanisms for Distant Metastasis—Molecular Biology. Visc Med, 2017, 33(1): 11-20

[5] SlattumGM, RosenblattJ. Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nat Rev Cancer, 2014, 14(7): 495-501

[6] EstellerM. Non-coding RNAs in human disease. Nat Rev Genet, 2011, 12(12): 861-874

[7] KongYW, Ferland-McColloughD, JacksonTJ, et al.. microRNAs in cancer management. Lancet Oncol, 2012, 13(6): e249-258

[8] GrossN, KroppJ, KhatibH. MicroRNA Signaling in Embryo Development. Biology (Basel), 2017, 6(3): 34

[9] LiuJ, ZhuH, YangX, et al.. MicroRNA-21 is a novel promising target in cancer radiation therapy. Tumour Biol, 2014, 35(5): 3975-3979

[10] PfefferSR, YangCH, PfefferLM. The Role of miR-21 in Cancer. Drug Dev Res, 2015, 76(6): 270-277

[11] MarkouA, ZavridouM, LianidouES. miRNA-21 as a novel therapeutic target in lung cancer. Lung Cancer (Auckl), 2016, 7: 19-27

[12] ZhaoJ, SchnitzlerGR, IyerLK, et al.. MicroRNAOffset RNA Alters Gene Expression and Cell Proliferation. PLoS One, 2016, 11(6): e0156772

[13] ZhuW, XuB. MicroRNA-21 identified as predictor of cancer outcome: a meta-analysis. PLoS One, 2014, 9(8): e103373

[14] WangW, LiJ, ZhuW, et al.. MicroRNA-21 and the clinical outcomes of various carcinomas: a systematic review and meta-analysis. BMC Cancer, 2014, 14: 819

[15] SchaferZT, GrassianAR, SongL, et al.. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature, 2009, 461(7260): 109-113

[16] LivakKJ, SchmittgenTD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta DeltaC(T)) method. Methods, 2001, 25(4): 402-408

[17] YuSJ, HuJY, KuangXY, et al.. MircroRNA-200a promotes anoikis resistance and metastasis by targeting YAP1 in human breast cancer. Clin Cancer Res, 2013, 19(6): 1389-1399

[18] WuMF, YangJ, XiangT, et al.. miR-21 targets Fas ligand-mediated apoptosis in breast cancer cell line MCF-7. J Huazhong Univ Sci Technolog Med Sci, 2014, 34(2): 190-194

[19] FeberA, XiL, LuketichJD, et al.. MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg, 2008, 135(2): 255-260

[20] MengXR, LuP, MeiJZ, et al.. Expression analysis of miRNA and target mRNAs in esophageal cancer. Braz J Med Biol Res, 2014, 47(9): 811-817

[21] WintherM, AlsnerJ, TrammT, et al.. Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer. Acta Oncol, 2015, 54(9): 1582-1591

[22] PanX, WangZX, WangR. MicroRNA-21: a novel therapeutic target in human cancer. Cancer Biol Ther, 2010, 10(12): 1224-1232

[23] YoungMR, SanthanamAN, YoshikawaN, et al.. Have tumor suppressor PDCD4 and its counteragent oncogenic miR-21 gone rogue. Mol Interv, 2010, 10(2): 76-79

[24] WangG, WangJJ, TangHM, et al.. Targeting strategies on miRNA-21 and PDCD4 for glioblastoma. Arch Biochem Biophys, 2015, 580: 64-74

[25] MingM, HeYY. PTEN in DNA damage repair. Cancer Lett, 2012, 319(2): 125-129

[26] KhalidA, HussainT, ManzoorS, et al.. PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma. Tumour Biol, 2017, 39(6): 1010428317705754

[27] KumarA, RajendranV, SethumadhavanR, et al.. AKT kinase pathway: a leading target in cancer research. Sci World J, 2013, 2013: 756134

[28] ChenJ, XuT, ChenC. The critical roles of miR-21 in anti-cancer effects of curcumin. Ann Transl Med, 2015, 3(21): 330

[29] GaudelotK, GibierJB, PottierN, et al.. Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma. Tumour Biol, 2017, 39(7): 1010428317707372

[30] HeC, DongX, ZhaiB, et al.. MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget, 2015, 6(30): 28867-28881

[31] YanLX, WuQN, ZhangY, et al.. Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth. Breast Cancer Res, 2011, 13(1): R2

[32] SicardF, GayralM, LulkaH, et al.. Targeting miR-21 for the therapy of pancreatic cancer. Mol Ther, 2013, 21(5): 986-994

This project was supported by grants from the National Natural Science Foundation of China (No. 81470818, No. 81472735 and No. 81472033).