Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Breast Cancer | Research article

MiR-7 reduces the BCSC subset by inhibiting XIST to modulate the miR-92b/Slug/ESA axis and inhibit tumor growth

Authors: Miao Li, Meng Pan, Chengzhong You, Fengshu Zhao, Di Wu, Mei Guo, Hui Xu, Fangfang Shi, Danfeng Zheng, Jun Dou

Published in: Breast Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown.

Methods

We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays.

Results

MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-κB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7.

Conclusions

The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer.
Appendix
Available only for authorised users
Literature
1.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.CrossRefPubMedPubMedCentral
2.
Mu C, Wu X, Zhou X, Wolfram J, Shen J, Zhang D, Mai J, Xia X, Holder AM, Ferrari M, et al. Chemotherapy sensitizes therapy-resistant cells to mild hyperthermia by suppressing heat shock protein 27 expression in triple-negative breast cancer. Clin Cancer Res. 2018;24(19):4900–12.CrossRefPubMedPubMedCentral
3.
Zhou J, Zhang H, Gu P, Margolick JB, Yin D, Zhang Y. Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model. Breast Cancer Res Treat. 2009;115(2):269–77.CrossRefPubMed
4.
Dou J, Pan M, Wen P, Li Y, Tang Q, Chu L, Zhao F, Jiang C, Hu W, Hu K, et al. Isolation and identification of cancer stem-like cells from murine melanoma cell lines. Cell Mol Immunol. 2007;4(6):467–72.PubMed
5.
Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, Mo YY, Iiizumi-Gairani M, Hirota S, Liu Y, et al. miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res. 2013;73(4):1434–44.CrossRefPubMedPubMedCentral
6.
Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, Jiang L, Zhang Y, Dou J. MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells. 2014;32(11):2858–68.CrossRefPubMed
7.
Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, Vielh P, Larsen AK, Thiery JP, Sabbah M, et al. Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene. 2015;34(17):2261–71.CrossRefPubMed
8.
Kretz M, Siprashvili Z, Chu C, Webster DE, Zehnder A, Qu K, Lee CS, Flockhart RJ, Groff AF, Chow J, et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature. 2013;493(7431):231–5.CrossRefPubMed
9.
10.
11.
Sun W, Yang Y, Xu C, Guo J. Regulatory mechanisms of long noncoding RNAs on gene expression in cancers. Cancer Genet. 2017;216-217:105–10.CrossRefPubMed
12.
Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537(7620):369–73.CrossRefPubMedPubMedCentral
13.
Xu R, Zhu X, Chen F, Huang C, Ai K, Wu H, Zhang L, Zhao X. LncRNA XIST/miR-200c regulates the stemness properties and tumourigenicity of human bladder cancer stem cell-like cells. Cancer Cell Int. 2018;18:41.CrossRefPubMedPubMedCentral
14.
Chen D, Wang J, Zhang Y, Chen J, Yang C, Cao W, Zhang H, Liu Y, Dou J. Effect of down-regulated transcriptional repressor ZEB1 on the epithelial-mesenchymal transition of ovarian cancer cells. Int J Gynecol Cancer. 2013;23(8):1357–66.CrossRefPubMed
15.
Ghader A, Ardakani AA, Ghaznavi H, Shakeri-Zadeh A, Minaei SE, Mohajer S, Ara MHM. Evaluation of nonlinear optical differences between breast cancer cell lines SK-BR-3 and MCF-7; an in vitro study. Photodiagn Photodyn Ther. 2018;23:171–5.CrossRef
16.
Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, Viale G, Sotiriou C, Piccart M. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794–803.CrossRefPubMed
17.
Wu D, Wang J, Cai Y, Ren M, Zhang Y, Shi F, Zhao F, He X, Pan M, Yan C, et al. Effect of targeted ovarian cancer immunotherapy using ovarian cancer stem cell vaccine. J Ovarian Res. 2015;8:68.CrossRefPubMedPubMedCentral
18.
Chen J, Wang J, Chen D, Yang J, Yang C, Zhang Y, Zhang H, Dou J. Evaluation of characteristics of CD44+CD117+ ovarian cancer stem cells in three dimensional basement membrane extract scaffold versus two dimensional monocultures. BMC Cell Biol. 2013;14:7.CrossRefPubMedPubMedCentral
19.
Chiyomaru T, Yamamura S, Fukuhara S, Yoshino H, Kinoshita T, Majid S, Saini S, Chang I, Tanaka Y, Enokida H, et al. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One. 2013;8(8):e70372.CrossRefPubMedPubMedCentral
20.
Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, Aken BL, Barrell D, Zadissa A, Searle S, et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012;22(9):1760–74.CrossRefPubMedPubMedCentral
21.
Nagle AM, Levine KM, Tasdemir N, Scott JA, Burlbaugh K, Kehm J, Katz TA, Boone DN, Jacobsen BM, Atkinson JM, et al. Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors. Clin Cancer Res. 2018;24(20):5165–77.PubMedPubMedCentral
22.
Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.CrossRefPubMedPubMedCentral
23.
Ceol CJ, Houvras Y, Jane-Valbuena J, Bilodeau S, Orlando DA, Battisti V, Fritsch L, Lin WM, Hollmann TJ, Ferre F, et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature. 2011;471(7339):513–7.CrossRefPubMedPubMedCentral
24.
Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell. 2011;19(2):232–43.CrossRefPubMed
25.
Li M, Shi F, Fei X, Wu S, Wu D, Pan M, Luo S, Gu N, Dou J. PEGylated long-circulating liposomes deliver homoharringtonine to suppress multiple myeloma cancer stem cells. Exp Biol Med (Maywood). 2017;242(9):996–1004.CrossRef
26.
Su X, Wang H, Ge W, Yang M, Hou J, Chen T, Li N, Cao X. An in vivo method to identify microRNA targets not predicted by computation algorithms: p21 targeting by miR-92a in cancer. Cancer Res. 2015;75(14):2875–85.CrossRefPubMed
27.
Ozawa T, Arora S, Szulzewsky F, Juric-Sekhar G, Miyajima Y, Bolouri H, Yasui Y, Barber J, Kupp R, Dalton J, et al. A de novo mouse model of C11orf95-RELA fusion-driven ependymoma identifies driver functions in addition to NF-kappaB. Cell Rep. 2018;23(13):3787–97.CrossRefPubMedPubMedCentral
28.
Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E 3rd, Zhang Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007;104(41):16158–63.CrossRefPubMedPubMedCentral
29.
Zhuang LK, Yang YT, Ma X, Han B, Wang ZS, Zhao QY, Wu LQ, Qu ZQ. MicroRNA-92b promotes hepatocellular carcinoma progression by targeting Smad7 and is mediated by long non-coding RNA XIST. Cell Death Dis. 2016;7:e2203.CrossRefPubMedPubMedCentral
30.
Wang X, Zhang G, Cheng Z, Dai L, Jia L, Jing X, Wang H, Zhang R, Liu M, Jiang T, et al. Knockdown of LncRNA-XIST suppresses proliferation and TGF-beta1-induced EMT in NSCLC through the Notch-1 pathway by regulation of miR-137. Genet Test Mol Biomarkers. 2018;22(6):333–42.CrossRefPubMed
31.
Liang S, Gong X, Zhang G, Huang G, Lu Y, Li Y. The lncRNA XIST interacts with miR-140/miR-124/iASPP axis to promote pancreatic carcinoma growth. Oncotarget. 2017;8(69):113701–18.CrossRefPubMedPubMedCentral
32.
Su C, Han Y, Zhang H, Li Y, Yi L, Wang X, Zhou S, Yu D, Song X, Xiao N, et al. CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-kappaB signalling. J Cell Mol Med. 2018;22(6):3097–107.CrossRefPubMedPubMedCentral
33.
Wu ZB, Cai L, Lin SJ, Lu JL, Yao Y, Zhou LF. The miR-92b functions as a potential oncogene by targeting on Smad3 in glioblastomas. Brain Res. 2013;1529:16–25.CrossRefPubMed
34.
35.
Li Y, Li L, Guan Y, Liu X, Meng Q, Guo Q. MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN. Biochem Biophys Res Commun. 2013;440(4):604–10.CrossRefPubMed
36.
Ma G, Jing C, Li L, Huang F, Ding F, Wang B, Lin D, Luo A, Liu Z. MicroRNA-92b represses invasion-metastasis cascade of esophageal squamous cell carcinoma. Oncotarget. 2016;7(15):20209–22.CrossRefPubMedPubMedCentral
37.
Werner TL, Ray A, Lamb JG, VanBrocklin M, Hueftle K, Cohen AL, Beck AC, Buys SS, Dyess DL, Butler TW, et al. A phase I study of neoadjuvant chemotherapy with nab-paclitaxel, doxorubicin, and cyclophosphamide in patients with stage II to III breast cancer. Clin Breast Cancer. 2017;17(7):503–9.CrossRefPubMed
38.
Ferreira AR, Metzger-Filho O, Sarmento RMB, Bines J. Neoadjuvant treatment of stage IIB/III triple negative breast cancer with cyclophosphamide, doxorubicin, and cisplatin (CAP regimen): a single arm, single center phase II study (GBECAM 2008/02). Front Oncol. 2017;7:329.CrossRefPubMed
39.
Dou J, Liu P, Zhang X. Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis. J Nanosci Nanotechnol. 2005;5(8):1230–5.CrossRefPubMed
40.
Rodriguez-Paredes M, Martinez de Paz A, Simo-Riudalbas L, Sayols S, Moutinho C, Moran S, Villanueva A, Vazquez-Cedeira M, Lazo PA, Carneiro F, et al. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene. 2014;33(21):2807–13.CrossRefPubMed
Metadata
Title
MiR-7 reduces the BCSC subset by inhibiting XIST to modulate the miR-92b/Slug/ESA axis and inhibit tumor growth
Authors
Miao Li
Meng Pan
Chengzhong You
Fengshu Zhao
Di Wu
Mei Guo
Hui Xu
Fangfang Shi
Danfeng Zheng
Jun Dou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01264-z

Other articles of this Issue 1/2020

Breast Cancer Research 1/2020 Go to the issue

Research article

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

Research article

Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort

Research article

Comparison of three scoring methods using the FDA-approved 22C3 immunohistochemistry assay to evaluate PD-L1 expression in breast cancer and their association with clinicopathologic factors

Review

Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women—a literature review and proposed guidelines

Research article

Shotgun proteomics coupled to nanoparticle-based biomarker enrichment reveals a novel panel of extracellular matrix proteins as candidate serum protein biomarkers for early-stage breast cancer detection

Research article

Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits