Autophagy Inhibits Cancer Stemness in Triple-negative Breast Cancer Via MiR-181a-mediated Regulation of ATG5 And/or ATG2B

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2022 Jan 14

PMID 35029026

Authors

Jee Won Park

Yesol Kim

Soo-Been Lee

Chae Won Oh

Eun Ji Lee

Je Yeong Ko

Jong Hoon Park

Affiliations

Soon will be listed here.

Abstract

Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple-negative breast cancers require distinct therapeutic approaches because of their different amounts of autophagy flux. We identified that autophagy flux was inhibited in triple-negative breast cancer (TNBC) CSCs. Moreover, miRNA-181a (miR-181a) expression is upregulated in both TNBC CSCs and patient tissues. Autophagy-related 5 (ATG5) and autophagy-related 2B (ATG2B) participate in the early formation of autophagosomes and were revealed as targets of miR-181a. Inhibition of miR-181a expression led to attenuation of TNBC stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR-181a-regulated mechanism in TNBC. Promoting tumor-suppressive autophagy using curcumin may be a potential method for the treatment of TNBC.

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References

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

Kim R, Nam J . OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer. Lab Anim Res. 2011; 27(2):147-52. PMC: 3145994. DOI: 10.5625/lar.2011.27.2.147. View

Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T . Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007; 131(6):1149-63. DOI: 10.1016/j.cell.2007.10.035. View

Shan J, Shen J, Liu L, Xia F, Xu C, Duan G . Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology. 2012; 56(3):1004-14. DOI: 10.1002/hep.25745. View

Park S, Lee H, Li H, Shipitsin M, Gelman R, Polyak K . Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 2010; 16(3):876-87. PMC: 2818503. DOI: 10.1158/1078-0432.CCR-09-1532. View

Atlasi Y, Mowla S, Ziaee S, Bahrami A . OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer. 2007; 120(7):1598-602. DOI: 10.1002/ijc.22508. View

Han Y, Fan S, Qin T, Yang J, Sun Y, Lu Y . Role of autophagy in breast cancer and breast cancer stem cells (Review). Int J Oncol. 2018; 52(4):1057-1070. DOI: 10.3892/ijo.2018.4270. View

Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F . Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ. 2019; 26(4):690-702. PMC: 6460398. DOI: 10.1038/s41418-019-0292-y. View

Ojha R, Bhattacharyya S, Singh S . Autophagy in Cancer Stem Cells: A Potential Link Between Chemoresistance, Recurrence, and Metastasis. Biores Open Access. 2015; 4(1):97-108. PMC: 4497670. DOI: 10.1089/biores.2014.0035. View

10.

N Almanaa T, Geusz M, Jamasbi R . A new method for identifying stem-like cells in esophageal cancer cell lines. J Cancer. 2013; 4(7):536-48. PMC: 3753528. DOI: 10.7150/jca.6477. View

11.

Park S, Choi J, Nam J . Targeting Cancer Stem Cells in Triple-Negative Breast Cancer. Cancers (Basel). 2019; 11(7). PMC: 6678244. DOI: 10.3390/cancers11070965. View

12.

Jing Z, Han W, Sui X, Xie J, Pan H . Interaction of autophagy with microRNAs and their potential therapeutic implications in human cancers. Cancer Lett. 2014; 356(2 Pt B):332-8. DOI: 10.1016/j.canlet.2014.09.039. View

13.

OConor C, Chen T, Gonzalez I, Cao D, Peng Y . Cancer stem cells in triple-negative breast cancer: a potential target and prognostic marker. Biomark Med. 2018; 12(7):813-820. DOI: 10.2217/bmm-2017-0398. View

14.

Lee C, Yu C, Wang B, Chang W . Tumorsphere as an effective in vitro platform for screening anti-cancer stem cell drugs. Oncotarget. 2015; 7(2):1215-26. PMC: 4811455. DOI: 10.18632/oncotarget.6261. View

15.

Ellis P, Fagan B, Magness S, Hutton S, Taranova O, Hayashi S . SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci. 2005; 26(2-4):148-65. DOI: 10.1159/000082134. View

16.

Son D, Kim Y, Lim S, Kang H, Kim D, Park J . miR-374a-5p promotes tumor progression by targeting ARRB1 in triple negative breast cancer. Cancer Lett. 2019; 454:224-233. DOI: 10.1016/j.canlet.2019.04.006. View

17.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

18.

Shalem O, Sanjana N, Hartenian E, Shi X, Scott D, Mikkelson T . Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2013; 343(6166):84-87. PMC: 4089965. DOI: 10.1126/science.1247005. View

19.

Matoulkova E, Michalova E, Vojtesek B, Hrstka R . The role of the 3' untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol. 2012; 9(5):563-76. DOI: 10.4161/rna.20231. View

20.

Boo L, Ho W, Ali N, Yeap S, Ky H, Chan K . Phenotypic and microRNA transcriptomic profiling of the MDA-MB-231 spheroid-enriched CSCs with comparison of MCF-7 microRNA profiling dataset. PeerJ. 2017; 5:e3551. PMC: 5511503. DOI: 10.7717/peerj.3551. View