Autophagic degradation of SQSTM1 inhibits ovarian cancer motility by decreasing DICER1 and AGO2 to induce <i>MIRLET7A-3P</i>
Creators: name: Chiao-Chun Liao
name: Ho, Ming-Yi
name: Liang, Shu-Mei
name: Liang, Chi-Ming
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Physiology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: 110309 Infectious Diseases
subject: FOS: Health sciences
subject: FOS: Health sciences

description: The relationship between macroautophagy/autophagy and miRNA in regulating cancer cell motility is not clearly delineated. Here, we found that induction of BECN1-dependent or -independent autophagy decreased ubiquitin-binding proteins SQSTM1/p62 and CALCOCO2/NDP52. Downregulation of SQSTM1 (but not CALCOCO2) led to a decrease of the miRNA-processing enzyme DICER1 and the miRNA effector AGO2. The autophagy-mediated reduction of levels of SQSTM1, DICER1 or AGO2 resulted in increased <i>MIRLET7A-3P</i> (but not <i>MIRLET7A-5P</i> or <i>PRE-MIRLET7A</i> miRNA) and suppressed ovarian cancer motility. The investigation of the <i>MIRLET7A</i> effects on cancer cell motility showed that synthetic <i>MIRLET7A-3P</i> (3 nM) inhibited, whereas <i>MIRLET7A-5P</i> (100 nM) increased cancer cell motility. Moreover, downregulation of <i>MIRLET7A-3P</i> with antisense of <i>MIRLET7A-3P</i> miRNA (<i>MIRLET7A-3P</i> inhibitor; 3 nM) reversed the nutrient depletion- and rVP1-mediated suppression of ovarian cancer cell motility. In addition, restoring SQSTM1, DICER1 and AGO2 with inhibition of autophagic degradation or overexpression of DICER1 and AGO2 reversed the autophagy-associated enhancement of <i>MIRLET7A-3P</i> and inhibition of motility. Examination of ovarian cancer tissue microarray further showed that the levels of SQSTM1, DICER1 and AGO2 in the tumor were higher than those in the non-tumor cells and negatively correlated with the levels of autophagy and <i>MIRLET7A-3P</i>. Our results demonstrated that induction of autophagy to decrease SQSTM1, DICER1 and AGO2 and increase <i>MIRLET7A-3P</i> is a potential therapeutic strategy for suppressing ovarian cancer cell motility. <b>Abbreviations</b>: ACTB: actin beta; AGO2: argonaute 2, RISC catalytic component; ATG: autophagy related; BCIP/NBT: 5-bromo-4-chloro-3-indolyl-phosphate/nitro blue tetrazolium; BECN1: beclin 1, autophagy related; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CQ: chloroquine; DICER1: dicer 1, ribonuclease III; EBSS: Earle balanced salt solution; FBS: fetal bovine serum; HGF: hepatocyte growth factor; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MIRLET7A: microRNA LET-7A: MIR16: microRNA 16; MIR29C: microRNA 29C; miRNA: microRNA; MMP: matrix metallopeptidase; PRE-MIRNA: precursor microRNA; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RISC: RNA-induced silencing complex; rVP1: recombinant foot-and-mouth disease virus capsid protein VP1; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; WIPI: WD repeat domain, phosphoinositide interacting.