title: iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling.
abstract: Epithelial-mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC.
  
  
  
  By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved.
  
  
  
  Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients.
  
  
  
  iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. tdken999@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Women's Health Educational System, Hokkaido University, Sapporo, 0608638, Japan. dpx1cn@gmail.com.
authors.forename: Peixin
authors.initials: P
authors.lastname: Dong
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, 0608638, Japan. watarih@med.hokudai.ac.jp.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Watari
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. jyue@uthsc.edu.|Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. jyue@uthsc.edu.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: Guangzhou Sagene Biotech Co., Ltd, Guangzhou International Biotech Island, Guangzhou, 510300, China.
authors.forename: Min-Fei
authors.initials: MF
authors.lastname: Yu
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Lan
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Ze-Biao
authors.initials: ZB
authors.lastname: Ma
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D044783:F-Box Proteins / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D011379:Prognosis; D011506:Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C521741:FBXL5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; C119612:PPP1R13L protein, human; D011506:Proteins; D012097:Repressor Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D002945:Cisplatin
keywords: BTG3; Cervical cancer; Chemoresistance; EMT; FBXL5; iASPP