title: Hypoxia promotes chemotherapy resistance by down-regulating SKA1 gene expression in human osteosarcoma.
abstract: Drug resistance has always been the main problem in osteosarcoma treatment, and hypoxia seems to be one of the many causes for drug resistance. Therefore, in this study, we investigated how hypoxia triggers chemotherapy resistance in osteosarcoma. We first screened hypoxia- and normoxia- cultured osteosarcoma cells in silico to identify the differentially expressed genes specifically related to drug resistance. This led to the identification of spindle and kinetochore associated complex subunit 1 (SKA1) as a probable gene of interest. SKA1 was further overexpressed by a lentiviral vector into an osteosarcoma cell line to study its role in chemoresistance. Our data revealed that SKA1 overexpression reduced the expression of some multidrug resistance genes, and enhanced the sensitivity of two common chemotherapeutic drugs used in osteosarcoma patients, epirubicin (EPI) and ifosfamide (IFO). In addition, we also confirmed the role of SKA1 in EPI drug sensitivity in vivo. Taken together, our study indicated that hypoxia mediated downregulation of SKA1 expression increased the chemotherapy resistance in human osteosarcoma cells.
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: b Department of Orthopaedics , The First Affiliated Hospital of Chinese People's Liberation Army General Hospital , Beijing , China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Jiang
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wen
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Fan
authors.affiliation: a Orthopaedic Oncology Institute, Tangdu Hospital, Fourth Military Medical University , Xi'an , Shaanxi , China.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Qiu
mesh_terms: D000293:Adolescent; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis / Q000379:methods; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C516427:SKA1 protein, human
keywords: Chemotherapy; MDR-related genes; drug resistance; human osteosarcoma; hypoxia; hypoxia-inducible factor 1-α; spindle and kinetochore associated complex subunit 1