title: HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer.
abstract: Bladder cancer (BCa) is the 9th most common malignant tumor and the 13th leading cause of death due to cancer. The development of surgery and target drugs bring new challenges for the traditional concept for BCa therapy, and chemotherapy is still the final option for many BCa patients, and cisplatin-containing regimen the most effective one. However, the ubiquitous application of cisplatin-containing regimen in BCa results in the cisplatin-resistance, in addition, the cisplatin‑resistant BCa manifests enhanced malignant behavior, the mechanism of which is unclear. In the present study, we used BCa cell lines to to clarify this point. BCa cell lines T24/J82 were pretreated with cisplatin >3 months to construct stable cisplatin-resistant cell lines (tagged T24(Cis-R) and J82(Cis-R)), which manifested as enhanced capacity of proliferation and malignant behavior in vivo and in vitro, accompanied by cisplatin, and even doxorubicin resistance. The following mechanism dissection revealed that prolonged treatment time of T24/J82 cells led to elevated expression of HIF-1α, which targeted the increased expression of MDR1 on the one hand, and contributed to BCa cell proliferation, migration/invasion on the other hand. Finally, IHC staining of human BCa tissue supported our conclusion that the expression of HIF-1α and MDR1 was higher in chemoresistant tissue vs. chemosensitive tissue. Our results provided a new view of HIF-1α in chemotherapy.
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Xu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D002945:Cisplatin