Background & Aim Cholangiocarcinoma is a liver cancer with high mortality. Chemotherapy with cisplatin
or gemcitabine is a main approach to treat cholangiocarcinoma patients at advanced
stage. However, efficiency of these drugs is poor due to chemoresistance. To date,
detailed mechanisms underlying chemoresistance in cholangiocarcinoma remain largely
unknown. In this study, we demonstrate a crucial role for the cold shock protein Y-box
binding protein-1 (YB-1) in cholangiocarcinoma chemoresistance to cisplatin.
Methods Expression of YB-1 was examined by immunohistochemistry in 28 cholangiocarcinoma
patients receiving surgery. Among them, 10 patients received chemotherapy following
operation. The function and relevant mechanisms of YB-1 in cholangiocarcinoma were
investigated in vitro.
Results YB-1 expression in cancer cells, in particular in nuclei, was closely associated
with survival of patients. From 10 patients receiving chemotherapy, 2 patients without
YB-1 expression, but only 3 out of 8 patients with YB-1 expression survived a 5-year
follow-up. In vitro, immunofluorescence staining showed that cisplatin administration
resulted in YB-1 nuclear translocation. ChIP assays further demonstrated YB-1 binding
to the multidrug resistance gene MDR1 promoter prior to expression induction. Impressively,
administration of cisplatin significantly increased YB-1 binding to the MDR1 promoter.
Functionally, knockdown of YB-1 by RNAi inhibited cancer cell proliferation and increased
cisplatin-dependent apoptosis.
Conclusions YB-1 nuclear expression plays a crucial role in cholangiocarcinoma chemoresistance
to cisplatin treatment through upregulating MDR1 expression. YB-1 expression in cancer
cells might be a useful biomarker to determine chemotherapy in cholangiocarcinoma.
Disruption of YB-1 is a potential approach to treat cholangiocarcinoma in clinical
