Overexpression of karyopherin-α2 in cholangiocarcinoma correlates with poor prognosis and gemcitabine sensitivity via nuclear translocation of DNA repair proteins.
Cholangiocarcinoma is a highly malignant tumor, and the development of new therapeutic strategies is critical. Karyopherin-α2 (KPNA2) functions as an adaptor that mediates nucleocytoplasmic transport. Specifically, KPNA2 transports one of the important DNA repair machineries, the MRE11-RAD50-NBS1 (MRN) complex, to the nucleus. In this study, we clarified the significance of KPNA2 in cholangiocarcinoma. KPNA2 expression evaluated by immunohistochemical analysis was common in malignant tissue but rare in adjacent noncancerous tissues. KPNA2 overexpression was significantly correlated with poor prognosis and was an independent prognostic factor after surgery. In patients with cholangiocarcinoma who received gemcitabine after surgery, KPNA2 overexpression tended to be a prognostic indicator of poor overall survival. In KPNA2-depleted cholangiocarcinoma cells, proliferation was significantly decreased and gemcitabine sensitivity was enhanced in vitro and in vivo. Expression of KPNA2 and the MRN complex displayed colocalization in the nucleus. In addition, nuclear localization of the MRN complex was regulated by KPNA2 in vitro. These results suggest that KPNA2 expression may be a useful prognostic and predictive marker of gemcitabine sensitivity and survival. The regulation of KPNA2 expression may be a new therapeutic strategy for cholangiocarcinoma.
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Mariko
M
Tsukagoshi
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Kenichiro
K
Araki
Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Takehiko
T
Yokobori
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Bolag
B
Altan
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Hideki
H
Suzuki
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Norio
N
Kubo
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Akira
A
Watanabe
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Norihiro
N
Ishii
Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Gunma 371-0821, Japan.
Yasuo
Y
Hosouchi
Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Masahiko
M
Nishiyama
Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Ken
K
Shirabe
Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.
Hiroyuki
H
Kuwano
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004260:DNA Repair; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D021381:Protein Transport; D034622:RNA Interference; D047368:Tumor Burden; D028901:alpha Karyopherins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D028901:alpha Karyopherins; C087978:karyopherin alpha 2; D003841:Deoxycytidine; D000093542:Gemcitabine
DNA repair; KPNA2; MRN complex; cholangiocarcinoma; gemcitabine