Research Papers:

Overexpression of karyopherin-α2 in cholangiocarcinoma correlates with poor prognosis and gemcitabine sensitivity via nuclear translocation of DNA repair proteins

Mariko Tsukagoshi, Kenichiro Araki, Takehiko Yokobori, Bolag Altan, Hideki Suzuki, Norio Kubo, Akira Watanabe, Norihiro Ishii, Yasuo Hosouchi, Masahiko Nishiyama, Ken Shirabe and Hiroyuki Kuwano _

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Oncotarget. 2017; 8:42159-42172. https://doi.org/10.18632/oncotarget.15020

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Mariko Tsukagoshi1,3, Kenichiro Araki1,3, Takehiko Yokobori4, Bolag Altan1, Hideki Suzuki1, Norio Kubo1,3, Akira Watanabe1,3, Norihiro Ishii1, Yasuo Hosouchi5, Masahiko Nishiyama4, Ken Shirabe2,3 and Hiroyuki Kuwano1,3

1Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

2Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

3Division of Hepatobiliary and Pancreatic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan

4Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

5Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Gunma 371-0821, Japan

Correspondence to:

Hiroyuki Kuwano, email: [email protected]

Keywords: KPNA2, cholangiocarcinoma, gemcitabine, MRN complex, DNA repair

Received: August 10, 2016     Accepted: January 04, 2017     Published: February 02, 2017


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.

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