Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1
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Norihiro Ishii1,2, Kenichiro Araki1,2, Takehiko Yokobori3, Dorgormaa Gantumur1, Takahiro Yamanaka1,2, Bolag Altan4, Mariko Tsukagoshi1,2, Takamichi Igarashi1,2, Akira Watanabe1,2, Norio Kubo1,2, Yasuo Hosouchi5, Hiroyuki Kuwano2 and Ken Shirabe1
1Department of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
2Department of General Surgical Science, Gunma University, Graduate School of Medicine, Showamachi, Maebashi, Japan
3Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi, Japan
4Department of Oncology Clinical Development, Gunma University, Graduate School of Medicine, Maebashi, Japan
5Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Japan
Hiroyuki Kuwano, email: [email protected]
Keywords: chemosensitivity, ubiquitin ligase, tumor suppressor, MCL1, nab-paclitaxel
Received: August 23, 2017 Accepted: October 05, 2017 Published: November 06, 2017
Pancreatic cancer is a highly malignant tumor type with poor outcomes, and elucidation of the mechanisms involved in cancer progression and therapeutic resistance is critical. FBXW7 is a key regulator of tumor malignant potential, and its substrate MCL1 regulates therapeutic resistance in human malignancies. Therefore, determination of the relevance of FBXW7 expression is critical for improving patient outcomes. In this study, we investigated the function and clinical significance of FBXW7 in pancreatic cancer. FBXW7 expression was evaluated by immunohistochemistry in 122 pancreatic cancer tissues. Reduced FBXW7 expression was significantly associated with advanced venous invasion, high MCL1 expression, enhanced Ki-67 expression, and poor prognosis and was an independent poor prognostic factor. Among patients who underwent gemcitabine treatment after surgery, reduced FBXW7 expression was also significantly associated with poor prognosis. Knockdown of FBXW7 in vitro enhanced cell proliferation, and migration, and invasion abilities and promoted gemcitabine and nab-paclitaxel chemoresistance in pancreatic cancer cells. Moreover, FBXW7-knockdown cells showed accumulation of MCL1, and the enhanced chemoresistance observed in FBXW7-knockdown cells was eliminated by MCL1 suppression. These results suggested that FBXW7 was associated with cancer progression and mediated sensitivity to gemcitabine and nab-paclitaxel via MCL1 accumulation in pancreatic cancer. Thus, the FBXW7/MCL1 axis may be a promising therapeutic tool to overcome refractory pancreatic cancer.
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