Abstract
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.
Highlights
Pancreatic cancer is a highly malignant tumor type with poor outcomes; the 5-year overall survival rate, including unresectable and metastatic cancer, is less than 10% [1, 2]
We demonstrated that low F-box and WD repeat domain-containing 7 (FBXW7) expression in pancreatic cancer tissue was associated with cancer progression and was an independent factor predicting poor prognosis
In our in vitro analysis, we found that knockdown of FBXW7 enhanced cell proliferation, migration, and invasion abilities, and decreased sensitivity to gemcitabine and nab-paclitaxel in pancreatic cancer cells
Summary
Pancreatic cancer is a highly malignant tumor type with poor outcomes; the 5-year overall survival rate, including unresectable and metastatic cancer, is less than 10% [1, 2]. To improve the prognosis of patients with pancreatic cancer, it is important to elucidate the mechanisms underlying therapeutic resistance and develop new therapeutic targets. In clinical samples, reduced expression of FBXW7 has been reported to be associated with poor prognosis and cancer progression in various human solid cancers, such as gastric cancer [9], esophageal cancer [10], colorectal cancer [11], and cholangiocarcinoma [12, 13], due to the accumulation of several oncoproteins. ERK directly phosphorylates FBXW7, which leads to the selfubiquitination and proteosomal degradation of FBXW7 itself. This low FBXW7 protein expression results in accumulation of multiple FBXW7 substrates in pancreatic cancer. The mechanisms regulating FBXW7 expression are gradually being elucidated, studies on the impact of FBXW7 expression and its substrate in pancreatic cancer are limited
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