Abstract
Aquaporin-9 (AQP9) expression is associated with arsenic sensitivity in leukemia cells. However, the role of AQP9 in regulating tumor sensitivity to adjuvant chemotherapy in colorectal cancer (CRC) has not been elucidated. In this study, we demonstrated that AQP9 can serve as an independent predictive marker for adjuvant chemotherapy in CRC. Patients with high AQP9 expression had higher rate of disease-free survival (DFS) than those with low AQP9 expression. Upregulation of AQP9 was associated with enhanced chemosensitivity to 5-fluorouracil (5-FU) both in vitro and in vivo. Overexpression of AQP9 resulted in an increased intracellular level of 5-FU in CRC cells, hence leading to a higher percentage of apoptosis after 5-FU treatment. Moreover, AQP9 is positively associated with RAS activation and other downstream signaling molecules in CRC. AQP9 overexpression resulted in p21 upregulation and induced S-phase arrest. Taken together, AQP9 enhances the cytotoxic response to 5-FU in CRC cells by simultaneously inducing S-phase arrest via activation of RAS signaling and facilitating drug uptake. Our results suggest that AQP9 might be a novel predictor for the benefit of 5-FU-based chemotherapy in CRC. The identification of AQP9-induced tumor sensitivity to 5-FU highlights the role of AQP9 in regulating chemosensitivity in CRC.
Highlights
CRC incidence in China is growing at the rate of 3.9%
AQP9 expression is positively correlated with better disease-free survival (DFS) in CRC patients treated with chemotherapy
By analyzing the available The Cancer Genome Atlas (TCGA) RNA-Seq data with clinical information downloaded on 16 December 2015 (n = 189), we found that AQP9 expression is positively correlated to primary tumor pathological spread in CRC (Supplementary Figure S1b)
Summary
CRC incidence in China is growing at the rate of 3.9%. There were about 376 000 new cases in 2015.1 5-FU-based chemotherapy regimens are routinely employed to treat patients at high risk of developing recurrence or those with metastatic disease. Other studies suggested that there was no differential response related to MSI status.[6,7] The role of MSI in stage III CRC is even more controversial.[8,9] defining new predictive markers for patients to derive clinical benefit remains a major challenge in current CRC therapies. Our previous microarray analysis showed that AQP9 was upregulated in stage III CRC adjuvant chemotherapy responders.[10] the mechanism underlying the effects of AQP9 on the regulation of chemosensitivity in CRC is unclear. We aimed to explore the association between AQP9 expression and FOLFOX-based adjuvant chemotherapy outcome in CRC patients. Our results demonstrated for the first time that AQP9 expression level is correlated with adjuvant chemotherapy response in CRC, in stage III CRC patients
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