Abstract
Clinically, one of the principal factors in the failure of advanced colorectal cancer (CRC) treatment is chemoresistance to 5-fluorouracil (5FU)-based chemotherapy. Although microRNA-375-3p (miR-375) is considered a tumor suppressor in multiple cancers, the mechanism of miR-375 in the regulation of drug resistance in CRC remains unclear. In this study, we investigated the chemosensitivity of miR-375 to 5FU in CRC from biological and clinical aspects. We found that miR-375 was significantly downregulated in CRC tissues and cell lines, and low miR-375 expression was strongly correlated with poor overall survival in CRC patients. Overexpression of miR-375 sensitized CRC cells to a broad spectrum of chemotherapeutic drugs in vitro and in vivo. Further mechanistic analysis demonstrated that miR-375 enhanced CRC cell sensitivity to 5FU by directly targeting YAP1 and SP1. MiR-375 downregulated YAP1, resulting in reduced expression of the Hippo-YAP1 pathway downstream genes CTGF, cyclin D1 and BIRC5 (also known as survivin). Overall, miR-375 was confirmed as a prospective molecular biomarker in the chemoresistance and prognosis of CRC patients, and the synergy between miR-375 and chemotherapeutic drugs could be a promising therapeutic strategy for CRC patients, especially with chemoresistance.
Highlights
Colorectal cancer is the fourth most lethal cancer worldwide, reaching up to almost 700,000 human deaths annually [1]
We found miR375 was genetically downregulated in colorectal cancer (CRC) tissues and cells, especially in resistant cell lines, and its low expression level correlated with chemoresistance, malignancy and poor prognosis
The results showed that miR-375 expression was much lower in the 5FU-resistant group (n=30) than in the 5FU-sensitive group (n=30), indicating that miR-375 expression was associated negatively with chemoresistance in CRC tissues (Figure 1C)
Summary
Colorectal cancer is the fourth most lethal cancer worldwide, reaching up to almost 700,000 human deaths annually [1]. It is estimated that the incidence of colorectal cancer will rise by 1.67 times by 2040 [2]. In China, there were 376,000 new cases of CRC that caused 191,000 deaths in 2015 [3]. Chemotherapy has become an advisable option for advanced CRC patients, especially for metastatic CRC [5]. 50–70% of advanced CRC patients develop tolerance to both classical and biological chemotherapy drugs [6]. Acquired drug resistance poses a major obstacle to curative therapy for CRC patients and leads to poor prognosis [7, 8]. Therapeutic strategies have made significant progress in recent decades, there is an urgent need to optimize multidrug treatment approaches to efficiently improve anticancerdrug effects as well as to achieve better prognosis and recovery
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