Abstract
The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.
Highlights
Gastric cancer (GC) is the most common solid tumor originating from the digestive system and is a major reason for cancer-related mortality in the world [1]
Compared to the adjacent non-tumor tissues, the miR4290 expression level was significantly decreased in GC tissues (Figure 1A and B), and the low expression level of miR-4290 was closely associated with shorter survival in GC cases (Figure 1C)
These results suggested that miR-4290 was lowly expressed in GC tissues and cells, indicating its potential role in GC progression
Summary
Gastric cancer (GC) is the most common solid tumor originating from the digestive system and is a major reason for cancer-related mortality in the world [1]. Accumulated evidence has demonstrated that the aberrant activation of glycolysis plays a crucial role in many kinds of diseases via various mechanisms, including the induction of cancer chemotherapy resistance [5,6,7]. PDK1 has been identified to be closely associated with cancer cell proliferation, metastasis, and chemotherapy resistance [9,10,11]. Qin et al [12] found that PDK1 inhibitor dichloroacetophenone significantly inhibited acute myeloid leukemia cell proliferation and autophagy, and induced apoptosis. These findings suggest that PDK1 might be a potent target for reversing chemotherapy resistance
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