Abstract
BackgroundTo test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis.MethodsThe component levels of the ERK-P65-miR23a/27a/24 axis in four fresh GC tissues, 101 paraffin-embedded GC tissues and four GC cell lines were determined by Western blotting, immunohistochemistry (IHC) or qRT-PCR. The effects of gastrin on GC were first evaluated by measuring gastrin serum levels in 30 healthy and 70 GC patients and performing a correlation analysis between gastrin levels and survival time in 27 GC patients after eight years of follow-up, then evaluated on GC cell lines, GC cell xenograft models, and patient-derived xenografts (PDX) mouse models. The roles of ERK-P65-miR23a/27a/24 axis in GC progression and in the effects of gastrin on GC were examined.ResultsERK- P65-miR23a/27a/24 axis was proved to be present in GC cells. The levels of components of ERK-P65-miR23a/27a/24 axis were decreased in GC tissue samples and PGC cells. The decreased levels of components of ERK-P65-miR23a/27a/24 axis were associated with poor prognosis of GC, and ERK-P65-miR23a/27a/24 axis played a suppressive role in GC progression. Low blood gastrin was correlated with poor prognosis of the GC patients and decreased expression of p-ERK and p-P65 in GC tissues. Gastrin inhibited proliferation of poorly-differentiated GC (PGC) cells through activating the ERK-P65-miR23a/27a/24 axis. Gastrin inhibited GC growth and enhanced the suppression of GC by cisplatin in mice or PGC cell culture models through activating the ERK-P65-miR23a/27a/24 axis or its components.ConclusionsERK-P65-miR23a/27a/24 axis is down-regulated, leading to excess GC growth and poor prognosis of GC. Low gastrin promoted excess GC growth and contributed to the poor prognosis of the GC patients by down-regulating ERK-P65-miR23a/27a/24 axis. Gastrin inhibits gastric cancer growth through activating the ERK-P65-miR23a/27a/24 axis.
Highlights
To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/ 27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis
The results showed that p-ERK, p-P65 miR-23a, miR-27a and miR-24 levels were decreased in MKN28 cells (WGC cells) after PD98059 treatment (Fig. 1a-b)
The levels of components of ERK-P65-miR23a/27a/24 axis were decreased in GC tissue samples and poorly-differentiated GC (PGC) cells and associated with poor prognosis of GC To examine the potential association of the ERK-P65-miR23a/27a/24 axis with GC progression, we determined the levels of the components of ERK-P65-miR23a/27a/24 axis in the GC tissue samples and PGC and Well-differentiated GC (WGC) cells using Western blotting, quantitative real time PCR (qRT-PCR), IHC and in situ hybridization microarrays
Summary
To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/ 27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis. Gastric cancer (GC) is the leading cause of cancer-related mortality worldwide and remains a considerable health burden throughout the world. Adjuvant or neoadjuvant therapy is usually implemented in combination with surgery. Outcomes in metastatic disease are poor, with median survival being around 1 year. Despite progress in deciphering its development, challenges with GC treatment remain. Many patients have inoperable disease at diagnosis or have recurrent disease after resection with curative intent [1,2,3,4]
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