Abstract
Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is responsible for over a million new cases and estimated 783,000 deaths globally in 2018 [1]
A tissue microarray containing 81 pairs of GC tissues and matched adjacent normal tissues was used to detect the integrin subunit alpha 2 (ITGA2) levels, and the results showed that ITGA2, mainly located in the cytoplasm and plasma membrane, was overexpressed in GC tissues compared to its expression in adjacent tissues (Figures 1B,C)
ITGA2 was correlated with the prognosis of GC patients who received 5-fluorouracil (5-FU) treatment, and an increased level of ITGA2 was correlated with decreased overall survival, first progression and post-progression survival times according to the Kaplan-Meier Plotter database [34] (Figure 1E)
Summary
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is responsible for over a million new cases and estimated 783,000 deaths globally in 2018 [1]. The effectiveness of chemotherapy largely depends on the resistance to chemotherapy, and chemoresistance has become the main cause of treatment failure [3]. Many factors are associated with the development of chemoresistance, including changes in the activity of membrane transporters, increased drug metabolism, alteration of drug targets, epithelial-mesenchymal transition (EMT), and tumor heterogeneity, all of which can affect the sensitivity of cancer cells to chemotherapeutic miR-135b-5p/ITGA2 Axis Modulates Chemoresistance drugs [4, 5]. Drug resistance-related genes (such as MDR and LRP) and various signaling pathways (such as MAPK, Wnt, and Notch) are reported to be significant causes of chemoresistance [6]. The molecular mechanisms of chemoresistance are still not fully understood, and more research is needed to discover and develop effective biomarkers and targets for GC chemoresistance
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