Journal of Gastrointestinal & Digestive System
Open Access

Abstract

Gastric cancer (GC) is associated with aberrant expression of miRNAs and deregulation in signaling pathways. We perform in silico predictive analysis to know which miRNAs could be regulating the PI3K/AKT/mTOR pathway and could play an important role in the development of GC. We found that miR-125b, miR-451 and miR-101 could target the mRNA of PI3K and AKT (miR-125b), TSC1 (miR-451) and mTOR and PI3K (miR-101), all members of this pathway. The aim of this study was to evaluate the transcriptional and protein expression of the most important components of PI3K/AKT/mTOR pathway in tissues and GC cell lines and associate their expression with the expression of miR- 125b, miR-451 and miR-101. Methods: The expression of PI3K, AKT, PTEN, TSC1, mTOR, P70S6K1, 4E-BP1 and eIF4E genes and expression of miR-125b, miR-451 and miR-101 were analyzed in 25 advanced GC tissues and their 25 paired non-tumor tissues (NT) and in AGS, MKN28 and MKN45 GC cell lines by qRT-PCR. The protein expression of PI3K/AKT/mTOR was performed by IHC in TMAs of 142 gastric tissue samples (71 advanced GC and 71 paired non-tumor tissues). The proteins studied were PI3K, PTEN, AKT, phospho-AKT, mTOR, phospho-mTOR, p70S6K1, phosphop70S6K1, 4E-BP1, phospho-4E-BP1, eIF4E and phospho-eIF4E. Clinical and pathological data of patients was used. Results: Increased protein expression was found by IHC for PI3K, AKT, phospho-AKT, phospho-mTOR, p70S6K, phospho-p70S6K, phospho- 4E-BP1, eIF4E and phospho-eIF4E in tumor tissues compared with non-tumor tissues (p<0.05). Conversely, levels of PTEN were higher in nontumor tissues (p<0.001). Moreover, Kaplan-Meier analysis showed a poor survival in those patients with low expression of 4E-BP1 (p=0.03). The gene expression of PI3K, AKT, mTOR, P70S6K1 y eIF4E in AGS, MKN28 and MKN45 cell lines was significantly higher compared with non-tumor cells. PTEN was down-regulated in these 3 cell lines. Decreased expressions of miR-125b (p=0.039), miR-451(p=0.0013) and miR- 101 (p=0.0005) were found in GC tissues compared with NT. Also, lower expressions of miR-451 and miR-101 were found in the three GC cell lines (p<0.0001 for all). Meanwhile, miR-125b was found decreased only in AGS and MKN45 cell lines (p<0.0001 both). Conclusion: This study has shown that PI3K/AKT/mTOR pathway is activated in tumor tissues of GC and these data could help us to validate this pathway as a potential therapeutic target for this malignancy. Moreover, miR-125b, miR-451 and miR-101 have association with the expression of some members of the PI3K/AKT/mTOR pathway. This relationship could be important in order to modulate the behavior of this pathway during carcinogenesis. However, further studies are necessary to confirm the direct interplay between these miRNAs and the PI3K/AKT/mTOR.

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