miR‐92b promotes gastric cancer growth by activating the DAB2IP‐mediated PI3K/AKT signalling pathway

Abstract

Gastric cancer (GC) is currently the most common malignancy of the gastrointestinal tract, with a high mortality rate that ranks as the second most diagnosed cause of cancer-related death worldwide. 1 According to recent statistics, approximately one million newly diagnosed cases of GC are reported annually, and in 2013, the number of GC-related deaths was nearly 723 000. 2,3 Surgical resection remains the primary treatment for GC patients and can provide the best chance of cure, and chemotherapy and radiotherapy for GC can inhibit tumour cell growth or invasion. 4,5 Despite multiple treatment interventions for GC patients, their 5-year survival rate remains pessimistic due to recurrence and metastasis. 6 Hence, in view of its poor outcomes, GC development and recurrence must be prevented, andThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. AbstractObjectives: miR-92b has been reported to play critical roles in several carcinomas; however, our understanding of the mechanisms by which miR-92b stimulates gastric cancer (GC) is incomplete. The aim of this study was to investigate the clinical significance and functional relevance of miR-92b in GC. Materials and methods:Expression of miR-92b in GC and peritumoural tissues was determined using qRT-PCR, in situ hybridization and bioinformatics. CCK-8, colony formation and fluorescence-activated cell sorting assays were utilized to explore the effect of miR-92b on GC cells. A luciferase reporter assay and Western blotting were employed to verify miR-92b targeting of DAB2IP. Furthermore, Western blotting was used to evaluate the levels of DAB2IP and PI3K/Akt signalling pathway-related proteins. Results:In this study, we found that miR-92b was upregulated in GC tissues compared with peritumoural tissues. Overexpression of miR-92b promoted cell proliferation, colony formation, and G 0 /G 1 transition and decreased apoptosis. Our results indicated that miR-92b repressed the expression of DAB2IP and that loss of DAB2IP activated the PI3K/AKT signalling pathway. Overexpression of DAB2IP rescued the effects of miR-92b in GC cells. Finally, our results demonstrated a significant correlation between miR-92b expression and DAB2IP expression in GC tissues. Conclusions:Our results suggest that miR-92b promotes GC cell proliferation by activating the DAB2IP-mediated PI3K/AKT signalling pathway. The miR-92b/DAB2IP/ PI3K/AKT signalling axis may be a potential therapeutic target to prevent GC progression.

Loss of DAB2IP Contributes to Cell Proliferation and Cisplatin Resistance in Gastric Cancer

“…To understand the underlying mechanisms of DAB2IP in this event, we explored possible downstream signaling pathways such as AKT and ERK, which are both closely associated with cancer cell proliferation and chemoresistance. [25][26][27] In line with previous studies, [20][21][22] we further confirmed the inhibitory effect of DAB2IP on AKT and ERK signaling pathway. We found that DAB2IP depletion notably increased the levels of phosphorylated AKT (p-AKT) and phosphorylated ERK (p-ERK) in both AGS and SGC7901 cells, but not their total protein levels ( Figure 5A).…”

“…7,[11][12][13][14][15][16] Recent studies [17][18][19] in prostate, bladder and renal cancer demonstrated that DAB2IP loss decreased cell sensitivity to chemotherapeutic agents or targeted drugs, suggesting a role for DAB2IP in chemoresistance in multiple cancer types. In consistency, previous studies [20][21][22] also showed that DAB2IP was significantly downregulated in GC tissues and DAB2IP knockdown promoted GC cell proliferation, migration as well as activation of the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways. However, the prognostic value and potential role of DAB2IP in GC cell sensitivity to chemotherapy have not been elucidated.…”

“…7,[11][12][13][14][15][16] Loss of DAB2IP also confers resistance to chemotherapy in prostate, bladder and renal cancers, [17][18][19] suggesting a role for DAB2IP as a potential target for cancer therapy. In GC, [20][21][22] DAB2IP was reported to be downregulated and DAB2IP knockdown enhanced the ability of cell proliferation and migration, but the potential effect of DAB2IP on chemosensitivity and the internal mechanism remain unclear and need to be explored.…”

Recent advances of miRNAs in the development and clinical application of gastric cancer

“…Ni et al found that miR-92b played a supporting role by targeting DOC-2/DAB2 interacting protein in GC cell proliferation. [ 28 ] Wang et al [ 29 ] showed that the up-regulation of miR-664a-3p remarkably enhanced the proliferation and invasion via the Hippo pathway in vitro and in vivo . MiR-192 and miR-215 target adenomatous polyposis coli, which is a well-known negative regulator of Wnt signaling function during the tumorigenesis of colorectal cancer to play an oncogenic in GC proliferation and migration.…”

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

“…A similar regulatory loop has been described in hepatocellular carcinoma, where DAB2IP mRNA and protein levels were upregulated upon overexpression of circ-5692, able to sponge the DAB2IP-targeting miR-328-5p [ 90 ]. Several miRNAs of the miR-92a family were reported to target DAB2IP in multiple tumors [ 86 , 91 , 92 , 93 ]. DAB2IP inhibition by miR-556 in bladder and esophageal cancer fosters cells proliferation and sustains tumor progression via aberrant Ras-MAPK signaling activation [ 94 , 95 ].…”