The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

Abstract

Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.

The emerging role of exosomes in the development of testicular

“…One of the relevant markers could be designed as promoter to verify whether miRNAs of exosomal origin affect the process of spermatogenesis through transcriptional regulation. 61 – 63 Exosomes from testicular injury models and normal testicular tissues can also be comparatively analyzed by transcriptome sequencing or proteomics. It is unknown whether these proteins, pathways, and miRNAs maintain the normal developmental process of the testis through a reciprocal relationship and whether up- or downregulation of some of these targets or genes has an effect on the formation and activity of sperm cells.…”

Molecular Insight into Gastric Cancer Invasion—Current Status and Future Directions

“…MiR-3648 negatively contributes to the invasion ability of GC via targeting FRAT1 and FRAT2, a negative modulator of the Wnt/β-catenin signaling. Upregulation of miR-3648 was negatively related to c-Myc, FRAT1, and FRAT2 expression, indicating that miR-3648 serve as a tumor-suppressive miRNA [ 154 ]. MiR-200b-3p suppressed the invasion and lung metastasis of GC cells and downregulated the expression of CXCL12 and CXCR7 [ 155 ].…”

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers

“…At the post-translational level, cell-type-specific protein half-life and activity, regulated by different enzymes (e.g., kinases, ubiquitin ligases, acetyltransferases) or other interacting proteins, have a significant impact on MYC function ( Figure 1 B). As a key signal node, many signal transduction pathways, including WNT, NOTCH, growth factors, or IL6, converge on MYC, influencing its activation and regulation of cell growth [ 42 , 43 , 44 , 45 ]. Checkpoint proteins, such as p53, ARF, BIM or PTEN, are also key mediators of MYC function as they inhibit its proliferation-promoting effect and ultimately cause cell cycle arrest or apoptosis upon any failure in the process ( Figure 1 B).…”

“…It has long been known that the loss of checkpoint proteins, such as p53 and PTEN, in parallel with MYC deregulation, contributes to the inability of the tumor cells to switch off MYC-driven metabolism and enforces cell expansion independent of growth factors and nutrient availability [ 46 , 47 , 48 , 131 , 132 ]. Similarly, since signaling pathways converge in MYC, for example, the overactivation of growth factor or mTOR signaling causes the upregulation of MYC and its modulated processes [ 42 , 43 , 44 , 45 , 131 ]. An interesting phenomenon is that MYC overexpression is not always necessary to achieve the “MYC effect”.…”

“…In gastric cancer (GC), since miR-3648 represses the WNT/β-catenin pathway via the inhibition of GSK-3-binding FRAT1/2 proto-oncogenes, its downregulation resulted in the upregulation of the WNT/β-catenin pathway, followed by the overexpression of MYC as a downstream effector. MYC then further downregulated miR-3648 expression by directly binding to its promoter [ 45 ]. In parallel, MYC can transactivate miR-210 and its hosting MIR210HG lncRNA, which can synergistically promote the distant metastatic process of GCs [ 108 ].…”