These data indicate that a SET/PP2A/E2F1 axis regulates cancer cell stemness and is a potential target for gastric cancer therapy.<b>Implications:</b> This study highlights the oncogenic role of SET/I2PP2A in gastric cancer and suggests that SET maintains cancer cell stemness by suppressing PP2A activity and stabilizing E2F1.<i></i>.
In GC, E2F1 expression is also aberrant, but the biological functions of E2F1 are controversial, and the correlation between E2F1 and lncRNAs remains unknown.
Furthermore, ectopic over-expression of MIR31HG could inhibit gastric cancer (GC) cell proliferation both in vitro and in vivo, while knockdown of MIR31HG by small interfering RNA (siRNA) promoted cell proliferation in GC cells partly via regulating E2F1 and p21 expression.
Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation.
The growth-curve of tumor volumes revealed that infection with E2F-1 recombinant lentiviral vectors significantly inhibited the growth of human GC xenografts (2.81 ± 1.02 vs 6.18 ± 1.15 in control vector infected and 5.87 ± 1.23 with no infection; both P < 0.05) at 15 d after treatment.
We also showed that E2F1 could induce ANRIL and ANRIL-mediated growth promotion is in part due to epigenetic repression of miR-99a/miR-449a in Trans (controlling the targets--mTOR and CDK6/E2F1 pathway) by binding to PRC2, thus forming a positive feedback loop, continuing to promote GC cell proliferation.
To explore the role of E2F-1 in the MDR process of gastric cancer in vitro and in vivo, a cisplatin-resistant gastric cancer cell line with stable downregulation of E2F-1 was established.
In summary, shRNA targeting of E2F-1 can effectively inhibits human gastric cancer MGC-803 cell growth in vivo and may be a potential therapeutic strategy for gastric cancer.
Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.