NF-κB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors

Abstract

Cigarette smoke is one of the risk factors for gastric cancer and nicotine has been reported to promote tumor growth. Deregulation of microRNA (miRNA) and cyclooxygenase-2 (COX-2) expressions are hallmarks of many cancers including gastric cancer. Here, we used an miRNA array platform covering a panel of 95 human miRNAs to examine the expression profile in nicotine-treated gastric cancer cells. We found that miR-16 and miR-21 were upregulated upon nicotine stimulation, transfection with anti-miR-16 or anti-miR-21 significantly abrogated cell proliferation. In contrast, ectopic miR-16 or miR-21 expression exhibited a similar stimulatory effect on cell proliferation as nicotine. Nicotine-mediated IkappaBα degradation and nuclear factor-kappa B (NF-κB) translocation dose-dependently. Knockdown of NF-κB by short interfering RNA (siRNA) or specific inhibitor (Bay-11-7085) markedly suppressed nicotine-induced cell proliferation and upregulation of miR-16 and miR-21. Interestingly, NF-κB-binding sites were located in both miR-16 and miR-21 gene transcriptional elements and we showed that nicotine enhanced the binding of NF-κB to the promoters of miR-16 and miR-21. Furthermore, activation of COX-2/prostaglandin E₂ (PGE₂) signaling in response to nicotine was mediated by the action of prostaglandin E receptors (EP2 and EP4). EP2 or EP4 siRNA or antagonists impaired the nicotine-mediated NF-κB activity, upregulation of miR-16 and miR-21 and cell proliferation. Taken together, these results suggest that miR-16 and miR-21 are directly regulated by the transcription factor NF-κB and yet nicotine-promoted cell proliferation is mediated via EP2/4 receptors. Perhaps this study may shed light on the development of anticancer drugs to improve the chemosensitivity in smokers.

Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer

“…Our results indicate an innovative molecular tool to inhibit FGF-2/FGFR1 signaling and, more importantly, propose a strategy to obtain a therapeutic targeting of both tumor and stroma compartments. Although the targets of miRNAs may vary depending on the cell type of tissue where they are expressed, we confirmed in CAFs (Shin et al, 2011;Navarro et al, 2011), a number of articles show that miR-15 and miR-16 act as tumor controller (Aqeilan et al, 2010). However, our data suggest, as proposed in Figure 5e, that miR-15 and miR-16 may be involved in a molecular loop in which the tumor and microenvironment co-evolve, underlining the importance of miRNA in microenvironment homeostasis and providing a proof-of-concept for innovative therapeutic applications directed against not only the cancer cells but also the tumor microenvironment.…”

Aberrant hypermethylation ofmiR-9genes in gastric cancer

“…[2][3][4] Previous studies have shown that many miRNAs are aberrantly overexpressed or downregulated during gastric cancer progression, including miR- 16, miR-21, miR-101, miR-126, miR-129, miR-181c, miR-196b and -200. [5][6][7][8][9][10][11][12] These miRNAs could play oncogenic or tumor-suppressive functions in the regulation of cell growth, apoptosis and cell migration by repressing their target genes.…”

A MicroRNA-Mediated Positive Feedback Regulatory Loop of the NF-κB Pathway in Litopenaeus vannamei

“…On the one hand, many miRNAs, such as miR-31, miR-223, and miR-195, could participate in the regulation of the NF-kB pathway through modulating the activities of many cellular adaptors (45)(46)(47). On the other hand, expression of many miRNAs, including miR-10a, miR-16, and miR-21, could be directly regulated by NF-kB (48,49). More interestingly, in some cases, a certain miRNA could play both the roles of the regulator and the effector of the NF-kB pathway, and thus mediate a feedback regulatory loop for NF-kB pathway activation.…”

“…Similarly, miR-155 is also an NF-kB transactivational target and could limit NF-kB activation through controlling the expression of both IKKb and IKKε, resulting in a negative regulatory feedback loop (52,53). In contrast, both miR-181b and miR-21 could mediate positive feedback regulatory loops, bypassing the IL-6 downstream effector STAT3, to activate the NF-kB pathway (49,54,55). Taken together, the presentation of the miRNA-mediated feedback loop suggests the complexity of the regulatory mechanism of the NF-kB pathway in mammals (56).…”