Zhao et al. reveal that the microRNA miR-7 suppresses gastric cancer by inhibiting NF-κB signaling, and that this protective mechanism is compromised by the cancer-causing bacterium Helicobacter pylori.
miR-7 is frequently down-regulated in gastric cancers and can suppress gastric cell metastasis by inhibiting the growth factor receptor IGF1R. Whether miR-7 also suppresses earlier stages of gastric carcinogenesis is unknown, however, so Zhao et al. screened for new targets of the microRNA.
The researchers found that miR-7 directly targets RELA and FOS, which encode transcription factors involved in the pro-oncogenic NF-κB and AP-1 signaling pathways, respectively. In human gastric cancer samples, low miR-7 levels correlated with elevated RELA and FOS expression and poor patient survival. Overexpressing miR-7 reduced RELA and FOS levels and inhibited both gastric cell proliferation and tumor growth in vivo.
Zhao et al. found that, as well as directly suppressing RELA expression, miR-7 reduced the transcription factor’s activity by targeting its upstream kinase IKKε. Yet IKKε and RELA were themselves able to repress miR-7 transcription, forming a feedback loop between the NF-κB and miR-7 pathways.
Chronic H. pylori infection is a major risk factor for gastric cancer, in part because the bacterium can hyperactivate the NF-κB pathway. Co-culturing H. pylori with gastric epithelial cells induced the expression of IKKε and RELA, and down-regulated the expression of miR-7, a potentially key step in gastric cell transformation. Senior author Dai-Ming Fan now wants to identify drugs capable of inducing miR-7 and suppressing tumorigenesis.
Text by Ben Short