A team of cancer researchers from the MD Anderson Cancer Center this week published new data indicating that microRNA-34a may play a key role in cancer metastasis, particularly in lung adenocarcinomas.
The miRNA is widely expressed, particularly in the brain and lung, and has been linked to cancer as a known transcriptional target of the tumor suppressor p53 (GSN 6/7/2006). As a result, a number of groups are exploring its therapeutic use, including Mirna Therapeutics, which is developing a miR-34a mimic for solid tumors (GSN 5/3/2012).
This week, the MD Anderson team added to the body of evidence supporting miR-34a's role in cancer, finding that the pro-metastatic functions of the ZEB1 transcriptional repressor are tied to its down-regulation of the miRNA.
According to the paper, which appeared in the Journal of Clinical Investigation, metastasis is initiated by tumor cells undergoing an epithelial-to-mesenchymal transition in response to “extracellular cues, leading to loss of polarized features, detachment from neighboring cells, increased motility, and invasion into surrounding matrix.”
This transition is driven by several families of transcriptional repressors including ZEB, which induce the epithelial-to-mesenchymal transition, or EMT, by down-regulating epithelial gene expression. In particular, ZEB1 over-expression is associated with numerous cancers, and in tumor cells, it suppresses a variety of miRNAs that are responsible for epithelial differentiation and stem cell factor repression.
“Given that each [miRNA] down-regulated by ZEB1 has the capacity to target multiple genes with diverse functions, we here posited that the scope of pro-metastatic biological processes controlled by ZEB1 extends beyond EMT and stemness,” the investigators wrote.
In a mouse model of ZEB1-driven human lung adenocarcinoma, as well as human lung cancer and breast cancer cells, the team found that ZEB1 controls the expression of miR-34a, in addition to the other miRNAs previously identified.
The miRNA's ectopic expression also decreased tumor cell invasion and metastasis, and inhibited the formation of pro-migratory cytoskeletal structures, suppressed activation of the Rho family of GTPases, and “regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas,” according to the paper.
In addition, several different miR-34a targets were identified, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion, the team noted.
“The evidence presented here that miR-34a is a potent repressor of tumor growth and metastasis in a mouse model of human lung cancer bolsters evidence from other mouse models that miR-34a is a promising therapeutic agent,” they concluded.