The notion that cancer is fuelled by self-renewing stem cells is gaining prominence, and so is the idea that microRNA (miRNA) can direct cell fate. Now, research from Sun-Yat-Sen University, in Guangzhou, China, and Harvard Medical School, in Boston, brings the two fields together by showing that a single miRNA molecule can regulate stemness in breast cancer cells1.

Cancer stem cells, or tumor-initiating cells (TICs), are believed to exist in solid tumors in areas including the brain, breast, prostate, liver, pancreas and colon. Such cells can self-renew and cause tumors in immunodeficient mice. They also resist chemotherapy, and the researchers exploited this trait to enrich populations of TICs in mice that received transplants of the cells.

The researchers next looked at how miRNA expression differed from nonenriched cell populations. The expression of the miRNA let-7 was particularly reduced in TICs.

This miRNA seems to control properties in tumor cells by silencing two targets: the oncogenes RAS and HMGA2. When the expression of let-7 was artificially boosted, breast TICs were less able to cause tumors in immunodeficient mice. The two silenced genes seem to have complementary effects: HMGA2 maintains multipotency but not self-renewal, while RAS maintains self-renewal but not multipotency.

The research has implications for two hypotheses of cancer metastasis: that cancer cells migrate and that tumor cells transition from epithelial to mesenchymal cells before moving to different tissues. Because HMGA2 is expressed in both TICs and mesenchymal tumor cells, it could facilitate that transition. But since it also suppresses cell differentiation, it could allow cancer cells to migrate without differentiating.

It is likely that let-7 regulates other genes not examined in this research, including several involved in cell-cycle regulation. Investigator Judy Lieberman, at Harvard, speculates that a drug based on let-7 could fight cancer through multiple mechanisms, such as causing cells to differentiate and become more sensitive to chemotherapy. Further research is needed to examine whether expression of let-7 is also reduced in cells that initiate other tumor types and the role that other miRNAs might play in cancer.

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