MiR-34a and miR-34b/c have distinct effects on the suppression of lung adenocarcinomas

Abstract

Three miR-34 family members (miR-34a, miR-34b, and miR-34c) are clustered on two different chromosomal loci, Mir34a and Mir34b/c. These miRNAs have identical seed sequences, which are predicted to target the same set of genes. However, miR-34a and miR-34c have different sets of negatively correlated genes in lung adenocarcinoma data from The Cancer Genome Atlas. Therefore, we hypothesized that the individual miR-34 family members, which are tumor suppressive miRNAs, would have varying effects on lung tumorigenesis. To show this, we overexpressed each miR-34 cluster in murine lung cancer cells. MiR-34b/c enhanced cancer cell attachment and suppressed cell growth and invasion compared with miR-34a. In a syngeneic mouse model, both miR-34a and miR-34b/c blocked lung metastasis. However, miR-34b/c suppressed tumor growth more than miR-34a. MiR-34b/c also decreased the expression of mesenchymal markers (Cdh2 and Fn1) and increased the expression of epithelial markers (Cldn3, Dsp, and miR-200) to a greater degree than miR-34a. These results imply that miR-34b and miR-34c inhibit epithelial-to-mesenchymal transition. Furthermore, knockout of all three miR-34 members promoted mutant Kras-driven lung tumor progression in mice. Similarly, lung adenocarcinoma patients with higher miR-34a/b/c levels had better survival rates than did those with lower levels. In summary, we suggest that miR-34b and miR-34c are more effective tumor suppressors than miR-34a. Exploring the effects of three similar small RNA molecules called micro-RNAs (miRNAs) that can restrict the activity of specific genes reveals how they might be used in cancer treatment. RNA is best known as messenger RNA, which carries a copy of a gene’s information into the cell cytoplasm to direct protein manufacture. Many small RNAs play less well-known but crucial roles by binding to messenger RNA molecules to regulate their activity. Researchers in South Korea and USA, led by Young-Ho Ahn at Ewha Womans University in Seoul, investigated how these miRNAs can suppress lung cancer in mice. Their results reveal details of how the miRNAs inhibit the expression of specific tumor-supporting genes. They suggest that three of the RNAs administered together might treat cancer more effectively than using only one as in previous trials.