let-7 miRNA Helps Suppress Lung Tumor Cells

The miRNA gene encodes for a double-stranded looped RNA structure called pre-miRNA. The pre-miRNA is then exported from the nucleus to the cytoplasm. In the cytoplasm, the enzyme Dicer unwinds and cleaves the pre-miRNA to be the single-stranded short mature miRNA.

When microRNAs (miRNAs) were first discovered in 2002, Science magazine referred to them as the “#1 breakthrough of the year.” Recently, Dr. Frank Slack, Associate Professor of Molecular, Cellular, and Developmental Biology, made further breakthroughs working with these miRNA molecules, specifically with the let-7 miRNA and its use as a lung tumor-suppressor.

Only about 21-23 nucleotides in length, miRNA molecules are non-coding. Yet these short, singlestranded RNA molecules are believed to be one of the primary modes of genetic regulation.

Victor Ambros from the University of Massachusetts Medical School and Gary Ruvkun from Harvard Medical School first discovered miRNA in their research with C. elegans, a nonsegmented nematode only 1 mm in length. This organism has only about one thousand cells and its genome is well known — making it an ideal model organism.

Throughout its lifetime, C. elegans goes through distinctive larval transitions dictated by a specific genetic pathway. The timing of these stages is regulated by miRNA, which provides a quick and efficient method to regulate the translation of messenger RNA (mRNA) into protein.

The miRNAs function by binding to a large protein complex, the RNA-induced silencing complex (RISC), and a specific sequence of mRNA. This mRNA is then degraded and unable to be translated into protein.

Alternatively, the miRNA-RISC complex can simply block the translation of this sequence of mRNA by the ribosome. If too much of a protein is being translated or more of a protein is needed, the miRNA can regulate this expression.

Slack’s research involves let-7 miRNA, which regulates the stem cell differentiation for the different larval stages of C. elegans. Specifically, let-7 negatively regulates the RAS oncogene. Slack’s research demonstrates that let-7 is a tumor suppressor gene for the lung.

Lung tumor tissues normally express only low levels of let-7. Studies were done both in vitro, using human lung cancer cell lines in culture, and in vivo, using immunodeficient mice with lung cancer. The results showed that when excess let-7 is transformed in the cancerous cell lines and injected into cancerous mouse lungs, the tumor cells are suppressed.

There are approximately one thousand miRNAs in mammalian genomes, but the specific function for only about twenty of these animal miRNAs are known. The field of miRNA is rapidly advancing and let-7 shows great promise for use as a therapeutic agent for lung cancer.

According to Slack, “this work represents one of the most significant pieces of work to come from our laboratories, as it relates to the greatest benefit to human health.”

Esquela-Kerscher, A., and Slack, F. “Oncomirs—microRNAs with a role in cancer.” Nature Reviews Cancer April 2006: 259-269.