RNAi Screening Redefines Gene's Role in Colorectal Cancer

In a recent paper, researchers working with cancer cell cultures reported that the Wnt target gene TCF7L2, which had been thought to promote growth of colorectal cancer (CRC), instead acted as a tumor suppressor.

Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer. Many Wnt genes in the mouse have been mutated, leading to very specific developmental defects. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to beta-catenin, which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) employed a high-throughput RNAi system to screen gene activity in cultures of colon cancer cells. They reported in the July 10, 2008, online issue of the Proceedings of the [U.S.] National Academy of Sciences (PNAS) that the presumed cancer-promoting gene TCF7L2 functioned instead as a transcriptional repressor that restricted colorectal cancer cell growth. Mutations in TCF7L2 abolished its ability to function as a transcriptional regulator and resulted in increased CRC cell growth.
"This finding reshapes a fundamental model of how colorectal cancer arises,” said senior author Dr. Lawrence Lum, assistant professor of cell biology at the University of Texas Southwestern Medical Center. "The function of TCF7L2 in cancer was previously determined from studies in animals but no one has genetically tested its role in human colorectal cancer cells before. Prior to the advent of RNAi technology, this was very difficult to do in human cultured cells.”


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University of Texas Southwestern Medical Center