Alternative splicing variant of NRP/B promotes tumorigenesis of gastric cancer
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Gastrointestinal cancer is associated with a high mortality rate. Here, we report that the splice variant of NRP/B contributes totumorigenic activity in highly malignant gastric cancer throughdissociation from the tumor repressor, HDAC5. NRP/B mRNAexpression is significantly higher in the human gastric cancertissues than in the normal tissues. Further, high levels of boththe NRP/B splice variant and Lgr5, but not the full-length protein,are found in highly tumorigenic gastric tumor cells, but notin non-tumorigenic cells. The loss of NRP/B markedly inhibitscell migration and invasion, which reduces tumor formation invivo. Importantly, the inhibition of alternative splicing increasesthe levels of NRP/B-1 mRNA and protein in AGS cells. The ectopicexpression of full-length NRP/B exhibits tumor-suppressiveactivity, whereas NRP/B-2 induces the noninvasive human gastriccancer cells tumorigenesis. The splice variant NRP/B-2 whichloses the capacity to interact with tumor repressors promotedoncogenic activity, suggesting that the BTB/POZ domain in theN-terminus has a crucial role in the suppression of gastric cancer. Therefore, the regulation of alternative splicing of the NRP/Bgene is a potential novel target for the treatment of gastrointestinalcancer.
Abstract
Gastrointestinal cancer is associated with a high mortality rate. Here, we report that the splice variant of NRP/B contributes totumorigenic activity in highly malignant gastric cancer throughdissociation from the tumor repressor, HDAC5. NRP/B mRNAexpression is significantly higher in the human gastric cancertissues than in the normal tissues. Further, high levels of boththe NRP/B splice variant and Lgr5, but not the full-length protein,are found in highly tumorigenic gastric tumor cells, but notin non-tumorigenic cells. The loss of NRP/B markedly inhibitscell migration and invasion, which reduces tumor formation invivo. Importantly, the inhibition of alternative splicing increasesthe levels of NRP/B-1 mRNA and protein in AGS cells. The ectopicexpression of full-length NRP/B exhibits tumor-suppressiveactivity, whereas NRP/B-2 induces the noninvasive human gastriccancer cells tumorigenesis. The splice variant NRP/B-2 whichloses the capacity to interact with tumor repressors promotedoncogenic activity, suggesting that the BTB/POZ domain in theN-terminus has a crucial role in the suppression of gastric cancer. Therefore, the regulation of alternative splicing of the NRP/Bgene is a potential novel target for the treatment of gastrointestinalcancer.
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