| Autor: |
Li, Danxiu, Wang, Xin, Miao, Hui, Liu, Hao, Pang, Maogui, Guo, Hao, Ge, Minghui, Glass, Sarah E., Emmrich, Stephan, Ji, Songtao, Zhou, Yun, Ye, Xiaoni, Mao, Huajie, Wang, Jing, Liu, Qi, Kim, Taewan, Klusmann, Jan-Henning, Li, Cunxi, Liu, Zhenxiong, Jin, Haifeng |
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| Zdroj: |
Science Signaling; 9/19/2023, Vol. 16 Issue 803, p1-18, 18p |
| Abstrakt: |
Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA (lncRNA) MIR99AHG regulated alternative splicing to alter the activity of a chromatin remodeler and promote metastatic behaviors in colorectal cancer (CRC). MIR99AHG was abundant in invasive CRC cells and metastatic tumors from patients and promoted motility and invasion in cultured CRC cells. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, and this complex increased cassette exon inclusion in the mRNA encoding the chromatin remodeling gene SMARCA1. Specifically, MIR99AHG altered the nature of PTBP1 binding to the splice sites on intron 12 of SMARCA1 pre-mRNA, thereby triggering a splicing switch from skipping to including exon 13 to produce the long isoform, SMARCA1-L. SMARCA1, but not SMARCA1-L, suppressed invadopodia formation, cell migration, and invasion. Analysis of CRC samples revealed that the abundance of MIR99AHG transcript positively correlated with that of SMARCA1-L mRNA and PTBP1 protein and with poor prognosis in patients with CRC. Furthermore, TGF-β1 secretion from cancer-associated fibroblasts increased MIR99AHG expression in CRC cells. Our findings identify an lncRNA that is induced by cues from the tumor microenvironment and that interacts with PTBP1 to regulate alternative splicing, potentially providing a therapeutic target and predictive biomarker for metastatic CRC. Editor's summary: Alternative splicing, a process through which different transcripts are produced from the same gene, is implicated in various cancers. Li et al. found that alternative splicing caused the formation of metastasis-associated structures called invadopodia in colorectal cancer (CRC) cells. Signaling from the tumor stroma induced the expression of the long-noncoding RNA MIR99AHG in CRC cells. MIR99AHG interacted with a splicing factor and altered the way it bound to and spliced a target pre-mRNA, resulting in more of the longer transcript and less of the shorter, tumor-suppressive transcript. This switch enabled invadopodia formation, cell migration, and invasion in CRC cells. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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