Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer
Alternative microexon splicing by RBFOX2 and PTBP1 is associated with metastasis in colorectal cancer
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DOI：
10.1002/ijc.33758
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发表时间：
2021-08-16
影响因子：
6.4
通讯作者：
Nakayama, Keiko
中科院分区：
文献类型：
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作者：
Mochizuki, Yasushi;Funayama, Ryo;Nakayama, Keiko
在自闭症谱系障碍患者的大脑中，微外显子（非常小的外显子）的剪接经常失调。然而，很少有人知道的模式，调控机制和微外显子剪接在癌症中的作用。我们在此研究了匹配的结直肠癌（CRC）和正常组织标本中微外显子剪接的全转录组特征。在1492个包含3至15个核苷酸的微外显子中，21个（1%）表现出CRC和正常组织之间的差异剪接。这21个包含差异剪接微外显子的基因在与细胞粘附和迁移相关的基因本体论术语中被富集。RNA干扰介导的敲低实验确定了两个剪接因子，RBFOX 2和PTBP 1，作为CRC细胞中微外显子剪接的调节因子。RBFOX2和PTBP1被发现直接结合到含有微外显子的前mRNA，并控制它们在这些细胞中的剪接。差异性微外显子剪接被证明是由于，至少部分是由于与匹配的正常组织相比，CRC组织中RBFOX 2和PTBP 1的表达改变。最后，我们发现微外显子剪接模式的改变与结直肠癌转移有关。因此，我们的数据表明，RBFOX2和PTBP 1的表达改变可能会影响CRC转移通过调节微外显子剪接。
The splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms and roles of microexon splicing in cancer. We here examined the transcriptome-wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference-mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing pre-mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing.