可变剪接调控着基因表达和功能多样性，往往在人类癌症中发生异常调控。在这项研究中，我们发现长链非编码RNA（lncRNA）MIR99AHG通过调控可变剪接，改变染色质重塑因子的活性，并在结直肠癌（CRC）中促进转移行为。MIR99AHG在侵袭性CRC细胞和患者的转移瘤中丰富，并且促进了体外培养的CRC细胞的运动性和侵袭性。MIR99AHG结合并稳定RNA剪接因子PTBP1，该复合物增加了对编码染色质重塑基因SMARCA1的mRNA的携带外显子的包含。具体地，MIR99AHG改变了PTBP1结合SMARCA1前体mRNA内含子12的剪接位点的方式，从而触发了剪接切换，从跳跃外显子13到包含外显子13，产生长的亚型SMARCA1-L。SMARCA1而非SMARCA1-L能够抑制侵袭突起的形成、细胞迁移和侵袭。对CRC样本的分析显示，MIR99AHG转录本的丰度与SMARCA1-L mRNA和PTBP1蛋白的丰度正相关，并与CRC患者的预后差相关。此外，从癌相关成纤维细胞中分泌的TGF-β1增加了CRC细胞中MIR99AHG的表达。我们的研究结果揭示了一种由肿瘤微环境信号诱导并与PTBP1相互作用的lncRNA，可以调控可变剪接，从而可能提供转移性CRC的治疗靶点和预测生物标志物。

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.