Transformation of the intestinal epithelium by the MSI2 RNA binding protein

The MSI2 RNA binding protein has recently emerged as a potent oncogene playing key roles in hematopoietic stem cell homeostasis and malignant hematopoiesis. Here we demonstrate that MSI2 is expressed in the intestinal stem cell compartment, that its expression is elevated in colorectal adenocarcinomas, and that MSI2 loss of function abrogates colorectal cancer cell growth. We thus examined the oncogenic consequences of MSI2 gain of function in the intestinal epithelium with a drug inducible mouse model. Strikingly, MSI2 induction alone was sufficient to phenocopy the majority of morphological and molecular consequences of acute loss of the APC tumor suppressor in the intestinal epithelium. We demonstrate that this phenotype is independent of both the activation of the other oncogenic Musashi family member, Msi1, and of canonical Wnt pathway activation. Transcriptome-wide RNA-binding analysis indicates that MSI2 acts as a pleiotropic inhibitor of known intestinal tumor suppressors including Lrig1, Bmpr1a, Cdkn1a, and Pten. Finally, we demonstrate that inhibition of the PDK-AKT-mTORC1 axis downstream of Pten rescues oncogenic consequences of MSI2 induction. Taken together, our findings identify MSI2 as a central component in an unappreciated oncogenic pathway promoting intestinal transformation. 2 wild-type samples, 2 TRE-Msi2 samples

MSI2 RNA结合蛋白（RNA binding protein）近来被证实为一种强效致癌基因，在造血干细胞稳态（hematopoietic stem cell homeostasis）与恶性造血过程中发挥关键调控作用。本研究证实，MSI2在肠道干细胞区室表达，结直肠腺癌（colorectal adenocarcinomas）中其表达水平显著上调，且MSI2功能缺失可抑制结直肠癌细胞的增殖。为此，我们利用药物诱导型小鼠模型，探究了MSI2功能获得在肠道上皮中的致癌效应。值得注意的是，仅诱导MSI2表达即可模拟肠道上皮中肿瘤抑制因子APC（APC tumor suppressor）急性缺失所引发的绝大多数形态学与分子学表型。进一步研究表明，该表型既不依赖于另一致癌性Musashi家族成员Msi1的激活，也不依赖于经典Wnt通路（canonical Wnt pathway）的激活。全转录组（transcriptome-wide）RNA结合分析显示，MSI2可作为多效性抑制剂，靶向调控包括Lrig1、Bmpr1a、Cdkn1a及Pten在内的已知肠道肿瘤抑制因子。最后，我们证实抑制Pten下游的PDK-AKT-mTORC1轴（PDK-AKT-mTORC1 axis）可逆转MSI2诱导产生的致癌效应。综上，本研究发现MSI2是一条此前未被阐明的肠道癌变致癌通路的核心组分。本数据集包含2份野生型样本、2份TRE-Msi2样本。