Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
JCI Insight. 2021 May 10;6(9):140382. doi: 10.1172/jci.insight.140382.
Most colorectal cancers (CRCs) are moderately differentiated or well differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a potentially novel posttranscriptional regulatory mechanism via a LIN28B/CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration, and tumorigenesis. Our RNA-binding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified α-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.
大多数结直肠癌（CRC）为中分化或高分化，即使在转移瘤中也保持这种状态。然而，CRC 分化的分子机制仍有待阐明。在此，我们通过 LIN28B/CDX2 信号轴揭示了一个潜在的新型转录后调控机制，该机制在介导 CRC 分化中起着关键作用。由于存在大量的 mRNA 靶标，mRNA 结合蛋白 LIN28B 在发育、代谢、组织再生和肿瘤发生中具有多种功能。我们的 RNA 结合蛋白 IP（RIP）分析表明，LIN28B 可直接结合 CDX2 mRNA，后者是正常肠上皮细胞特性和分化的关键同源盒转录因子。此外，LIN28B 的过表达导致 CDX2 表达增强，从而促进 CRC 细胞皮下异种移植肿瘤的分化以及 CRC 肝转移小鼠模型中通过间质上皮转化进行的转移性肿瘤定植。针对 CDX2 的 ChIP 序列鉴定出 α-甲基酰基辅酶 A 消旋酶（AMACR）为 LIN28B 过表达时 CDX2 的一个潜在新的转录靶标。我们还发现 AMACR 通过上调丁酸来增强已知为肠分化关键成分的肠碱性磷酸酶活性。总的来说，我们证明 LIN28B 通过 CDX2/AMACR 轴促进 CRC 分化。
