Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Experimental Medicine I, Nikolaus-Feibiger-Center for Molecular Medicine, University of Erlangen-Nuernberg, 91054 Erlangen, Germany.
Cells. 2024 Nov 2;13(21):1810. doi: 10.3390/cells13211810.
The cell adhesion molecule L1CAM (L1), mainly known for its function in brain cells, is a Wnt/β-catenin signaling target gene in colorectal cancer (CRC) cells, where it promotes invasion and liver metastasis. We interrogated which genes are expressed at increased levels in human CRC tissue and induced in CRC cell lines overexpressing L1. We found increased cyclin D2 levels in CRC tissue and LS 174T and HCT 116 human CRC cells overexpressing L1. Increased cyclin D2 in CRC cells was associated with higher proliferation rates, faster motility, tumorigenesis, and liver metastasis. The suppression of cyclin D2 expression by shRNA to cyclin D2 blocked the increase in these cellular properties of L1-expressing cells. The overexpression of cyclin D2 in the absence of L1 also conferred tumorigenic properties similar to L1 expression. The pathways involved in the elevation of cyclin D2 by L1 include NF-κB, Akt, and β-catenin signaling but not the Erk pathway. We found that in a significant percentage of human CRC tissue samples, cyclin D2 is expressed at high levels in the nuclei of cancer cells. At the same time, the adjacent normal mucosa was negative for cyclin D2 staining. The results suggest that the increased cyclin D2 expression by L1 is required to induce proliferative, motile tumor development in CRC tissue and can serve as a diagnostic marker and a target for CRC therapy.
细胞黏附分子 L1CAM（L1）主要因其在脑细胞中的功能而闻名，是结直肠癌细胞（CRC）中 Wnt/β-catenin 信号通路的靶基因，可促进侵袭和肝转移。我们研究了在人 CRC 组织中表达水平升高并在过表达 L1 的 CRC 细胞系中诱导表达的基因。我们发现 CRC 组织和过表达 L1 的 LS 174T 和 HCT 116 人 CRC 细胞中 cyclin D2 水平升高。CRC 细胞中 cyclin D2 的增加与更高的增殖率、更快的运动性、致瘤性和肝转移相关。用 shRNA 抑制 cyclin D2 的表达可阻断 L1 表达细胞这些细胞特性的增加。即使没有 L1 的过表达，cyclin D2 的过表达也赋予了类似于 L1 表达的致瘤特性。L1 升高 cyclin D2 的途径包括 NF-κB、Akt 和 β-catenin 信号通路，但不包括 Erk 通路。我们发现，在大量人 CRC 组织样本中，cyclin D2 在癌细胞核中高表达。与此同时，相邻的正常黏膜对 cyclin D2 染色呈阴性。结果表明，L1 诱导的 cyclin D2 表达增加是诱导 CRC 组织中增殖性、运动性肿瘤发展所必需的，可作为 CRC 治疗的诊断标志物和靶点。
