Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Med. 2023 Jun;12(12):13426-13437. doi: 10.1002/cam4.5970. Epub 2023 Apr 25.
Abnormal activation of Wnt/β-catenin signaling is associated with various aspects of cancer development. This study explored the roles of novel target genes of the Wnt/β-catenin signaling pathway in cancer cells.
Using the haploid chronic myelogenous leukemia cell line HAP1, RNA sequencing (RNA-seq) was performed to identify genes whose expression was increased by APC disruption and reversed by β-catenin knockdown (KD). The regulatory mechanism and function of one of the candidate genes was investigated in colorectal cancer (CRC) cells.
In total, 64 candidate genes whose expression was regulated by Wnt/β-catenin signaling were identified. Of these candidate genes, the expression levels of six were reduced by β-catenin KD in HCT116 CRC cells in our previous microarray. One of these genes was Visinin-like 1 (VSNL1), which belongs to the neuronal calcium-sensor gene family. The expression of VSNL1 was regulated by the β-catenin/TCF7L2 complex via two TCF7L2-binding elements in intron 1. VSNL1 KD-induced apoptosis in VSNL1-positive CRC cells. Additionally, forced expression of wild-type VSNL1, but not a myristoylation, Ca -binding, or dimerization-defective mutant, suppressed the apoptosis induced by camptothecin and doxorubicin in VSNL1-negative CRC cells.
Our findings suggest that VSNL1, a novel target gene of the Wnt/β-catenin signaling pathway, is associated with apoptosis resistance in CRC cells.
Wnt/β-catenin 信号通路的异常激活与癌症发展的各个方面有关。本研究探讨了 Wnt/β-catenin 信号通路的新靶基因在癌细胞中的作用。
使用单倍体慢性髓性白血病细胞系 HAP1，进行 RNA 测序（RNA-seq），以鉴定 APC 破坏后表达增加且 β-catenin 敲低（KD）后逆转的基因。在结直肠癌（CRC）细胞中研究了一个候选基因的调控机制和功能。
总共鉴定出 64 个受 Wnt/β-catenin 信号调节的候选基因。在我们之前的微阵列中，这些候选基因中有 6 个在 HCT116 CRC 细胞中因β-catenin KD 而降低。其中一个是类视蛋白样 1（VSNL1），属于神经元钙传感器基因家族。VSNL1 的表达受 β-catenin/TCF7L2 复合物通过 1 号内含子中的两个 TCF7L2 结合元件调节。VSNL1 KD 诱导 VSNL1 阳性 CRC 细胞凋亡。此外，野生型 VSNL1 的强制表达，而不是豆蔻酰化、Ca 结合或二聚化缺陷突变体，抑制了 VSNL1 阴性 CRC 细胞中喜树碱和阿霉素诱导的凋亡。
我们的研究结果表明，Wnt/β-catenin 信号通路的新靶基因 VSNL1 与 CRC 细胞的凋亡抵抗有关。
