Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
PLoS One. 2023 Jun 22;18(6):e0286486. doi: 10.1371/journal.pone.0286486. eCollection 2023.
Liver metastases severely reduce the long term survival of colorectal cancer patients. Long non-coding RNAs (lncRNAs) CCAT1 and CCAT2 have previously been found to be associated with impaired patient outcomes in primary colorectal cancer. We aimed to elucidate the role of CCAT1 and CCAT2 in colorectal liver metastases.
Total RNA was isolated from 97 human tissue samples of colorectal liver metastases and adjacent normal liver tissue. Gene expression analysis was performed by RT-qPCR and Multiplex ELISA and correlated with patient characteristics and survival. Gene expression, cancer cell migration, invasion, and proliferation were studied after siRNA-mediated knockdown of CCAT1, CCAT2, and MYC in metastatic colorectal cancer cell lines Colo205 and HROC277Met2.
Elevated expression levels of lncRNAs CCAT1 and CCAT2, and their common target MYC in colorectal liver metastases were associated with prolonged progression-free survival after liver resection. High expression of CCAT1 was likewise associated with prolonged overall survival. Knockdown of CCAT1, CCAT2, and MYC resulted in increased migratory and invasive potential in metastatic colorectal cancer cell lines. Gene expression analysis revealed alterations in constituents of Wnt signaling following knockdown.
Our findings demonstrate tumor-suppressive functions of lncRNAs CCAT1 and CCAT2 in colorectal liver metastases. They suppress Wnt signaling directly and indirectly through target gene MYC and might prevent further metastatic spread from colorectal liver metastases.
肝转移严重降低了结直肠癌患者的长期生存率。先前发现长链非编码 RNA（lncRNA）CCAT1 和 CCAT2 与原发性结直肠癌患者预后不良有关。我们旨在阐明 CCAT1 和 CCAT2 在结直肠肝转移中的作用。
从 97 个人类结直肠肝转移组织样本和相邻正常肝组织中分离总 RNA。通过 RT-qPCR 和多重 ELISA 进行基因表达分析，并与患者特征和生存相关联。在转移性结直肠癌细胞系 Colo205 和 HROC277Met2 中，通过 siRNA 介导的 CCAT1、CCAT2 和 MYC 敲低，研究基因表达、癌细胞迁移、侵袭和增殖。
结直肠肝转移中 lncRNA CCAT1 和 CCAT2 的表达水平升高及其共同靶基因 MYC 与肝切除后无进展生存期延长相关。CCAT1 高表达同样与总生存期延长相关。CCAT1、CCAT2 和 MYC 的敲低导致转移性结直肠癌细胞系的迁移和侵袭潜力增加。基因表达分析显示，敲低后 Wnt 信号通路成分发生改变。
我们的研究结果表明，lncRNA CCAT1 和 CCAT2 在结直肠肝转移中具有肿瘤抑制功能。它们通过靶基因 MYC 直接和间接抑制 Wnt 信号通路，可能防止结直肠肝转移进一步转移扩散。
