Colorectal liver metastases (CRLM) continue to have a low survival rate. The number of CRLM regulators and clinical indicators remains limited. Long non-coding RNAs (lncRNAs) are a new master regulator of cell invasion and metastasis. However, the function and regulation mechanism of lncRNAs in colorectal cancer (CRC) metastasis are yet unknown. To screen and identify CRLM-related lncRNAs, public transcriptome data were used. Gain and loss of function experiments were carried out to investigate the biological activities of lncRNA CRLM1 in vitro and in vivo. RNA sequencing (RNA-seq), chromatin isolation by RNA purification (ChIRP), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), western blotting, and rescue experiments were performed to explore the molecular mechanism of CRLM1. Moreover, identified the proteins, DNAs, and RNAs that interact with CRLM1. The investigation of lncRNA expression dynamics in CRLM, primary CRC, and normal tissues in this work resulted in identifying a series of lncRNAs associated with metastasis, including CRLM1. CRLM1 inhibited apoptosis of CRC cells and promoted liver metastasis in Balb/C nude mice. CRLM1 was weakly associated with the chromatin regions of genes involved in cell adhesion and DNA damage, and this association was bidirectionally correlated with CRLM1-regulated pro-metastatic gene expression. CRLM1 physically interacts with the hnRNPK protein and promotes its nuclear localization. CRLM1 effectively enhances hnRNPK promoter occupancy and co-regulates the expression of a panel of metastatic genes. The finding of the clinically significant lncRNA CRLM1 in promoting metastasis and regulating gene expression suggests a potential biomarker and target for CRLM therapy.

中文翻译：

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LncRNA CRLM1通过转录调控与hnRNPK协同作用在结直肠癌中抑制细胞凋亡并促进转移

结直肠肝转移瘤（CRLM）的存活率仍然很低。CRLM 调节剂和临床指标的数量仍然有限。长链非编码 RNA (lncRNA) 是一种新的细胞侵袭和转移的主要调节因子。然而，lncRNA在结直肠癌（CRC）转移中的功能和调控机制尚不清楚。为了筛选和鉴定 CRLM 相关的 lncRNA，使用了公共转录组数据。为了研究lncRNA CRLM1在体外和体内的生物学活性，进行了功能增益和丧失实验。进行了RNA测序（RNA-seq）、RNA纯化染色质分离（ChIRP）、免疫荧光（IF）、定量实时PCR（qRT-PCR）、蛋白质印迹和拯救实验，以探索CRLM1的分子机制。此外，还鉴定了蛋白质、DNA、和与 CRLM1 相互作用的 RNA。在这项工作中，对 CRLM、原发性 CRC 和正常组织中 lncRNA 表达动态的研究导致鉴定了一系列与转移相关的 lncRNA，包括 CRLM1。CRLM1 抑制 CRC 细胞凋亡并促进 Balb/C 裸鼠的肝转移。CRLM1 与参与细胞粘附和 DNA 损伤的基因的染色质区域弱相关，并且这种关联与 CRLM1 调节的前转移基因表达双向相关。CRLM1 与 hnRNPK 蛋白物理相互作用并促进其核定位。CRLM1 有效增强 hnRNPK 启动子的占有率并共同调节一组转移基因的表达。