Tumor metastasis is an essential cause of the poor prognosis of colon cancer. DC-SIGNR is a C-type lectin that is frequently found on human liver sinusoidal endothelial cells. LSECtin, which is a homologue of DC-SIGNR, has been demonstrated to participate in colon cancer liver metastasis. Due to the similarities in the expression pattern and structure of the two proteins, we speculated that DC-SIGNR could also be involved in this process. Colon cancer cells were treated with the DC-SIGNR protein or control IgG, after which cell migration, invasion, and morphology were assayed. Xenograft mouse models were used to determine the role of DC-SIGNR in colon cancer liver metastasis in vivo. In addition, a human gene expression array was used to detect differential gene expression in colon cancer cells stimulated with the DC-SIGNR protein. The serum level of DC-SIGNR was examined in colon cancer patients by ELISA, and the significance of DC-SIGNR was determined. In our research, we investigated whether DC-SIGNR promotes colon cancer cell adhesion, migration, and invasion. Knocking down mouse DC-SIGNR decreased the liver metastatic potency of colon cancer cells and increased survival time. Expressing human DC-SIGNR enhanced colon cancer liver metastasis. Furthermore, DC-SIGNR conferred metastatic capability on cancer cells by upregulating various metallothionein isoforms. To validate the above results, we also found that the serum DC-SIGNR level was statistically higher in colon cancer patients with liver metastasis compared with those without metastasis. These results imply that DC-SIGNR may promote colon carcinoma hepatic metastasis and could serve as a promising therapeutic target for anticancer treatment.

Profiling evidences of selectin demonstrate that they play an crucial role in cancer progression and metastasis. However, DC-SIGNR as a family member of selectin participates in gastric cancer liver metastasis remains unknown. The serum level of DC-SIGNR was evaluated in gastric cancer patients by ELISA. Manipulation DC-SIGNR expression in BGC823 and SGC7901 cell lines was mediated by lentivirus. Investigation the biological effects of DC-SIGNR were verified by MTT, wounding and transwell in vitro and experiments on animals to confirm gastric cancer liver metastasis by IVIS. Insights of the mechanism were employed microarray and bioinformatic analysis. Further to confirm the results were conducted by qRT-PCR, western blot and by flow cytometry. DC-SIGNR serum level was significantly increased in gastric cancer patients compared with healthy group. Additionally, DC-SIGNR level was associated with an advanced pathological stage in gastric cancer patients. DC-SIGNR knockdown inhibited the proliferation, migration and invasion of gastric cancer cells in vitro and suppressed the liver metastasis in vivo. While, DC-SIGNR overexpression promoted cell proliferation, migration and invasion. In mechanism, HNRNPKP2 as a lncRNA was upregulated after DC-SIGNR knockdown. Importantly, STAT5A promoted HNRNPKP2 expression after knockdown DC-SIGNR. Furthermore after HNRNPKP2 depletion, the downstream target gene CXCR4 was downregulated. DC-SIGNR promoted gastric cancer liver metastasis mediated with HNRNPKP2 which expression was regulated by STAT5A. And HNRNPKP2 decreased the expression of downstream target gene CXCR4. These findings indicated potential therapeutic candidates for gastric cancer liver metastasis.

Introduction: Liver metastasis is a common cause of death in patients with colorectal cancer (CRC); however, its molecular mechanism remains unclear. Here, we aimed to reveal the role of the lncRNA STEAP3-AS1 in regulating chromatin remodelling and histone lactylation and explore the mechanism by which the lncRNA STEAP3-AS1 promotes CRC liver metastasis. This study provide new research ideas and a theoretical basis for the clinical treatment of cancer. Methods: In this study, we used CRC organoid and nude mouse liver metastasis models to analyse the effect of the lncRNA STEAP3-AS1 on CRC liver metastasis. ATAC-seq, RNA-seq, DRIP-seq and Western blotting were used to screen for the lncRNA STEAP3-AS1 downstream prometastatic molecule MMP9 and the chromatin remodelling factor BRG1. The protein interactions between BRG1, p300, and HDAC3 were evaluated by Co-IP. The the binding of BRG1, ERG, P300, and H3K18la to the MMP9 gene promoter was detected using ChIP-qPCR. Results: The lncRNA STEAP3-AS1 interacts with its parental gene, STEAP3, to form an R-loop on the key chromatin remodelling factor BRG1, regulating the expression of BRG1. Further evidence suggests that BRG1 forms a protein complex with the histone lactylation eraser HDAC3 and the writer P300 to regulate the expression of H3K18la. Moreover, the ATAC-seq analysis revealed that the lncRNA STEAP3-AS1 promotes the chromatin accessibility of MMP9, and a motif and database analysis identified the tumour metastasis factor ERG as an MMP9 transcription factor. The lncRNA STEAP3-AS1 mediates regulation of H3K18la activation of MMP9 by the BRG1/ERG/P300 complex. Conclusions: In summary, these findings revealed that the lncRNA STEAP3-AS1 interacts with its parental gene STEAP3 to regulate H3K18la through BRG1, resulting in changes in chromatin accessibility, thereby driving ERG enrichment an the MMP9 promoter to activate MMP9 transcription and promote CRC liver metastasis. Our findings reveal a novel mechanism by which the lncRNA STEAP3-AS1 promotes CRC metastasis from an epigenetic perspective.

Previous studies have reported that long noncoding RNAs (lncRNAs) have acted as new players during tumorigenesis. Metallothionein also plays an important role in tumor progression. It is mainly considered to be involved in the process of cell proliferation, oxidative stress, and multidrug resistance. However, the potential involvement of metallothionein-related lncRNAs in colon cancer remains poorly understood. In our study, we found that MT1M affected the expression of lncRNA STEAP3-AS1. STEAP3-AS1 is located in physical contiguity with STEAP3 and notably increased in colon cancer tissues and cell lines. STEAP3-AS1 expression was negatively associated with the expression of STEAP3. High levels of STEPA3-AS1 were associated with poor overall survival in colon cancer patients. In in vitro assays, STEAP3-AS1 knockdown could inhibit colon cancer cell proliferation and migration and arrest colon cancer cells at the G0-G1 phase. In tumorigenicity assays, STEAP3-AS1 knockdown could strongly inhibit tumor growth. Mechanistic investigations demonstrated that STEAP3-AS1 downregulation could increase the expression of cyclin-dependent kinase inhibitor 1C (CDKN1C) by STEAP3 upregulation. Overall, we identify the underlying role of MT1M-related lncRNA STEAP3-AS1 in colon cancer progression, which provides a novel strategy for colon cancer therapy.