DC-SIGNR在结肠癌肝转移中的作用及其机制

The liver is the most common target organ for hematogenous metastasis of colon cancer. The genes and mechanisms responsible for liver metastasis are the most important considerations for improving colon cancer survival.Instead of randomly metastasizing to the various tissues and organs of the body, tumor cells specifically go to certain organs. Accumulated evidence has shown that the adhesion of tumor cells and endothelial cells plays an important role in organ-specific metastasis. However, progress toward clarifying the specific adhesion molecules involved in organ-specific metastasis has proven difficult. In this study, we aimed to determine the role of liver sinusoidal endothelial cell lectin DC-SIGNR in colon carcinoma metastasis to the liver. DC-SIGNR is an adhesion molecule which shows high and specific expression on hepatic and lymph node sinusoidal endothelial cells. lymphocyte adhesion molecules and their ligands can also be involved in tumor cell adhesion and metastasis. Both of them are highly targeted organs of tumor metastasis; other members of the DC-SIGNR family, such as selectin, mannose receptor have shown to be involved in tumor metastasis. Cell adhesion experiments in vitro demonstrated LS174T, loVo and sw480 colorectal tumor cells combined with DC-SIGNR to accelerate tumor metastasis. With the gene of DC-SIGNR knocked out, the ratio of hepatic metastasis displayed a significantly reduction. Thus, we hypothesized that DC-SIGNR may play a role in liver metastasis of the colon carcinoma. We selected the high frequency liver metastases colon cancer cells as a research object, used in vivo/vitro adhesion, invasion，migration and animal experiments to reveal the roles in colon carcinoma cell metastasis to the Liver.This study may be a promising new target for intervention in metastasis formation and made theoretical significance and great prospect in clinical trials.

肿瘤转移具有器官特异性。研究发现，肿瘤细胞与靶器官内皮细胞的粘附在肿瘤转移中起重要作用。目前对内皮细胞的特征粘附分子所知有限。因而，在阐明具体机制时进展缓慢。已知，DC-SIGNR是肝脏和淋巴结窦内皮细胞特异高表达的粘附分子，两者正是肿瘤高转移的靶器官；DC-SIGNR同家族的某些成员已经被证明参与肿瘤转移；前期实验证明DC-SIGNR的同一家族分子LSECtin参与了结肠癌肝转移；肝转移的患者血清中可溶性DC-SIGNR水平显著高于未发生肝转移的患者和正常人；体外粘附实验证明结肠癌细胞LS174T可以与肝脏上DC-SIGNR结合；将DC-SIGNR基因敲低后，LS174T等结肠癌细胞向肝脏转移率显著降低。因而，推测DC-SIGNR可能在肿瘤的肝脏转移中发挥作用。本项目拟通过体内/外粘附和动物整体实验，揭示DC-SIGNR在结肠癌肝转移中的作用，为临床诊断和治疗结肠癌肝转移提供理论依据。

肿瘤细胞与靶器官内皮细胞的粘附在肿瘤转移中起重要作用。目前对内皮细胞的特征粘附分子所知有限。因而，在阐明具体机制时进展缓慢。已知，DC-SIGNR是肝脏和淋巴结窦内皮细胞特异高表达的粘附分子，两者正是肿瘤高转移的靶器官；DC-SIGNR同家族的某些成员已经被证明参与肿瘤转移；前期实验证明DC-SIGNR的同一家族分子LSECtin参与了结肠癌肝转移；本课题研究结果证明：体外黏附实验表明DC-SIGNR蛋白能以钙离子依赖的方式与结肠癌细胞株LoVo，LS174T和HCT-116黏附，并且与其未知配体的糖链结合；体内外实验结果表明DC-SIGNR参与了结肠癌细胞肝转移；人类表达谱芯片、定量PCR和Western blot技术结果显示DC-SIGNR可上调结肠癌细胞LoVo中的金属硫蛋白家族上调；血清学结果表明血清中可检测到可溶性DC-SIGNR的表达，III/IV期结肠癌患者血清中的DC-SIGNR的表达水平明显高于健康对照组；结肠癌肝转移患者血清中的DC-SIGNR表达水平较结肠癌未发生转移的患者显著性增高。在胃癌患者血清中检测到sDC-SIGNR的表达，并且随着肿瘤分期级别的递增而升高；发生肝脏转移和未发生肝脏转移的胃癌患者表达sDC-SIGNR的水平不同；体内体外实验证明DC-SIGNR促进胃癌细胞的增殖、迁移和侵袭；通过高通量LncPath芯片研究发现了与DC-SIGNR表达相关的多个lncRNAs分子；lncRNA HNRNPKP2是参与DC-SIGNR介导胃癌发生肝转移的关键lncRNAs分子之一；CXCR4是lncRNA HNRNPKP2的功能性靶基因。结果提示DC-SIGNR参与了结肠癌和胃癌的肝转移，为临床诊断和治疗结肠癌和胃癌肝转移提供了理论依据。