NISCH通过阻断间皮细胞内RAC1/SMAD3/FN1信号抑制卵巢癌腹腔转移

The peritoneal metastasis is very common in ovarian cancer and interactions between ovarian cancer cells and mesothelial cells were believed to be critical for this procedure.As we previously demonstrated, NISCH was frequently silenced in ovarian cancer, which led to the activation of the integrin α5/FAK signal, promoted the invasion and peritoneal metastasis of ovarian cancer.We also detected the notable downregulation of NISCH protein secreted by ovarian cancer and the elevation of RAC1 activity in mesothelial cells. In vitro, the recombinant NISCH protein could suppress the RAC1 activity and reduce the mRNA and protein level of FN1 in mesothelial cells. Based on these findings, we hypothesize that loss of NISCH secreted by ovarian cancer tissues may be able to activate the RAC1/SMAD3/FN1 signal pathway in mesothelial cells, ehhance the adhesion/invasion of ovarian cancer cells on mesothelium, which sequentially promotes the peritoneal metastasis. In the present project, we aim to focus on the roles of NISCH in tumor microenvironment, use a panel of in vitro (primary cell and tissue culture, plasmids construction/tranfection, 3-dimension cell co-culture system) and in vivo (ovarian cancer peritoneal metastasis mouse model and bioluminescent imaging system) to explore how NISCH affect the biological behaviors of mesothelial cells and its underlying mechanisms. Our results may provide more solid evidences for target preventing and treating the peritoneal metastasis of ovarian cancer.

卵巢癌极易发生腹腔转移，由癌细胞、间皮细胞等组成的腹腔微环境在此过程中发挥重要作用。课题组已证实：卵巢癌中NISCH表达显著下降，导致integrin α5/FAK信号异常激活，促进卵巢癌的侵袭和腹腔转移；同时，卵巢癌分泌的NISCH也明显减少，腹膜间皮细胞内RAC1激酶活性升高，而重组人NISCH蛋白则能抑制间皮细胞内RAC1激酶活性和FN1表达。我们推测：卵巢癌分泌NISCH减少可激活间皮细胞内RAC1/SMAD3/FN1信号，进而增强腹膜与卵巢癌的黏附，促进其腹腔转移。课题以NISCH在腹腔微环境中的作用模式为切入点，借助多种体外（原代细胞/组织培养、质粒转染、荧光素酶报告系统、细胞三维共培养）、体内（腹腔转移模型、动物活体成像）实验技术，探讨NISCH对腹膜间皮细胞的调控模式及其分子机制，阐明NISCH在卵巢癌腹腔转移中的功能，为靶向NISCH治疗卵巢癌腹腔转移提供理论和实验依据。

卵巢癌极易发生腹腔转移，由癌细胞、间皮细胞等组成的腹腔微环境在此过程中发挥重要作用。课题组前期发现卵巢癌中NISCH表达显著下降，导致FAK信号异常激活，促进卵巢癌的侵袭和腹腔转移；同时，卵巢癌分泌的NISCH也明显减少，腹膜间皮细胞内RAC1激酶活性升高，而重组人NISCH蛋白则能抑制间皮细胞内RAC1激酶活性和FN1表达。在本研究中，借助多种体外（原代细胞/组织培养、质粒转染、荧光素酶报告系统、细胞三维共培养）、体内（腹腔转移模型、动物活体成像）实验技术，我们证实：卵巢癌分泌NISCH减少可激活间皮细胞内RAC1/SMAD3/FN1信号，进而增强腹膜与卵巢癌的黏附，促进其腹腔转移。本研究确立了卵巢癌的腹腔微环境中NISCH下游同时存在FAK信号通路（卵巢癌细胞中）和RAC1/SMAD3/FN1信号通路（腹膜间皮细胞中），两者相互配合，最终发挥抑制卵巢癌腹腔内播散种植的作用，为靶向NISCH治疗卵巢癌腹腔转移提供理论和实验依据。