CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways.
CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways.
复制标题
CSRP2 通过 p130Cas/Rac1 轴介导的 ERK、PAK 和 HIPPO 信号通路抑制结直肠癌进展
作者：
Chen L;Long X;Duan S;Liu X;Chen J;Lan J;Liu X;Huang W;Geng J;Zhou J
转移是结直肠癌（CRC）患者死亡的主要原因。最近发现富含半胱氨酸的蛋白 2 (CSRP2) 与多种癌症的进展和转移有关。然而，CSRP2 在调节 CRC 进展中的生物学功能和潜在机制尚不清楚。方法：采用免疫组化、实时定量聚合酶链反应（qPCR）和蛋白质印迹（WB）检测结直肠癌组织及癌旁组织中CSRP2的表达情况。 CSRP2 在 CRC 中的功能通过一系列体内和体外功能测试来确定。 WB和免疫荧光用于确定CSRP2与上皮间质转化（EMT）之间的关系。采用免疫共沉淀和扫描电镜研究CSRP2在结直肠癌中的分子机制。结果：结直肠癌组织中CSRP2的表达水平低于癌旁正常组织，提示结直肠癌患者预后较差。从功能上来说，CSRP2可以在体外抑制CRC细胞的增殖、迁移和侵袭，在体内抑制CRC肿瘤的发生和转移。机制研究揭示了 CSRP2 和 p130Cas 之间的物理相互作用。 CSRP2可以通过阻止p130Cas的磷酸化来抑制Rac1的激活，从而激活Hippo信号通路，同时抑制ERK和PAK/LIMK/cortactin信号通路，从而抑制CRC的EMT和转移。拯救实验表明，阻断p130Cas和Rac1激活可以抑制CSRP2沉默诱导的EMT。结论：我们的结果表明CSRP2/p130Cas/Rac1轴可以通过Hippo、ERK和PAK信号通路抑制CRC的侵袭性和转移。因此，CSRP2可能是CRC的潜在治疗靶点。
Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.