The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

Figure 2

Signaling pathways mediated by CTHRC1 involved in the progression and metastasis of tumor. (1) TGF-β signaling pathway is quite complex, especially in terms of its effects, which are often contradictory depending on location and time. There exists a critical negative feedback regulatory loop between TGF-β-smad2/3 signaling pathway and CTHRC1. (2) WNT signaling includes WNT/β-catenin canonical pathway and β-catenin-independent noncanonical pathway. In the canonical WNT signaling, Fzd receptor and LRP5/LRP6 coreceptor are transduced to β-catenin signaling cascade for the maintenance of stem and progenitor cells. In the noncanonical WNT signaling, Fzd receptor and ROR2/PTK7/RYK coreceptor are transduced to RhoA, JNK signaling cascades for the control of tissue polarity, cell adhesion, or cell movement. The downstream molecules of the WNT/PCP pathway mainly include the small GTPase family, such as Rac1, RhoA, and JNK, which play essential roles in cancer cell migration and invasion. (3) CTHRC1 signal via WAIF1 can activate PKCδ, which is an essential component of the WNT/PCP pathway. Furthermore, PKCδ is responsible for the activation of the CTHRC1-induced ERK signaling pathway. (4) In CTHRC1/integrin β signaling pathway, the upregulation of CTHRC1 is related to the progression and metastasis of several cancers through the activation of several key signaling molecules, including Src, FAK, paxillin, MEK, ERK, and Rac1. FAK promotes cancer cell migration by regulating focal adhesion formation and turnover, which involve activation of Src and paxillin. FRA-1 is activated by CTHRC1 through the MAPK/MEK/ERK signaling, which leads to the upregulation of cyclin D1 and that promotes cell proliferation. FRA-1 also induces snail1-mediated MMP14 expression to facilitate ESCC cell invasion, migration, and metastasis. PI3K/AKT signaling pathway induces EMT change and MMP2/MMP9 expression. (5) HIF-1α and VEGF are activated by CTHRC1 through activating the PI3K/AKT/mTOR signaling pathway, which promotes tumor angiogenesis. CTHRC1 also participates in tumor cell migration and invasion through HIF-1α/CXCR4 signals.