Research progress of ECT2 and RhoA-related signaling pathways in gynecological tumors

Abstract

Epithelial Cell Transformation Factor 2 (ECT2) is highly expressed in a variety of cancers, including gynecological tumors. The mislocalization of ECT2 can abnormally activate Ras homolog family member A (RhoA) in the Ras homolog gene family (Rho) Guanine nucleotide Exchange Factor (GEF) family. Activated RhoA binds to Rho-associated protein kinase (ROCK), phosphorylates various target proteins, triggers a cascade reaction, regulates the functions of downstream proteins, and thereby plays an important role in the occurrence and development of tumors. This article reviews the roles of ECT2 and RhoA/ROCK signaling pathways in ovarian cancer, cervical cancer, and endometrial cancer, and summarizes and discusses the research progress of downstream molecules, transduction pathways, and mechanisms related to them. Through comprehensive analysis and summary of the current research results, it is revealed that the ECT2/RhoA/ROCK signaling pathway and related crosstalk pathways play an important role in the occurrence, development, and metastasis of gynecological tumors. This article aims to provide a basis for related research and offer relevant references for the treatment of gynecological tumors in the future.

Keywords: Ect2; ROCK; RhoA; cervical cancer; endometrial cancer; ovarian cancer.

FIGURE 1

(A) Model of ECT2 structure; (B) Rho GTPase is involved in cell proliferation, invasion, and induction of tumor angiogenesis; (C) ECT2 catalyzes the conversion of GDP to GTP, which then binds to and activates the Rho protein; When RhoA binds to ROCK, it binds to or phosphorylates various target proteins to regulate the function of downstream proteins.

FIGURE 2

(A) The expression of ECT2 in ovarian cancer tissues is significantly higher than that in normal ovarian tissues; (B) The survival time of the ECT2 high-expression group was shorter than that of the ECT2 low-expression group; (C) The expression of ECT2 in ovarian cancer was significantly positively correlated with RhoA, ROCK1, and ROCK2.

FIGURE 3

(A) RhoA is involved in cell metastasis by forming complexes with RAN and activating ROCK to regulate the mechanosensitivity of tumor cells; (B) ECT2 can bind Cdc42 and GTP to activate various downstream effectors; Cdc42-v1 and Cdc42-v2 have the opposite effect; (C) Rac is activated by VEGF, Ang-1, FGF, etc., which then mediates cascades of downstream molecules; Rac and RhoA are antagonistic to each other.

FIGURE 4

(A) The expression of ECT2 in cervical cancer tissues is significantly higher than that in normal cervical tissues; (B) The survival time of the ECT2 high-expression group was shorter than that of the ECT2 low-expression group; (C) The expression of ECT2 in cervical cancer was significantly positively correlated with RhoA, ROCK1, and ROCK2.

FIGURE 5

(A1) ECT2 binds RhoA to GTP, which then activates ERK to produce p-ERK, which in turn increases the expression levels of MMP and VEGF; (A2) ATM activates RhoA and mediates the MAPK and ROCK pathways to regulate the expression level of cyclin D1 and participate in the DDR process; (A3) p53 is the substrate of ATM participating in DDR; ECT2 assists in ATM-mediated phosphorylation of p53; (B) The ECT2-RhoB-JNK pathway leads to cell death by triggering the pro-apoptotic protein Bim.

FIGURE 6

The carcinogenic potential of hr-HPV is associated with E6 and E7. E6 is associated with high expression of RhoA. E7 regulates the expression levels of RhoA and Rac1 through ARHGAP35. SDF-1α stimulates CXCR4, which in turn activates the RhoA/ROCK-mediated cascade. On the one hand, the interaction between SDF-1α and CXCR4 can remodel the basement membrane of cells. On the other hand, the RhoA/ROCK-mediated cascade can reconstitute the actin cytoskeleton.

FIGURE 7

(A) The expression of ECT2 in endometrial cancer tissues is significantly higher than that in normal endometrial tissues; (B) The survival time of the ECT2 high-expression group was shorter than that of the ECT2 low-expression group; (C) The expression of ECT2 in endometrial cancer was significantly positively correlated with RhoA, ROCK1, and ROCK2.

FIGURE 8

(A) Calcium influx from TRPV4 and L-type calcium channels activates the RhoA-ROCK-LIMK-cofilin pathway involved in cytoskeletal regulation; (B) The RhoA-ROCK1 signaling pathway promotes the transformation of fibroblasts to CAF, which in turn leads to physical remodeling of the pro-aggressive ECM; (C) Ang II enhances cell contraction by activating the JAK2-RhoA-ROCK-MLC signaling pathway through G protein-coupled receptors; (D) B3GNT3 is expressed at high levels in EC cells, where it mediates the regulation of the RhoA-RAC1 signaling pathway.