Expression and function of the Rho guanine nucleotide exchange factor ECT2 in colorectal cancer

Abstract

Rho GTPases contribute to multiple cellular processes that could affect cancer progression, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation and cell survival. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). Here, we aim to identify RhoGEFs that mediate colorectal cancer progression. Using a TCGA transcriptome data, we identified that ECT2 (epithelial cell transforming sequence 2), one of the RhoGEFs family, is more over-expressed in colorectal cancer than in adjacent normal tissue. We also confirmed this by using quantitative real-time PCR. Knockdown of ECT2 by siRNA regulates the activity of RHOA but not CDC42 and RAC1. Inhibition of ECT2 suppresses cell migration, invasion and proliferation in colorectal cancer cell lines via regulating RHOA/AKT pathway. In addition, we investigated the therapeutic use of ECT2. ECT2 is down-regulated by chemotherapy drugs like oxaliplatin, irinotecan, 5-FU in p53 wild type cell lines. Conversely in p53 mutant cell lines, ECT2 is up-regulated. Knockdown of ECT2 and chemotherapy alone generally inhibited cell proliferation. However, in p53 mutant cell line, the combination of siRNA ECT2 with chemotherapy had more effect on the inhibition of cell proliferation. This study suggests that ECT2 could be a potential biomarker and a therapeutic target for treating colorectal cancer. Also that combination of siRNA ECT2 with chemotherapy could be a novel molecular therapy for the patients with p53 mutation.