DLC2 operates as a tumor suppressor gene in breast cancer via the RhoGTPase pathway

Abstract

Deleted in liver cancer 2 (DLC2) is a tumor suppressor, associated with various types of cancer. The aim of the present study was to analyze the expression of DLC2 in breast cancer, its clinical significance and its effect on breast cancer cell behavior. The expression of DLC2 was evaluated by immunohistochemistry in 131 cases of breast cancer. Associations among DLC2 expression and clinicopathological features were analyzed, and its effects on proliferation, motility, migration and invasion in DLC2-knockdown breast cancer cell lines were observed. The results indicated that DLC2 was expressed in 42.75% of breast cancer cases (56/131) and in 79.39% of adjacent normal tissues (104/131). Lower expression of DLC2 in breast cancer was associated with tumor differentiation (P<0.001), lymph node metastasis (P<0.001) and poor prognosis (P<0.001). The silencing of the DLC2 gene in human breast cancer cell indicated an increased number of cells entering S phase, and increased abilities of clone formation, cell migration and invasion. Downregulated expression of DLC2 was associated with activated Ras homolog family member A and decreased Rac family small GTPase 1, cell division cycle 42 and Rho-associated protein kinase-2 expression levels, indicating that DLC2 may serve a regulatory function in breast cancer cell proliferation and invasion via the RhoGTPase pathway. The results of the present study suggested that DLC2 serves as a suppressor gene in the development of breast cancer and may be a prognostic marker for patients with breast cancer.

Differential regulation of rho GTPases during lung adenocarcinoma migration and invasion reveals a novel role of the tumor suppressor StarD13 in invadopodia regulation

“…Other groups also identified StarD13 as an invasion suppressor in solid tumors. Yang et al also showed that knocking down StarD13 enhances breast cancer cell invasion in a transwell membrane assay, through Rho GTPases [36]. This was reported in another study which further identified StarD13 as a miR-125b microRNA target and showed that StarD13 silencing (being complementary to StarD13's 3'UTR) increases the metastatic ability of gastric cancer [63,64].…”

StarD13 negatively regulates invadopodia formation and invasion in high-grade serous (HGS) ovarian adenocarcinoma cells by inhibiting Cdc42

“…Immunohistochemistry and data microarray analysis revealed a lower expression of StarD13 in ovarian cancer tissues as compared to the normal ovarian tissues, which is similar to the results observed in lung and hepatocellular cancers ( Al Haddad et al, 2020 ; Ching et al, 2003 ). StarD13 inhibition of cell proliferation is also in line with a potential tumor suppressor function of this protein ( Al Haddad et al, 2020 ; El-Sitt et al, 2012 ; Hanna et al, 2014a ; Khalil et al, 2014 ; Nasrallah et al, 2014 ; Yang et al, 2019b , 2019a ; Zhang et al, 2017 ).…”

“…Cdc42 is directly implicated in the regulation of cancer cell invasion, therefore we investigated the role of StarD13 in regulating the invasion of ovarian cancer cells ( Al-Koussa et al, 2020a ; Al Haddad et al, 2020 ; Evers et al, 2000 ; Fortin Ensign et al, 2013 ; Keely et al, 1997 ; Kwiatkowska et al, 2012 ; Yang et al, 2019b ). Using transwell inserts, we tested the ability of control, StarD13 siRNA or StarD13 siRNA + Cdc42 siRNA transfected SKOV-3 or Caov-3 cells to invade in vitro.…”

Silibinin Inhibit Cell Migration through Downregulation of RAC1 Gene Expression in Highly Metastatic Breast Cancer Cell Line

“…Rho GTPase family plays a crucial role in all levels of cancer development, metastasis and invasion. This protein family control signal transduction cascades from cell surface receptors to a variety of intracellular response, including microtubule dynamic and cell polarity via the actin cytoskeleton rearrangement [5]. Among the Rho family GTPases, Ras related C3 botulinum toxin substrate 1 (Rac1) is of special interest because of their hyper activation or frequent overexpression in epithelial cancers including breast cancer [6].…”

“…RAC1 also is participating in integrin-mediated adhesion. Given the roles mentioned for this molecule, the disruption of its expression regulation causes that aberrant cell signaling and numerous pathological conditions [5,[8][9][10].…”