ARHGEF37 overexpression promotes extravasation and metastasis of hepatocellular carcinoma via directly activating Cdc42

Abstract

Background The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear. Methods The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models. Results In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice. Conclusion Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis.

TRIM56 acts through the IQGAP1-CDC42 signaling axis to promote glioma cell migration and invasion

“…One of the most well-researched Rho GTPase subfamilies is CDC42 (CDC42, RHOJ, and RHOQ) [ 25 ]. Cell division cycle 42 (CDC42) plays a vital regulatory role in cellular motility and polarization, which are closely related to the cytoskeleton and cell adhesion [ 26 – 28 ]. Considering that the differentially expressed genes regulated by TRIM56 knockdown were highly enriched in the Rho GTPase signaling and the motility-promoting effect of TRIM56 on glioma cells, we further assessed the effect of TRIM56 on CDC42 activation.…”

“…CDC42 activation is directly regulated by various proteins, such as Rho guanine nucleotide exchange factor 37 (ARHGEF37) [ 26 ], IQ motif containing GTPase activating protein 1 (IQGAP1) [ 30 – 32 ], and N-myc downstream regulated 1 (NDRG1) [ 33 ]. In U87 and U251 cells, TRIM56 overexpression and knockdown increased and suppressed IQGAP1 expression, respectively, at protein level (Fig.…”

“…CDC42 activation is modulated by various factors. For example, in hepatocellular carcinoma cells, ARHGEF37 can activate CDC42 by interacting with it [ 26 ]. IQGAP1, a member of the IQGAP family, is a scaffold protein that regulates cell migration by weakening cell-cell adhesion and degrading the extracellular matrix [ 53 – 55 ].…”

FSCN1/METTL3/TLN1 axis promotes the malignant progression in bladder carcinoma

“…In this study, we found that FSCN1 promotes the invasion and metastasis of BLCA cells by directly binding to and inhibiting the TLN1, RAF1, CDC42, VAV2 and GRB2 mRNAs. RAF1 regulates the progression of endometrial cancer and hypopharyngeal cancer [27,28], CDC42 promotes metastasis in hepatocellular carcinoma [29], and TLN1 has a pro-metastatic function in prostate cancer [30]. Therefore, we hypothesize that FSCN1 forms an RBP regulatory network with multiple mRNAs, which is the molecular basis of the metastasis in various tumors.…”

Dahuang—Taoren, a botanical drug combination, ameliorates adenomyosis via inhibiting Rho GTPases

“…Though AM is benign, it shares certain characteristics with cancers, such as the ability to invade and metastasize. Growing evidence indicates that Rho GTPases, one of the most important regulators of cytoskeletal protein ( Guan et al, 2020 ), play a crucial role in the abnormal motility of tumor cells ( Kim et al, 2022 ; Qiu et al, 2022 ; Zhang et al, 2022 ). The Rho GTPases consist of 60 members and can be divided into multiple subfamilies ( Jansen et al, 2018 ; Clayton and Ridley, 2020 ).…”