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

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.

 

Comments:

The study you provided describes a detailed investigation into the role of Rho guanine nucleotide exchange factor 37 (ARHGEF37) in hepatocellular carcinoma (HCC) lung metastasis. The key findings and conclusions from this study can be summarized as follows:

### **Summary of Key Findings:**

1. **ARHGEF37 Upregulation in HCC:** ARHGEF37 was found to be upregulated in human HCC samples. Its expression was correlated with tumor invasiveness, pulmonary metastasis, and poor prognosis.

2. **Enhanced Extravasation and Metastatic Capability:** Overexpression of ARHGEF37 significantly increased the extravasation and metastatic capability of HCC cells. This effect was achieved by enhancing tumor cell adhesion to endothelial cells and promoting trans-endothelial migration.

3. **Activation of Cdc42:** Mechanistically, ARHGEF37 directly interacted with and activated Cdc42, a protein involved in cell signaling and cytoskeletal reorganization.

4. **Involvement of Invadopodia Formation:** ARHGEF37/Cdc42 interaction promoted invadopodia formation in HCC cells. Invadopodia are actin-rich membrane protrusions that facilitate cancer cell invasion by breaking down the extracellular matrix.

5. **Disruption of Endothelial-Pericyte Interaction:** Invadopodia formation disrupted the interaction between endothelial cells and pericytes. This disruption likely contributed to the extravasation process, allowing cancer cells to escape the bloodstream and invade surrounding tissues.

6. **Therapeutic Intervention:** Treatment with ZCL278, a specific inhibitor of Cdc42, effectively inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells. It also suppressed adherence and extravasation in the lung alveoli, leading to the inhibition of lung metastasis in mice.

### **Conclusion and Implications:**

The study's findings shed light on the mechanisms underlying ARHGEF37-mediated extravasation and pulmonary metastasis of HCC cells. By elucidating the interaction between ARHGEF37 and Cdc42 and their role in invadopodia formation, the research provides valuable insights into the metastatic process of HCC. Importantly, the study identifies Cdc42 as a potential therapeutic target.

### **Clinical Implications:**

1. **Prognostic Marker:** ARHGEF37 expression could serve as a prognostic marker for HCC patients, helping clinicians assess the likelihood of metastasis and disease progression.

2. **Therapeutic Target:** Targeting the ARHGEF37/Cdc42 pathway, particularly with inhibitors like ZCL278, holds promise as a therapeutic strategy to prevent and treat HCC pulmonary metastasis.

3. **Further Research:** Continued research into the ARHGEF37/Cdc42 pathway and its interactions could lead to the development of more targeted and effective therapies for HCC patients, potentially improving their outcomes and quality of life.

In summary, this study not only advances our understanding of the molecular mechanisms involved in HCC metastasis but also provides a foundation for future therapeutic interventions in the prevention and treatment of HCC pulmonary metastasis.