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.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Lung Neoplasms , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement , Endothelial Cells/metabolism , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/pathology , Lung Neoplasms/pathology , Mice , Neoplasm Metastasis/pathologyABSTRACT
OBJECTIVE: We conducted a meta-analysis to systematic assess the diagnostic value of computed tomography (CT)-based pulmonary artery to aorta (PA:A) ratio measurement in COPD with pulmonary hypertension (COPD-PH). METHODS: Published studies referring to diagnostic accuracy of PA:A ratio for COPD-PH were screened out from PubMed, Embase, Web of science, China National Knowledge databases (CNKI), Wan fang databases, and VIP databases. We used bivariate random-effects model to estimate pooled sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR, respectively), and diagnostic odds ratios (DOR). Summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were also calculated to summarize the aggregate diagnostic performance. RESULTS: Nine eligible studies were included and the pooled SEN was 69% (95% CI: 59 ~ 78), SPE was 85% (95% CI: 77 ~ 90), PLR was 4.5 (95% CI: 2.8 ~ 7.5), and NLR was 0.36 (95% CI: 0.26 ~ 0.51), respectively. DOR reached 13.00 (95% CI: 6.00 ~ 28.00), and value of AUC was 0.84 (95% CI: 0.81 ~ 0.87). Subgroup analysis indicated that when the value of PA:A ratio was equal or greater than one (PA/A ≥ 1), the combined SEN, SPE, AUC, and DOR was 69%, 89%, 0.90, and 19.65, respectively. CONCLUSIONS: PA:A ratio is helpful for appraisal of COPD-PH, and PA/A ≥ 1 possessed prominent diagnostic accuracy.
