Downregulation of JWA promotes tumor invasion and predicts poor prognosis in human hepatocellular carcinoma

Abstract

We previously identified JWA as a novel microtubule-associated protein (MAP), which is implicated in carcinogenesis and tumor progression. The aims of the present study were to investigate the biological action and the prognostic significance of JWA in hepatocellular carcinoma (HCC). Quantitative real-time PCR and Western blot were used to detect JWA mRNA and protein expression, respectively, in stepwise metastatic HCC cell lines and HCC tissues. Short hairpin RNA was used to inhibit JWA expression in HCC cells. The effects of JWA depletion on cell migration, invasion, adhesion and in vivo metastasis were investigated. Immunohistochemistry of JWA was conducted in microarrays with tissue from 314 HCC patients who had undergone surgical resection. Prognostic significance was assessed using the Kaplan-Meier method and log-rank tests. The result showed JWA expression was decreased in the highly metastatic HCC cell lines and HCC tissues. Depletion of JWA caused a notable increase in cell migration, invasion and adhesion in vitro and metastasis in vivo. Furthermore, there was an inverse correlation between JWA expression and FAK expression and phosphorylation, RhoA activation and matrix metalloproteinase-2 (MMP-2) activity in HCC cells. More notably, multivariate analysis revealed that a low level of JWA expression was an independent prognosticator for both recurrence-free and overall survival for HCC patients after surgical resection, especially for AFP-normal HCC patients. Taken together, our data demonstrate that JWA plays a crucial role in HCC progression and suggest JWA may be a potential prognostic biomarker and therapeutic target for HCC.

Loss of ARHGDIA expression is associated with poor prognosis in HCC and promotes invasion and metastasis of HCC cells

“…Numerous studies indicate that deregulated signaling of Rho GTPases plays an important role in HCC progression and metastasis (9). RhoA pathway associates with venous invasion, cell differentiation and poor prognosis (22), correlating with tumor progression and metastasis (23)(24)(25). Rac1 GTPase is crucial for actin cytoskeleton reorganization at the cell cortex and is involved in processes of HCC migration and invasion (26)(27)(28)(29).…”

JWA deficiency induces malignant transformation of murine embryonic fibroblast cells

“…Additionally, JWA protein expression levels are closely correlated with the occurrence, invasion and metastasis of malignant tumors (15). Using liver cells with different metastatic potential, a previous study revealed that reduced expression levels of JWA protein resulted in increased metastasis potential (6). Previous results have indicated that downregulation of JWA expression may affect cell function, such as proliferation, apoptosis, migration and invasion via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway of mitogen-activated protein kinase signaling cascades (16).…”

“…MEF cells (1x10 6 ) were seeded in a 100 mm culture dish. NU1025 (Sigma-Aldrich; Merck KGaA Darmstadt, Germany), a specific inhibitor of PARP-1, was used to inhibit the function of PARP-1 in MEF cells.…”

“…It has been reported that JWA is essential for promoting cell survival and protection from DNA damage induced by oxidative stress, which may result in cancer cell apoptosis by chemical methods (2,3). Previous studies have associated the JWA gene with reduced cancer risk in various types of cancer, including gastric cancer (4), bladder cancer (5) and hepatocellular carcinoma (6). In addition, previous results have demonstrated the important role of JWA downregulation in promoting cell invasion using Matrigel-coated chambers and accelerating melanoma cell migration and adhesion (7).…”

<b>O C-terminal da proteína S100A9 murina modula os eventos envolvidos na angiogênese e na progressão tumoral em modelos <i>in vitro</i></b>

“…Para este ensaio foi utilizado o Matrigel, uma membrana basal reconstituída, que pode propiciar condições similares ao observado em microambiente tumoral, uma vez que é proveniente do sarcoma de murinos. Em adição, esta matriz permite rápida formação das estruturas tubulares em sistema 3D, as quais são facilmente quantificáveis (ARNAOUTOVA et al, 2009;BAZZA et al, 2010 , 1996), principal ligante das células tumorais mamárias a estes componentes, bem como a expressão de α 3 β 1 , principal integrina ligante de laminina (CHEN et al, 2014), poderiam contribuir para a compreensão da seletividade da ação inibitória do pS100A9m sobre a célula tumoral.…”