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Inhibition of Invasion and Metastasis of Hepatocellular Carcinoma Cells via Targeting RhoC In vitro and In vivo

Authors' Affiliations: ¹ Liver Cancer Laboratory and ² Department of Surgery, Xiangya Hospital, Central South University, Hunan, People's Republic of China

Requests for reprints: Lianyue Yang, Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People's Republic of China. Phone: 86-731-4327326; Fax: 86-731-4327332; E-mail: lianyueyang{at}hotmail.com.

Purpose: Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Our previous work identified a strong correlation between increased expression of RhoC and HCC metastasis. Here, we investigate to define the role of RhoC in HCC metastasis. Furthermore, we sought to determine whether inhibition of the expression of RhoC might block the metastasis of HCC in vivo.

Experimental Design: A stable retroviral small interfering RNA approach was employed to selectively knockdown the expression of RhoC in vitro and in vivo. Invasion and migration assay, MTT and fluorescence-activated cell sorting analysis, Rho activity assay, and immunofluorescence staining were carried out to characterize RhoC in vitro. An anti-RhoC retroviral gene delivery BALB/c nude mice model was established to investigate whether knockdown of the expression of RhoC might inhibit the metastasis of HCC in vivo.

Results: We confirmed the correlation of RhoC expression and metastatic potentials of HCC cell lines. We also showed that suppression of RhoC expression resulted in inhibition of invasion and migration without an apparent effect on cell survival and proliferation in HCCLM3 cells. Furthermore, a similar effect of RhoC on autotaxin-induced invasion of HCCLM3 cells was also observed. Significantly, we successfully adopted an HCC metastatic mouse model that allowed us to show that knockdown of the RhoC expression resulted in inhibition of metastasis of HCC in vivo for the first time.

Conclusions: Our results show a critical role of RhoC in metastasis of HCC, implicating RhoC as a potential therapeutic target to block HCC metastasis.