What is the relationship between epidermal growth factor–like domain 7 and RhoC in metastasis of hepatocellular carcinoma?


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What is the Relationship Between Epidermal Growth Factor–Like Domain 7 and RhoC in Metastasis of Hepatocellular Carcinoma?

To the Editor:

We read with great interest the article written by Yang et al.1 in which they showed for the first time that epidermal growth factor-like domain 7 (Egfl7) promotes metastasis of hepatocellular carcinoma (HCC) by enhancing cell motility through epidermal growth factor receptor (EGFR)-dependent focal adhesion kinase (FAK) phosphorylation. They suggested Egfl7 as a novel prognostic marker for metastasis of HCC and a potential therapeutic target. Very interestingly, the same group demonstrated in previous work that RhoC also plays a critical role in metastasis of HCC,2, 3 which is consistent with our result of RhoC in gastric cancer.4 So what is the relationship between Egfl7 and RhoC in metastasis of HCC?

Yang et al. showed in figures 4C and 5B that recombinant Egfl7 protein stimulated the reorganization of actin, leading to the formation of stress-fiber–like structures in HCCLM3Egfl7RNAi+ cells and EGFR inhibitor could inhibit this effect. It is known that RhoC protein plays an important role in controlling stress fiber and focal adhesion contact formation.4 In another article from the same group, Yang et al. also observed that inhibition of RhoC in HCCLM3 (hepatocellular carcinoma lung metastasis 3rd selection) cells blocked autotoxin-induced stress fiber formation.2 So, is RhoC involved in the cytoskeletal change induced by Egfl7 protein? The authors interpreted this change due to FAK phosphorylation stimulated by Egfl7 protein, but we found some reports demonstrating that RhoC can activate FAK.5, 6 One group indicated that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2 (Proline-rich tyrosine kinase 2), FAK, MAPK (mitogen-activated protein kinase), and Akt followed by the up-regulation of matrix metalloproteinase 2(MMP2) and MMP9, which results in the stimulation of invasiveness of tumor cells.5 So, can we hypothesize that Egfl7 activates FAK through RhoC protein in HCC cells?

We also noticed one article from the same group showing that overexpression of RhoC in HCC tissues was highly correlated with tumor invasion and poor prognosis,3 which is similar with the results of Egfl7.4 The HCC specimens used in the article regarding Egfl7 were from 112 patients with HCC in Xiangya Hospital of Central South University between 1998 and 2005,1 and specimens used in the RhoC article were collected from the same hospital between 1994 and 2002,3 so the period from 1998 to 2002 was overlapped. If the expression pattern of RhoC in these specimens is strongly correlated with that of Egfl7, it will further confirm our hypothesis.

Na Liu*, Hongbo Zhang*, Kaichun Wu*, Daiming Fan*, * State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.