Loss of RhoB Expression in Human Lung Cancer Progression

Abstract

Purpose: RhoB is a low molecular weight GTPase belonging to the Ras protein superfamily. Whereas most Rho proteins have been shown to have a positive role in proliferation and malignant transformation, the specific role of RhoB appears more divergent. We reported previously that RhoB inhibits cell proliferation in various human cancer cells. Here, we studied the specific role played by RhoB in human lung cancer.Experimental Design: We analyzed the expression of RhoB protein by immunostaining in human lung tissues ranging from normal to invasive carcinoma from different histological types in two large independent studies of, respectively, 94 and 45 samples. We then studied the cellular effect of RhoB overexpression in a model of lung cancer (A549, adenocarcinoma) and tumorigenicity in nude mice.Results: We showed in both studies that RhoB protein was expressed in normal lung and decreased dramatically through lung cancer progression (P < 0.01). Interestingly, RhoB expression was lost in 96% of invasive tumors and reduced by 86% in poorly differentiated tumors compared with the nonneoplastic epithelium. Moreover, the loss of expression of RhoB correlated significantly with tumor stage and proliferative index, whereas no correlation was found between RhoB and p53 or Bcl-2 expression. We then showed that ectopic expression of RhoB in lung cancer cell line A549 suppressed cell proliferation, anchorage-independent growth, and xenograft tumor growth in nude mice.Conclusions: RhoB loss of expression occurs very frequently in lung carcinogenesis, reinforcing its putative tumor suppressive activity, and raising the value of its potential use in cancer therapy.

Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter

“…Fourth, we have shown that RhoB overexpression inhibits oncogenic signaling and cell proliferation in cultured human cancer cell lines and tumor growth in nude mice as well as induces apoptosis . Furthermore, we and others have recently shown that RhoB expression is suppressed during tumor progression in human head and neck, lung and brain cancer patients (Adnane et al, 2002;Mazieres et al, 2004). Finally, RhoB expression was found to be very low in 130 human cancer cell lines (Wang et al, 2003), giving further support to RhoB tumor suppressive activity.…”

In vivo restoration of RhoB expression leads to ovarian tumor regression

“…Several studies have already shown that RhoB has a pivotal role in the apoptotic response of neoplastic cells to DNA damage. 7,10,12 However, to our knowledge this study represents the first demonstration that the overexpression RhoB expression leads to in vivo tumor regression B Couderc et al of RhoB on its own using viral adenoviral transduction could induce apoptosis of cultured tumor cells.…”

“…14,29 Numerous studies have indicated a repression of GTPase RhoB in a significant number of cancers including ovarian cancer. 7,14,16 Moreover, the ability of RhoB to inhibit the tumoral growth of many cancer cell lines both in vitro and in vivo 6,7 suggests that RhoB may play a tumor suppressor role. 5 Here, we examined whether in vivo restoration of RhoB expression in RhoB downregulated ovarian cancer cells would reverse malignancy.…”

“…Ectopic expression of RhoB inhibits tumor growth in vitro and in vivo and metastasis, and also inhibits oncogenic signaling. [5][6][7][8] Moreover, rhoBÀ/À transformed cells are very aggressive and RhoB knockout mice show increased sensitivity to chemically induced tumors. 9 Ectopic expression of RhoB induces apoptosis in some cell models, 8,10,11 whereas rhoBÀ/À cells show resistance to apoptosis induced by radiation and cytotoxic agents.…”

“…9,13 Moreover, RhoB expression is dramatically decreased in numerous cell lines, including ovarian, lung or breast cancer, 14,15 as well as in brain, head and neck cancer where the tumors become more aggressive and highly invasive. 7,16,17 These studies suggest that RhoB could play a critical role in suppressing malignant transformation by blocking oncogenic and tumor survival pathways. These observations prompted us to investigate the potential use of gene modification of tumor cells by RhoB, as has been suggested with other tumor suppressor genes, such as p53, Rb or WWOX.…”