Abstract
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. 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. 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. 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.
Highlights
Lung cancer is the leading cause of cancer-related deaths in the world [1]
We studied the cellular effect of RhoB overexpression in a model of lung cancer (A549, adenocarcinoma) and tumorigenicity in nude mice
We showed in both studies that RhoB protein was expressed in normal lung and decreased dramatically through lung cancer progression (P < 0.01)
Summary
Lung cancer is the leading cause of cancer-related deaths in the world [1]. Despite advances in surgery, chemotherapy, and radiation therapy, survival rates have changed little in the last decade, and long-term survival remains dramatically poor. It has been established that lung cancer arises as a consequence of the accumulation of multiple somatic genetic changes involving critical genes of which the protein products control cell motility, proliferation, differentiation, and apoptosis [2]. Ras proteins regulate important cellular functions ranging from cell differentiation to cell proliferation. They function as molecular switches, cycling between the inactive GDP- and the active GTP-bound states [4]. Related family members of Ras, such as Ras-homologous (Rho) small guanosine triphosphatases (GTPases) are involved in the regulation of a variety of cellular processes such as organization of the actin cytoskeleton [6], genotoxic stress-induced signaling [7], and malignant transformation [8]. Analyses in human tumors demonstrate overexpression of several Rho proteins in breast cancers [12], of RhoA in testicular germ cell tumors [13], and of RhoC in pancreatic adenocarcinoma [14], in melanoma [15], and in breast cancer [16]
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