Loss of RhoB expression in human lung cancer progression.
OBJECTIVE
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.


METHODS
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.
Mazieres
Julien
J
Institut National de la Santé et de la Recherche Médicale U563, Department of Therapeutic Innovation and Molecular Oncology. Claudius Regaud Institute, Toulouse, France.
Antonia
Teresita
T
Daste
Ghislaine
G
Muro-Cacho
Carlos
C
Berchery
Delphine
D
Tillement
Vanessa
V
Pradines
Anne
A
Sebti
Said
S
Favre
Gilles
G
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D020743:rhoB GTP-Binding Protein / Q000096:biosynthesis*
D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D020743:rhoB GTP-Binding Protein