In vivo restoration of RhoB expression leads to ovarian tumor regression

Couderc, Bettina; Pradines, Anne; Rafii, Arash; Golzio, Muriel; Deviers, A.; Allal, Ben; Berg, D; Pénary, Marie; Teissié, Justin; Favre, Gilles

doi:10.1038/cgt.2008.12

Cited by 49 publications

(36 citation statements)

References 29 publications

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“…We also observed that loss of RhoB was correlated with a more aggressive pattern of these tumors with a greater Ki67 index, which is fully consistent with our previous observations in human invasive carcinomas (6), and with susceptibility to carcinogens in KO mice (14). RhoB loss has already been shown to be associated with the development of lung tumors in nude mice (18) or intraperitoneal tumors in syngeneic mice (14), whereas the in vivo restoration of RhoB expression leads to ovarian tumor regression (17). Although classical tumor-suppressor genes generally require mutation or loss of both alleles to facilitate tumor progression, we showed here that rhob heterozygosity is sufficient to increase lung tumorigenicity in an EGFR-mutated context.…”

Section: Discussionsupporting

confidence: 79%

“…RhoB belongs to the Rho-GTPase family involved in many cell functions, such as survival, migration, and angiogenesis and is implicated in tumorigenesis and metastasis (8)(9)(10) RhoB is likely acting as a tumor suppressor (8) demonstrated by four lines of evidence: ectopic expression of RhoB in cancer cell lines suppresses tumorigenesis (6,(11)(12)(13), Rhob null mice show higher frequency of tumor formation (14), RhoB expression is frequently down regulated in cancer tumors (6,7,15,16), and in vivo restoration of RhoB expression leads to tumor regression (17). Interestingly, we reported that RhoB protein expression decreases as lung cancer progress (6) and that RhoB loss relates to the acquisition of invasiveness mediated by the PI3K/AKT pathway (18), positioning RhoB as a candidate gene for lung tumor progression.…”

Section: Introductionmentioning

confidence: 99%

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RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer

Calvayrac

Pradines

Raymond‐Letron

et al. 2014

Clinical Cancer Research

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Purpose: A crucial event in lung adenocarcinoma progression is the switch from an aerogenous spread toward an infiltrating tumor. Loss of RhoB expression has been suggested to be critical for lung cancer invasion. Here, we tested RhoB expression as a prognostic biomarker in non-small cell lung cancer (NSCLC) with a special focus on lepidic pattern.Experimental Design: We analyzed RhoB expression using both IHC and RT-qPCR in two series of operated patients (n ¼ 100 and 48, respectively) and in a series of advanced lepidic adenocarcinoma (n ¼ 31) from different hospitals. Next, we examined the role of RhoB in lung cancer progression in transgenic mice that express inducible EGFR L858R crossed with Rhob null mice.Results: We identified that loss of RhoB expression was strongly associated with worse survival (P ¼ 0.0001) and progression-free survival (P < 0.001) in the first series. We then confirmed these results after multivariate analyses of the second series. In the series of adenocarcinoma with lepidic features issued from a clinical trial (IFCT-0401), we showed that loss of RhoB expression was associated with higher aggressiveness of stage IV. Finally, we showed that EGFR L858R /Rhob þ/þ mice developed mainly diffuse lung tumors with a lepidic pattern, whereas EGFR L858R /Rhob þ/À and EGFR L858R /Rhob À/À developed a greater number of tumors, and aggressive adenocarcinomas with invasive properties. Conclusions:We showed that RhoB is not only a strong prognostic factor in NSCLC but it is also critical for the acquisition of an aggressive phenotype of adenocarcinoma.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer

Calvayrac

Pradines

Raymond‐Letron

et al. 2014

Clinical Cancer Research

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“…In contrast to RhoA and RhoC that are frequently overexpressed in various human tumours, RhoB levels decrease in various types of cancer including lung cancer, gastric cancer, ovary carcinoma and head and neck cancer [31][32][33][34][35] , suggesting that RhoB suppresses tumorigenesis. Consistently, overexpression of RhoB potently inhibits tumour growth in nude mice [36][37][38] , whereas RhoB knockout in mice leads to increased susceptibility to chemical-induced skin carcinogenesis 39 . Mechanistic studies show that lack of RhoB significantly attenuates DNA damage-induced apoptosis of transformed cells 40 , and RhoB overexpression induces apoptosis in diverse cancer cell lines [41][42][43][44][45][46] , indicating that RhoB may exerts its tumour suppressor role through promoting cell apoptosis.…”

mentioning

confidence: 82%

ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance

Wang

Guo

et al. 2014

Nat Commun

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ATM-and RAD3-related (ATR)/Chk1 and ataxia-telangiectasia mutated (ATM)/Chk2 signalling pathways play critical roles in the DNA damage response. Here we report that the E3 ubiquitin ligase Smurf1 determines cell apoptosis rates downstream of DNA damageinduced ATR/Chk1 signalling by promoting degradation of RhoB, a small GTPase recognized as tumour suppressor by promoting death of transformed cells. We show that Smurf1 targets RhoB for degradation to control its abundance in the basal state. DNA damage caused by ultraviolet light or the alkylating agent methyl methanesulphonate strongly activates Chk1, leading to phosphorylation of Smurf1 that enhances its self-degradation, hence resulting in a RhoB accumulation to promote apoptosis. Suppressing RhoB levels by overexpressing Smurf1 or blocking Chk1-dependent Smurf1 self-degradation significantly inhibits apoptosis. Hence, our study unravels a novel ATR/Chk1/Smurf1/RhoB pathway that determines cell fate after DNA damage, and raises the possibility that aberrant upregulation of Smurf1 promotes tumorigenesis by excessively targeting RhoB for degradation.

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“…Adenoviral constructs and transduction protocol. Replicationdefective (DE1, E3) adenoviral (Ad) vectors expressing RhoB under the transcriptional control of the cytomegalovirus promoter were constructed with the AdEasy System (MP Biomedical), as described previously (16). For rescue experiments, 140 Â 10 3 cells were plated on a 35-mm dish 24 h before transduction with adenoviral vectors at a multiplicity of infection (MOI) of 5:1 for BEAS-2B cells and HBE-135 and 30:1 for K-RasV12-transformed BEAS-2B cells.…”

Section: Methodsmentioning

confidence: 99%

Loss of RhoB Expression Promotes Migration and Invasion of Human Bronchial Cells Via Activation of AKT1

et al. 2009

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Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to KRasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation. [Cancer Res 2009;69(15):6092-9]

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In vivo restoration of RhoB expression leads to ovarian tumor regression

Cited by 49 publications

References 29 publications

RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer

RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer

ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance

Loss of RhoB Expression Promotes Migration and Invasion of Human Bronchial Cells Via Activation of AKT1

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