[en] RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor alpha (RhoGDIalpha) and the overexpression of a RhoA mutant unable to bind RhoGDIalpha suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIalpha. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Ho, Thi Thanh Giang ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Stultiens, Audrey; Université de Liège - ULiège > Dpt des sciences biomédicales et Précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Dubail, Johanne ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Lapiere, Charles M; Université de Liège - ULiège
Nusgens, Betty ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Deroanne, Christophe ; Université de Liège - ULiège > Dept des Sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Language :
English
Title :
RhoGDI alpha-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis
Publication date :
2011
Journal title :
Molecular Biology of the Cell
ISSN :
1059-1524
eISSN :
1939-4586
Publisher :
American Society for Cell Biology, Bethesda, United States - Maryland
Bauskin, A.R., Brown, D.A., Kuffner, T., Johnen, H., Lou, X.W., Hunter, M., Breit, S.N., Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer (2006) Cancer Research, 66 (10), pp. 4983-4986. , DOI 10.1158/0008-5472.CAN-05-4067
Bellovin, D.I., Simpson, K.J., Danilov, T., Maynard, E., Rimm, D.L., Oettgen, P., Mercurio, A.M., Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma (2006) Oncogene, 25 (52), pp. 6959-6967. , DOI 10.1038/sj.onc.1209682, PII 1209682
Berenjeno, I.M., Nunez, F., Bustelo, X.R., Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases (2007) Oncogene, 26 (29), pp. 4295-4305. , DOI 10.1038/sj.onc.1210194, PII 1210194
Bielek, H., Anselmo, A., Dermardirossian, C., Morphological and proliferative abnormalities in renal mesangial cells lacking RhoGDI (2009) Cell Signal, 21, pp. 1974-1983
Boulter, E., Garcia-Mata, R., Guilluy, C., Dubash, A., Rossi, G., Brennwald, P.J., Burridge, K., Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1 (2010) Nat Cell Biol, 12, pp. 477-483
Carracedo, A., The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells (2006) Cancer Cell, 9, pp. 301-312
Chen, N., Ye, X.-C., Chu, K., Navone, N.M., Sage, E.H., Yu-Lee, L.-Y., Logothetis, C.J., Lin, S.-H., A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells (2007) Cancer Research, 67 (14), pp. 6544-6548. , http://cancerres.aacrjournals.org/cgi/reprint/67/14/6544, DOI 10.1158/0008-5472.CAN-07-1330
Chiba, Y., Tanabe, M., Goto, K., Sakai, H., Misawa, M., Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells (2009) Am J Respir Crit Care Med, 180, pp. 713-719
Clark, D.W., Mitra, A., Fillmore, R.A., Jiang, W.G., Samant, R.S., Fodstad, O., Shevde, L.A., NUPR1 interacts with p53, transcriptionally regulates p21 and rescues breast epithelial cells from doxorubicin-induced genotoxic stress (2008) Curr Cancer Drug Targets, 8, pp. 421-430
Clark, E.A., Golub, T.R., Lander, E.S., Hynes, R.O., Genomic analysis of metastasis reveals an essential role for RhoC (2000) Nature, 406 (6795), pp. 532-535. , DOI 10.1038/35020106
Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H., Crespo, P., Xu, N., Miki, T., Gutkind, J.S., The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway (1995) Cell, 81, pp. 1137-1146
DerMardirossian, C., Rocklin, G., Seo, J.-Y., Bokoch, G.M., Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling (2006) Molecular Biology of the Cell, 17 (11), pp. 4760-4768. , DOI 10.1091/mbc.E06-06-0533
Deroanne, C., Vouret-Craviari, V., Wang, B., Pouyssegur, J., EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway (2003) Journal of Cell Science, 116 (7), pp. 1367-1376. , DOI 10.1242/jcs.00308
Deroanne, C.F., Hamelryckx, D., Ho, T.T.G., Lambert, C.A., Catroux, P., Lapiere, C.M., Nusgens, B.V., Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway (2005) Journal of Cell Science, 118 (6), pp. 1173-1183. , DOI 10.1242/jcs.01707
Dovas, A., Choi, Y., Yoneda, A., Multhaupt, H.A., Kwon, S.H., Kang, D., Oh, E.S., Couchman, J.R., Serine34 phosphorylation of RHO guanine dissociation inhibitor (RHOGDIalpha) links signaling from conventional protein kinase C to RHO GTPase in cell adhesion (2010) J Biol Chem, 285, pp. 23296-23308
Fei, F., Kweon, S.M., Haataja, L., De Sepulveda, P., Groffen, J., Heisterkamp, N., The Fer tyrosine kinase regulates interactions of Rho GDP-dissociation inhibitor alpha with the small GTPase Rac (2010) BMC Biochem, 11, p. 48
Hill, C.S., Wynne, J., Treisman, R., The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF (1995) Cell, 81, pp. 1159-1170
Ho, T.T., Merajver, S.D., Lapiere, C.M., Nusgens, B.V., Deroanne, C.F., RhoA-GDP regulates RhoB protein stability. Potential involvement of RhoGDIalpha (2008) J Biol Chem, 283, pp. 21588-21598
Hooi, C.F., ST7-mediated suppression of tumorigenicity of prostate cancer cells is characterized by remodeling of the extracellular matrix (2006) Oncogene, 25, pp. 3924-3933
Huelsenbeck, J., Dreger, S.C., Gerhard, R., Fritz, G., Just, I., Genth, H., Upregulation of the immediate early gene product RhoB by exoenzyme C3 from Clostridium limosum and toxin B from Clostridium difficile (2007) Biochemistry, 46 (16), pp. 4923-4931. , DOI 10.1021/bi602465z
Iiizumi, M., RhoC promotes metastasis via activation of the Pyk2 pathway in prostate cancer (2008) Cancer Res, 68, pp. 7613-7620
Jaffe, A.B., Hall, A., Rho GTPases:Biochemistry and biology (2005) Annu Rev Cell Dev Biol, 21, pp. 247-269
Jiang, H.-Y., Wek, S.A., McGrath, B.C., Lu, D., Hai, T., Harding, H.P., Wang, X., Wek, R.C., Activating Transcription Factor 3 Is Integral to the Eukaryotic Initiation Factor 2 Kinase Stress Response (2004) Molecular and Cellular Biology, 24 (3), pp. 1365-1377. , DOI 10.1128/MCB.24.3.1365-1377.2004
Jiang, L., Liu, X., Kolokythas, A., Yu, J., Wang, A., Heidbreder, C.E., Shi, F., Zhou, X., Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma (2010) Int J Cancer, 127, pp. 505-512
Kim, J.-S., Baek, S.J., Sali, T., Eling, T.E., The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15 (2005) Molecular Cancer Therapeutics, 4 (3), pp. 487-493
Kleer, C.G., Van Golen, K.L., Zhang, Y., Wu, Z.-F., Rubin, M.A., Merajver, S.D., Characterization of RhoC expression in benign and malignant breast disease: A potential new marker for small breast carcinomas with metastatic ability (2002) American Journal of Pathology, 160 (2), pp. 579-584
Kong, W., Yang, H., He, L., Zhao, J.J., Coppola, D., Dalton, W.S., Cheng, J.Q., MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA (2008) Mol Cell Biol, 28, pp. 6773-6784
Kostenko, E.V., Olabisi, O.O., Sahay, S., Rodriguez, P.L., Whitehead, I.P., Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs (2006) Molecular and Cellular Biology, 26 (23), pp. 8964-8975. , DOI 10.1128/MCB.00670-06
Laboisse, C.L., Augeron, C., Potet, F., Growth and differentiation of human gastrointestinal adenocarcinoma stem cells in soft agarose (1981) Cancer Research, 41 (1), pp. 310-315
Liu, A., Cerniglia, G.J., Bernhard, E.J., Prendergast, G.C., RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage (2001) Proc Natl Acad Sci USA, 98, pp. 6192-6197
Ma, L., Teruya-Feldstein, J., Weinberg, R.A., Tumour invasion and metastasis initiated by microRNA-10b in breast cancer (2007) Nature, 449 (7163), pp. 682-688. , DOI 10.1038/nature06174, PII NATURE06174
Marinissen, M.J., Chiariello, M., Tanos, T., Bernard, O., Narumiya, S., Gutkind, J.S., The small GTP-binding protein RhoA regulates c-jun by a ROCK-JNK signaling axis (2004) Molecular Cell, 14 (1), pp. 29-41. , DOI 10.1016/S1097-2765(04)00153-4, PII S1097276504001534
Mazieres, J., Antonia, T., Daste, G., Muro-Cacho, C., Berchery, D., Tillement, V., Pradines, A., Favre, G., Loss of RhoB Expression in Human Lung Cancer Progression (2004) Clinical Cancer Research, 10 (8), pp. 2742-2750. , DOI 10.1158/1078-0432.CCR-03-0149
Mazieres, J., Tillement, V., Allal, C., Clanet, C., Bobin, L., Chen, Z., Sebti, S.M., Pradines, A., Geranylgeranylated, but not farnesylated, RhoB suppresses Ras transformation of NIH-3T3 cells (2005) Experimental Cell Research, 304 (2), pp. 354-364. , DOI 10.1016/j.yexcr.2004.10.019
Michaelson, D., Silletti, J., Murphy, G., D'Eustachio, P., Rush, M., Philips, M.R., Differential localization of Rho GTPases in live cells: Regulation by hypervariable regions and RhoGDI binding (2001) Journal of Cell Biology, 152 (1), pp. 111-126. , DOI 10.1083/jcb.152.1.111
Miralles, F., Posern, G., Zaromytidou, A.-I., Treisman, R., Actin dynamics control SRF activity by regulation of its coactivator MAL (2003) Cell, 113 (3), pp. 329-342. , DOI 10.1016/S0092-8674(03)00278-2
Sahai, E., Marshall, C.J., ROCK and Dia have opposing effects on adherens junctions downstream of Rho (2002) Nature Cell Biology, 4 (6), pp. 408-415. , DOI 10.1038/ncb796
Sander, E.E., Ten Klooster, J.P., Van Delft, S., Van Der Kammen, R.A., Collard, J.G., Rac downregulates Rho activity:Reciprocal balance between both GTPases determines cellular morphology and migratory behavior (1999) J Cell Biol, 147, pp. 1009-1022
Shikada, Y., Yoshino, I., Okamoto, T., Fukuyama, S., Kameyama, T., Maehara, Y., Higher Expression of RhoC Is Related to Invasiveness in Non-Small Cell Lung Carcinoma (2003) Clinical Cancer Research, 9 (14), pp. 5282-5286
Shim, M., Eling, T.E., Protein kinase C-dependent regulation of NAG-1/placental bone morphogenic protein/MIC-1 expression in LNCaP prostate carcinoma cells (2005) Journal of Biological Chemistry, 280 (19), pp. 18636-18642. , DOI 10.1074/jbc.M414613200
Simpson, K.J., Dugan, A.S., Mercurio, A.M., Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma (2004) Cancer Research, 64 (23), pp. 8694-8701. , DOI 10.1158/0008-5472.CAN-04-2247
Steffan, J.J., Snider, J.L., Skalli, O., Welbourne, T., Cardelli, J.A., Na/H Exchangers and RhoA regulate acidic extracellular pH-induced lysosome trafficking in prostate cancer cells (2009) Traffic, 10, pp. 737-753
Teramoto, H., Malek, R.L., Behbahani, B., Castellone, M.D., Lee, N.H., Gutkind, J.S., Identification of H-Ras, RhoA, Rac1 and Cdc42 responsive genes (2003) Oncogene, 22 (17), pp. 2689-2697. , DOI 10.1038/sj.onc.1206364
Tillement, V., Lajoie-Mazenc, I., Casanova, A., Froment, C., Penary, M., Tovar, D., Marquez, R., Pradines, A., Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization (2008) Exp Cell Res, 314, pp. 2811-2821
Wang, W., Wu, F., Fang, F., Tao, Y., Yang, L., Inhibition of invasion and metastasis of hepatocellular carcinoma cells via targeting RhoC in vitro and in vivo (2008) Clin Cancer Res, 14, pp. 6804-6812
Wang, W., Yang, L.-Y., Huang, G.-W., Lu, W.-Q., Yang, Z.-L., Yang, J.-Q., Liu, H.-L., Genomic analysis reveals RhoC as a potential marker in hepatocellular carcinoma with poor prognosis (2004) British Journal of Cancer, 90 (12), pp. 2349-2355
Wu, M., Wu, Z.-F., Kumar-Sinha, C., Chinnaiyan, A., Merajver, S.D., RhoC induces differential expression of genes involved in invasion and metastasis in MCF10A breast cells (2004) Breast Cancer Research and Treatment, 84 (1), pp. 3-12. , DOI 10.1023/B:BREA.0000018426.76893.21
Yao, H., Dashner, E.J., Van Golen, C.M., Van Golen, K.L., RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility (2006) Oncogene, 25, pp. 2285-2296
Zu, K., Bihani, T., Lin, A., Park, Y.-M., Mori, K., Ip, C., Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells (2006) Oncogene, 25 (4), pp. 546-554. , DOI 10.1038/sj.onc.1209071, PII 1209071
