RhoC (Ras homolog gene family, member C) is a small (~21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases.[5] It is encoded by the gene RHOC.[6]
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It is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. It cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades.
Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskeleton.[7][8][9]
Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant.[10] It causes degradation and reconstruction of the Extracellular Matrix (ECM) which helps cells escape the tissue they are currently in. It enhances cell motility giving it the ability to become invasive.[11] It has been found to have a direct relationship to advanced tumor stage and metastasis, with increases in stage being related to increases in RhoC expression.[12] RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.[13]
It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant.[12][14]
In a study by Vega,[15] RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC was disabled, the cell's abilities to move in a specific direction and migrate was impaired. It also reduced the cell's speed of movement, because it was difficult, and sometimes impossible, to polarize the cell.
RhoC expression has been associated with several signaling pathways and effectors. Here is a list of the ones found so far:
- IQGAP1 (IQ-domain GTP-ase Activating Protein): an effector of RhoC to enhance expression of cyclin E and cyclin D1. This resulted in cells being promoted to enter S phase more rapidly [16]
- ROCK-1 [12][17]
- MMP9: necessary for ECM regulation[12]
- FMNL3: a Formin downstream target, which is used to regulate where Rac1 is active [15]
- MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression [14][18]
- Notch1 [14]
- PI3K/AKt pathway: Proliferation and invasiveness [14][19]
- Pyk2: metastasis [14][20]
RhoC has been found to be overexpressed in:
- Lung Cancer [11]
- Gastric Cancer [16]
- Ovarian cancer [12]
- Breast Cancer [18][21]
- Hepatocellular Cancer [22]
- Pancreatic Cancer [12]
- Colorectal Cancer [23]
- Cancer of the Urogenital System [12]
- Melanoma [12]
- Prostate Cancer [20]
- Cervical Carcinoma [14]
RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers [16][23]
RhoC can be used as a biomarker for judging the metastatic potential of tumors[21][24]
One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC [23]
It has been found that RhoC expression is not important for embryogenesis but it is only important for metastasis, which would make it a good target for treatments.[14]
A RhoC targeted therapy (RV001 by RhoVac) is currently tested in prostate cancer in an ongoing clinical phase 2b program in the US and Europe. Results are expected mid 2022 (Reference: https://clinicaltrials.gov/ct2/show/NCT04114825)
Zhao Y, Zhi-hong Z, Hui-mian X (2010). "RhoC Expression Level Is Correlated with the Clinicopathological Characteristics of Ovarian Cancer and the Expression Levels of ROCK-I, VEGF, and MMP9". Gynecologic Oncology. 116 (3): 563–71. doi:10.1016/j.ygyno.2009.11.015. PMID 20022093.
Genda T, Sakamoto M, Ichida T, Asakura H, Kojiro M, Narumiya S, Hirohashi S (1999). "Cell Motility Mediated by Rho and Rho-Associated Protein Kinase Plays a Critical Role in Intrahepatic Metastasis of Human Hepatocellular Carcinoma". Hepatology. 30 (4): 1027–36. doi:10.1002/hep.510300420. PMID 10498656. S2CID 35864555.
Van Golen KL, Bao LW, Pan Q, Miller FR, Wu ZF, Merajver SD (2002). "Mitogen Activated Protein Kinase Pathway Is Involved in RhoC GTPase Induced Motility, Invasion and Angiogenesis in Inflammatory Breast Cancer". Clinical & Experimental Metastasis. 19 (4): 301–11. doi:10.1023/A:1015518114931. hdl:2027.42/42584. PMID 12090470. S2CID 211284.
- Adamson P, Paterson HF, Hall A (1992). "Intracellular localization of the P21rho proteins". J. Cell Biol. 119 (3): 617–27. doi:10.1083/jcb.119.3.617. PMC 2289677. PMID 1383236.
- Arthur WT, Ellerbroek SM, Der CJ, et al. (2003). "XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC". J. Biol. Chem. 277 (45): 42964–72. doi:10.1074/jbc.M207401200. PMID 12221096.
- Chardin P, Madaule P, Tavitian A (1988). "Coding sequence of human rho cDNAs clone 6 and clone 9". Nucleic Acids Res. 16 (6): 2717. doi:10.1093/nar/16.6.2717. PMC 336400. PMID 3283705.
- Clark EA, Golub TR, Lander ES, Hynes RO (2000). "Genomic analysis of metastasis reveals an essential role for RhoC". Nature. 406 (6795): 532–5. doi:10.1038/35020106. PMID 10952316. S2CID 4301092.
- Diviani D, Soderling J, Scott JD (2001). "AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation". J. Biol. Chem. 276 (47): 44247–57. doi:10.1074/jbc.M106629200. PMID 11546812.
- Kleer CG, van Golen KL, Zhang Y, et al. (2002). "Characterization of RhoC expression in benign and malignant breast disease: a potential new marker for small breast carcinomas with metastatic ability". Am. J. Pathol. 160 (2): 579–84. doi:10.1016/S0002-9440(10)64877-8. PMC 1850656. PMID 11839578.
- Madaule P, Axel R (1985). "A novel ras-related gene family". Cell. 41 (1): 31–40. doi:10.1016/0092-8674(85)90058-3. PMID 3888408. S2CID 32708060.
- Maekawa M, Ishizaki T, Boku S, et al. (1999). "Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase". Science. 285 (5429): 895–8. doi:10.1126/science.285.5429.895. PMID 10436159.
- Reid T, Furuyashiki T, Ishizaki T, et al. (1996). "Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain". J. Biol. Chem. 271 (23): 13556–60. doi:10.1074/jbc.271.23.13556. PMID 8662891.
- Shao F, Dixon JE (2004). "YopT is a Cysteine Protease Cleaving Rho Family GTPases". The Genus Yersinia. Advances in Experimental Medicine and Biology. Vol. 529. pp. 79–84. doi:10.1007/0-306-48416-1_14. ISBN 0-306-47759-9. PMID 12756732.
- van Golen KL, Bao LW, Pan Q, et al. (2002). "Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer" (PDF). Clin. Exp. Metastasis. 19 (4): 301–11. doi:10.1023/A:1015518114931. hdl:2027.42/42584. PMID 12090470. S2CID 211284.
- Wheeler AP, Ridley AJ (2004). "Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility". Exp. Cell Res. 301 (1): 43–9. doi:10.1016/j.yexcr.2004.08.012. PMID 15501444.