RhoC explained

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.^[1] It is encoded by the gene RHOC.^[2]

Mechanism and function

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.^{[3] [4] [5]}

Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant.^[6] 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.^[7] 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.^[8] RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis.^[9] It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant.^[10] In a study by Vega,^[11] 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.

Associated Signaling Pathways

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 ^[12]
• ROCK-1 ^[13]
• MMP9: necessary for ECM regulation
• FMNL3: a Formin downstream target, which is used to regulate where Rac1 is active
• MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression ^[14]
• Notch1
• PI3K/AKt pathway: Proliferation and invasiveness ^[15]
• Pyk2: metastasis ^[16]

Types of Cancer RhoC has been studied in

RhoC has been found to be overexpressed in:

• Lung Cancer
• Gastric Cancer
• Ovarian cancer
• Breast Cancer ^[17]
• Hepatocellular Cancer ^[18]
• Pancreatic Cancer
• Colorectal Cancer ^[19]
• Cancer of the Urogenital System
• Melanoma
• Prostate Cancer
• Cervical Carcinoma

Potential Therapies

RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers RhoC can be used as a biomarker for judging the metastatic potential of tumors^[20] One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC 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.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)

Further reading

• Adamson P, Paterson HF, Hall A . Intracellular localization of the P21rho proteins. . J. Cell Biol. . 119 . 3 . 617–27 . 1992 . 1383236 . 10.1083/jcb.119.3.617 . 2289677.
• Arthur WT, Ellerbroek SM, Der CJ, etal . XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. . J. Biol. Chem. . 277 . 45 . 42964–72 . 2003 . 12221096 . 10.1074/jbc.M207401200 . free.
• Chardin P, Madaule P, Tavitian A . Coding sequence of human rho cDNAs clone 6 and clone 9. . Nucleic Acids Res. . 16 . 6 . 2717 . 1988 . 3283705 . 10.1093/nar/16.6.2717 . 336400.
• Clark EA, Golub TR, Lander ES, Hynes RO . Genomic analysis of metastasis reveals an essential role for RhoC. . Nature . 406 . 6795 . 532–5 . 2000 . 10952316 . 10.1038/35020106. 4301092 .
• Diviani D, Soderling J, Scott JD . AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation. . J. Biol. Chem. . 276 . 47 . 44247–57 . 2001 . 11546812 . 10.1074/jbc.M106629200 . free.
• Kleer CG, van Golen KL, Zhang Y, etal . 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 . 2002 . 11839578 . 10.1016/S0002-9440(10)64877-8. 1850656.
• Madaule P, Axel R . A novel ras-related gene family. . Cell . 41 . 1 . 31–40 . 1985 . 3888408 . 10.1016/0092-8674(85)90058-3. 32708060 .
• Maekawa M, Ishizaki T, Boku S, etal . Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. . Science . 285 . 5429 . 895–8 . 1999 . 10436159 . 10.1126/science.285.5429.895.
• Reid T, Furuyashiki T, Ishizaki T, etal . 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 . 1996 . 8662891 . 10.1074/jbc.271.23.13556 . free.
• Book: Shao F, Dixon JE . The Genus Yersinia . YopT is a Cysteine Protease Cleaving Rho Family GTPases . Advances in Experimental Medicine and Biology . 2004 . 529 . 79–84 . 12756732 . 10.1007/0-306-48416-1_14. 0-306-47759-9 .
• van Golen KL, Bao LW, Pan Q, etal . Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. . Clin. Exp. Metastasis . 19 . 4 . 301–11 . 2002 . 12090470 . 10.1023/A:1015518114931 . 2027.42/42584 . 211284 . free .
• Wheeler AP, Ridley AJ . Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. . Exp. Cell Res. . 301 . 1 . 43–9 . 2004 . 15501444 . 10.1016/j.yexcr.2004.08.012.

External links

• 10.1038/mp.a002065.01 . RhoC . 2008 . AfCS-Nature Molecule Pages . Laudanna C. 2024-04-13 .
• Web site: RhoC : Abstract : UCSD-Nature Molecule Pages . 2009-06-16 . 2021-12-04 . https://web.archive.org/web/20211204141528/http://www.signaling-gateway.org/molecule/query?afcsid=A002065 . dead .

Notes and References

1. Ridley A. . 2006 . Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking . Trends Cell Biol . 16 . 10 . 522–9 . 10.1016/j.tcb.2006.08.006 . 16949823.
2. Web site: Entrez Gene: RHOC ras homolog gene family, member C.
3. Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R . Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC . Oncogene . 29 . 16 . 2441–8 . April 2010 . 20101212 . 10.1038/onc.2009.515 . 25556221 .
4. Jaffe AB, Hall A . 2005 . Rho GTPases: Biochemistry and Biology . Annual Review of Cell and Developmental Biology . 21 . 247–69 . 10.1146/annurev.cellbio.21.020604.150721 . 16212495 .
5. Vega FM, Ridley AJ . 2008. Rho GTPases in Cancer Cell Biology . FEBS Letters . 582 . 14. 2093–2101 . 10.1016/j.febslet.2008.04.039 . 18460342. free . 2008FEBSL.582.2093V.
6. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I. Up-Regulation of Small GTPases, RhoA and RhoC, Is Associated with Tumor Progression in Ovarian Carcinoma. Laboratory Investigation. 83. 6. June 2003. 861–870. 10.1097/01.LAB.0000073128.16098.31. 12808121. 22119772. free.
7. Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, Fujiwara T, Fujiwara H, Kosai K. A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice. Clinical Cancer Research. 10. 3. February 2004. 1192–1200. 10.1158/1078-0432.ccr-03-0275 . 14871999. free.
8. 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 . 10.1016/j.ygyno.2009.11.015 . 20022093.
9. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW . RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis . Genes Dev. . 19 . 17 . 1974–9 . September 2005 . 16107613 . 1199568 . 10.1101/gad.1310805 .
10. Srivastava S, Ramdass B, Nagarajan S, Rehman M, Mukherjee G, Krishna S . 2010. Notch1 Regulates the Functional Contribution of RhoC to Cervical Carcinoma Progression . British Journal of Cancer . 102 . 1. 196–205 . 10.1038/sj.bjc.6605451 . 19953094. 2813755. free .
11. Vega FM, Fruhwirth G, Ng T, Ridley AJ . 2011. RhoA and RhoC Have Distinct Roles in Migration and Invasion by Acting through Different Targets . The Journal of Cell Biology . 193 . 4. 655–65 . 10.1083/jcb.201011038 . 21576392. 3166870. free .
12. Wu Y, Tao Y, Chen Y, Xu W . RhoC Regulates the Proliferation of Gastric Cancer Cells through Interaction with IQGAP1 . PLOS ONE . 2012 . 7 . 11. e48917 . 10.1371/journal.pone.0048917 . 23145020 . 3492142 . 2012PLoSO...748917W . free .
13. 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 . 10.1002/hep.510300420 . 10498656. 35864555.
14. 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 . 12090470 . 10.1023/A:1015518114931. 2027.42/42584 . 211284 . free .
15. Sun HW, Tong SL, He J, Wang Q, Zou L, Ma SJ, Tan HY, Luo JF, Wu HX . 2007. RhoA and RhoC -siRNA Inhibit the Proliferation and Invasiveness Activity of Human Gastric Carcinoma by Rho/PI3K/Akt Pathway . World Journal of Gastroenterology . 13 . 25. 3517–22 . 10.3748/wjg.v13.i25.3517 . 17659701. 4146790 . free.
16. Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T . etal . 2008. RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer . Cancer Research . 68 . 18. 7613–20 . 10.1158/0008-5472.CAN-07-6700 . 18794150 . 2741300 . free .
17. Kleer CG, Griffith KA, Sabel MS, Gallagher G, van Golen KL, Wu ZF, Merajver SD . 2005. RhoC-GTPase Is a Novel Tissue Biomarker Associated with Biologically Aggressive Carcinomas of the Breast . Breast Cancer Research and Treatment . 93 . 2. 101–10 . 10.1007/s10549-005-4170-6 . 16187229. 2027.42/44231 . 9215922. free .
18. Wang W, Wu F, Fang F, Tao Y, Yang L . 2008. RhoC Is Essential for Angiogenesis Induced by Hepatocellular Carcinoma Cells via Regulation of Endothelial Cell Organization . Cancer Science . 99 . 10. 2012–18 . 10.1111/j.1349-7006.2008.00902.x . 19016761. 23715139. 11160101 .
19. Wang H, Zhao G, Liu X, Sui A, Yang K, Yao R, Wang Z, Shi Q . 2010 . Silencing of RhoA and RhoC Expression by RNA Interference Suppresses Human Colorectal Carcinoma Growth in Vivo . Journal of Experimental & Clinical Cancer Research . 29 . 1 . 123 . 10.1186/1756-9966-29-123 . 20828398 . 2945978 . free .
20. Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S . etal . Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies . PLOS Medicine . 2008 . 5 . 12. e232 . 10.1371/journal.pmed.0050232 . 19053170 . 2592352 . free .