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RhoC

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RHOC
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRHOC, ARH9, ARHC, H9, RHOH9, RhoC, ras homolog family member C
External IDsOMIM: 165380; MGI: 106028; HomoloGene: 90945; GeneCards: RHOC; OMA:RHOC - orthologs
Orthologs
SpeciesHumanMouse
Entrez

389

11853

Ensembl

ENSG00000155366

ENSMUSG00000002233

UniProt

P08134
Q5JR06

Q62159

RefSeq (mRNA)

NM_175744
NM_001042678
NM_001042679

NM_001291859
NM_007484

RefSeq (protein)

NP_001036143
NP_001036144
NP_786886

NP_001278788
NP_031510

Location (UCSC)Chr 1: 112.7 – 112.71 MbChr 3: 104.7 – 104.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Mechanism and function

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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.

Associated Signaling Pathways

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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]

Types of Cancer RhoC has been studied in

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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]

Potential Therapies

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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)

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000155366 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000002233 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ridley A. (2006). "Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking". Trends Cell Biol. 16 (10): 522–9. doi:10.1016/j.tcb.2006.08.006. PMID 16949823.
  6. ^ "Entrez Gene: RHOC ras homolog gene family, member C".
  7. ^ Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R (April 2010). "Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC". Oncogene. 29 (16): 2441–8. doi:10.1038/onc.2009.515. PMID 20101212. S2CID 25556221.
  8. ^ Jaffe AB, Hall A (2005). "Rho GTPases: Biochemistry and Biology". Annual Review of Cell and Developmental Biology. 21: 247–69. doi:10.1146/annurev.cellbio.21.020604.150721. PMID 16212495.
  9. ^ Vega FM, Ridley AJ (2008). "Rho GTPases in Cancer Cell Biology". FEBS Letters. 582 (14): 2093–2101. Bibcode:2008FEBSL.582.2093V. doi:10.1016/j.febslet.2008.04.039. PMID 18460342.
  10. ^ Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I (June 2003). "Up-Regulation of Small GTPases, RhoA and RhoC, Is Associated with Tumor Progression in Ovarian Carcinoma". Laboratory Investigation. 83 (6): 861–870. doi:10.1097/01.LAB.0000073128.16098.31. PMID 12808121. S2CID 22119772.
  11. ^ a b Ikoma T, Takahashi T, Nagano S, Li YM, Ohno Y, Ando K, Fujiwara T, Fujiwara H, Kosai K (February 2004). "A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice". Clinical Cancer Research. 10 (3): 1192–1200. doi:10.1158/1078-0432.ccr-03-0275. PMID 14871999.
  12. ^ a b c d e f g h 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.
  13. ^ Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, Mak TW (September 2005). "RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis". Genes Dev. 19 (17): 1974–9. doi:10.1101/gad.1310805. PMC 1199568. PMID 16107613.
  14. ^ a b c d e f g 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. doi:10.1038/sj.bjc.6605451. PMC 2813755. PMID 19953094.
  15. ^ a b 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. doi:10.1083/jcb.201011038. PMC 3166870. PMID 21576392.
  16. ^ a b c Wu Y, Tao Y, Chen Y, Xu W (2012). "RhoC Regulates the Proliferation of Gastric Cancer Cells through Interaction with IQGAP1". PLOS ONE. 7 (11): e48917. Bibcode:2012PLoSO...748917W. doi:10.1371/journal.pone.0048917. PMC 3492142. PMID 23145020.
  17. ^ 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.
  18. ^ a b 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.
  19. ^ 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. doi:10.3748/wjg.v13.i25.3517. PMC 4146790. PMID 17659701.
  20. ^ a b Iiizumi M, Bandyopadhyay S, Pai SK, Watabe M, Hirota S, Hosobe S, Tsukada T, et al. (2008). "RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer". Cancer Research. 68 (18): 7613–20. doi:10.1158/0008-5472.CAN-07-6700. PMC 2741300. PMID 18794150.
  21. ^ a b 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. doi:10.1007/s10549-005-4170-6. hdl:2027.42/44231. PMID 16187229. S2CID 9215922.
  22. ^ 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. doi:10.1111/j.1349-7006.2008.00902.x. PMC 11160101. PMID 19016761. S2CID 23715139.
  23. ^ a b c 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. doi:10.1186/1756-9966-29-123. PMC 2945978. PMID 20828398.
  24. ^ Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S, et al. (2008). "Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies". PLOS Medicine. 5 (12): e232. doi:10.1371/journal.pmed.0050232. PMC 2592352. PMID 19053170.

Further reading

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