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RhoC

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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.[8][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 [8][13]
  • MMP9: necessary for ECM regulation[8]
  • FMNL3: a Fromin downstream target, which is used to regulate where Rac1 is active [11]
  • MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression [10][14]
  • Notch1 [10]
  • PI3K/AKt pathway: Proliferation and invasiveness [10][15]
  • Pyk2: metastasis [10][16]

Types of Cancer RhoC has been studied in

RhoC has been found to be overexpressed in:

  • Lung Cancer [7]
  • Gastric Cancer [12]
  • Ovarian cancer [8]
  • Breast Cancer [14][17]
  • Hepatocellular Cancer [18]
  • Pancreatic Cancer [8]
  • Colorectal Cancer [19]
  • Cancer of the Urogenital System [8]
  • Melanoma [8]
  • Prostate Cancer [16]
  • Cervical Carcinoma [10]

Potential Therapies

RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers [12][19] RhoC can be used as a biomarker for judging the metastatic potential of tumors[17][20] One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC [19] 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.[10]

References

  1. ^ 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.
  2. ^ "Entrez Gene: RHOC ras homolog gene family, member C".
  3. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Jaffe, Aron B, and Alan Hall. “Rho GTPases: Biochemistry and Biology.” Annual Review of Cell and Developmental Biology 21 (2005): 247–69. doi:10.1146/annurev.cellbio.21.020604.150721
  5. ^ Vega, Francisco M, and Anne J Ridley. “Rho GTPases in Cancer Cell Biology.” FEBS Letters 582, no. 14 (June 18, 2008): 2093–2101. doi:10.1016/j.febslet.2008.04.039.
  6. ^ Horiuchi, Akiko, Tsutomu Imai, Cuiju Wang, Satoshi Ohira, Yuzhen Feng, Toshio Nikaido, and Ikuo Konishi. “Up-Regulation of Small GTPases, RhoA and RhoC, Is Associated with Tumor Progression in Ovarian Carcinoma.” Laboratory Investigation 83, no. 6 (June 2003): 861–70.
  7. ^ a b Ikoma, Tetsuro, Tomoyuki Takahashi, Satoshi Nagano, Yun-Mo Li, Yasushi Ohno, Kazuki Ando, Takako Fujiwara, Hisayoshi Fujiwara, and Ken-ichiro Kosai. “A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 10, no. 3 (February 1, 2004): 1192–1200.
  8. ^ a b c d e f g h Zhao, Yang, Zhi-hong Zong, and Hui-mian Xu. “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, no. 3 (March 2010): 563–71. doi:10.1016/j.ygyno.2009.11.015.
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b c d e f g Srivastava, S, B Ramdass, S Nagarajan, M Rehman, G Mukherjee, and S Krishna. “Notch1 Regulates the Functional Contribution of RhoC to Cervical Carcinoma Progression.” British Journal of Cancer 102, no. 1 (January 5, 2010): 196–205. doi:10.1038/sj.bjc.6605451.
  11. ^ a b Vega, Francisco M, Gilbert Fruhwirth, Tony Ng, and Anne J Ridley. “RhoA and RhoC Have Distinct Roles in Migration and Invasion by Acting through Different Targets.” The Journal of Cell Biology 193, no. 4 (May 16, 2011): 655–65. doi:10.1083/jcb.201011038.
  12. ^ a b c Wu, Yan, Yan Tao, Yongchang Chen, and Wenrong Xu. “RhoC Regulates the Proliferation of Gastric Cancer Cells through Interaction with IQGAP1.” PloS One 7, no. 11 (2012): e48917. doi:10.1371/journal.pone.0048917.
  13. ^ Genda, T, M Sakamoto, T Ichida, H Asakura, M Kojiro, S Narumiya, and S Hirohashi. “Cell Motility Mediated by Rho and Rho-Associated Protein Kinase Plays a Critical Role in Intrahepatic Metastasis of Human Hepatocellular Carcinoma.” Hepatology (Baltimore, Md.) 30, no. 4 (October 1999): 1027–36. doi:10.1002/hep.510300420.
  14. ^ a b Van Golen, Kenneth L, Li Wei Bao, Quintin Pan, Fred R Miller, Zhi Fen Wu, and Sofia D Merajver. “Mitogen Activated Protein Kinase Pathway Is Involved in RhoC GTPase Induced Motility, Invasion and Angiogenesis in Inflammatory Breast Cancer.” Clinical & Experimental Metastasis 19, no. 4 (2002): 301–11.
  15. ^ Sun, Hua-Wen, Shi-Lun Tong, Jie He, Qi Wang, Li Zou, Shu-Jing Ma, Hai-Yan Tan, Jian-Fei Luo, and Hong-Xue Wu. “RhoA and RhoC -siRNA Inhibit the Proliferation and Invasiveness Activity of Human Gastric Carcinoma by Rho/PI3K/Akt Pathway.” World Journal of Gastroenterology: WJG 13, no. 25 (July 7, 2007): 3517–22.
  16. ^ a b Iiizumi, Megumi, Sucharita Bandyopadhyay, Sudha K Pai, Misako Watabe, Shigeru Hirota, Sadahiro Hosobe, Taisei Tsukada, et al. “RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer.” Cancer Research 68, no. 18 (September 15, 2008): 7613–20. doi:10.1158/0008-5472.CAN-07-6700.
  17. ^ a b Kleer, Celina G, Kent A Griffith, Michael S Sabel, Gary Gallagher, Kenneth L van Golen, Zhi-Fen Wu, and Sofia D Merajver. “RhoC-GTPase Is a Novel Tissue Biomarker Associated with Biologically Aggressive Carcinomas of the Breast.” Breast Cancer Research and Treatment 93, no. 2 (September 2005): 101–10. doi:10.1007/s10549-005-4170-6.
  18. ^ Wang, Wei, Fan Wu, Feng Fang, Yiming Tao, and Lianyue Yang. “RhoC Is Essential for Angiogenesis Induced by Hepatocellular Carcinoma Cells via Regulation of Endothelial Cell Organization.” Cancer Science 99, no. 10 (October 2008): 2012–18. doi:10.1111/j.1349-7006.2008.00902.x.
  19. ^ a b c Wang, Haibo, Gang Zhao, Xiangping Liu, Aihua Sui, Kun Yang, Ruyong Yao, Zongbao Wang, and Qiang Shi. “Silencing of RhoA and RhoC Expression by RNA Interference Suppresses Human Colorectal Carcinoma Growth in Vivo.” Journal of Experimental & Clinical Cancer Research: CR 29 (2010): 123. doi:10.1186/1756-9966-29-123
  20. ^ Köbel, Martin, Steve E Kalloger, Niki Boyd, Steven McKinney, Erika Mehl, Chana Palmer, Samuel Leung, et al. “Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies.” PLoS Medicine 5, no. 12 (December 2, 2008): e232. doi:10.1371/journal.pmed.0050232.

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