Aim: In view of accumulating evidence supporting a pivotal role of the Rho/ROCK pathway in cancer, we investigated Rho-kinase polymorphisms as potential susceptibility factors in colorectal cancer (CRC) in a representative sample of the Italian population. Methods: DNA obtained from the peripheral blood samples of 137 CRC patients and 141 healthy controls was genotyped for four ROCK1 (rs35996865; rs73963110; rs2127958; rs288980) and five ROCK2 (rs12692437; rs7563468; rs35768389; rs17463896; rs16857265) selected single nucleotide polymorphisms. Results: None of the allelic variants of the nine selected markers was associated with the occurrence of CRC or with the development of regional lymph node metastasis. By contrast, the ROCK1 rs35996865 G variant allele was significantly more frequent in male patients (p = 0.028) than in the control group. Conclusion: This finding is, at present, the first that points to a possible gender-related modulation by the ROCK1 gene in CRC susceptibility.

1.
Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N: Colorectal cancer. Lancet 2010;375:1030-1047.
2.
Nassiri M, Kooshyar MM, Roudbar Z, Mahdavi M, Doosti M: Genes and SNPs associated with non-hereditary and hereditary colorectal cancer. Asian Pac J Cancer Prev 2013;14:5609-5614.
3.
Mimori K, Tanaka F, Shibata K, Mori M: Review: single nucleotide polymorphisms associated with the oncogenesis of colorectal cancer. Surg Today 2012;42:215-219.
4.
Martinelli M, Ugolini G, Scapoli L, Rivetti S, Lauriola M, Mattei G, Rosati G, Montroni I, Manaresi A, Zattoni D, Taffurelli M, Solmi R: The EGFR R521K polymorphism influences the risk to develop colorectal cancer. Cancer Biomark 2010;8:61-65.
5.
Martinelli M, Scapoli L, Cura F, Rodia MT, Ugolini G, Montroni I, Solmi R: Colorectal cancer susceptibility: apparent gender-related modulation by ABCB1 gene polymorphisms. J Biomed Sci 2014;21:89.
6.
Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K: Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996;271:20246-20249.
7.
Kureishi Y, Kobayashi S, Amano M, Kimura K, Kanaide H, Nakano T, Kaibuchi K, Ito M: Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 1997;272:12257-12260.
8.
Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K: Phosphorylation of myosin-binding subunit (Mbs) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol 1999;147:1023-1038.
9.
Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K: Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996;273:245-248.
10.
Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S, Tsukita S: Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol 1998;140:647-657.
11.
Fukata Y, Oshiro N, Kinoshita N, Kawano Y, Matsuoka Y, Bennett V, Matsuura Y, Kaibuchi K: Phosphorylation of adducin by Rho-kinase plays a crucial role in cell motility. J Cell Biol 1999;145:347-361.
12.
Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S: Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999;285:895-898.
13.
Riento K, Ridley AJ: ROCKs: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 2003;4:446-456.
14.
Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S: ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996;392:189-193.
15.
Yoneda A, Multhaupt HA, Couchman JR: The Rho kinases I and II regulate different aspects of myosin ii activity. J Cell Biol 2005;170:443-453.
16.
Yoneda A, Ushakov D, Multhaupt HA, Couchman JR: Fibronectin matrix assembly requires distinct contributions from Rho kinases I and II. Mol Biol Cell 2007;18:66-75.
17.
Lock FE, Ryan KR, Poulter NS, Parsons M, Hotchin NA: Differential regulation of adhesion complex turnover by ROCK1 and ROCK2. PloS One 2012;7:e31423.
18.
Wong CC, Wong CM, Tung EK, Man K, Ng IO: Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology 2009;49:1583-1594.
19.
Liu X, Choy E, Hornicek FJ, Yang S, Yang C, Harmon D, Mankin H, Duan Z: ROCK1 as a potential therapeutic target in osteosarcoma. J Orthop Res 2011;29:1259-1266.
20.
Zucchini C, Manara MC, Pinca RS, De Sanctis P, Guerzoni C, Sciandra M, Lollini PL, Cenacchi G, Picci P, Valvassori L, Scotlandi K: CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity. Oncogene 2014;33:1912-1921.
21.
Lane J, Martin TA, Watkins G, Mansel RE, Jiang WG: The expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer. Int J Oncol 2008;33:585-593.
22.
Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, Ito Y, Yoshida K: Overexpression of Rhoa, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 2004;10:4799-4805.
23.
Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H: Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 2003;9:2632-2641.
24.
Vishnubhotla R, Sun S, Huq J, Bulic M, Ramesh A, Guzman G, Cho M, Glover SC: ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging. Lab Invest 2007;87:1149-1158.
25.
Nakajima M, Hayashi K, Egi Y, Katayama K, Amano Y, Uehata M, Ohtsuki M, Fujii A, Oshita K, Kataoka H, Chiba K, Goto N, Kondo T: Effect of Wf-536, a novel ROCK inhibitor, against metastasis of B16 melanoma. Cancer Chemother Pharmacol 2003;52:319-324.
26.
Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S: An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 1999;5:221-225.
27.
Paduch R, Kandefer-Szerszen M, Szuster-Ciesielska A, Plewka K: Transforming growth factor-beta1 modulates metalloproteinase-2 and -9, nitric oxide, RhoA and alpha-smooth muscle actin expression in colon adenocarcinoma cells. Cell Biol Int 2010;34:213-223.
28.
Takamura M, Sakamoto M, Genda T, Ichida T, Asakura H, Hirohashi S: Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632. Hepatology 2001;33:577-581.
29.
Patel RA, Liu Y, Wang B, Li R, Sebti SM: Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 2014;33:550-555.
30.
Zhang C, Zhang S, Zhang Z, He J, Xu Y, Liu S: ROCK has a crucial role in regulating prostate tumor growth through interaction with c-Myc. Oncogene 2014;33:5582-5591.
31.
Sari I, Berberoglu B, Ozkara E, Oztuzcu S, Camci C, Demiryurek AT: Role of Rho-kinase gene polymorphisms and protein expressions in colorectal cancer development. Pathobiology 2013;80:138-145.
32.
de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D: Efficiency and power in genetic association studies. Nat Genet 2005;37:1217-1223.
33.
Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008;66:87-98.
34.
Adachi S, Yasuda I, Nakashima M, Yamauchi T, Yoshioka T, Okano Y, Moriwaki H, Kozawa O: Rho-kinase inhibitor upregulates migration by altering focal adhesion formation via the Akt pathway in colon cancer cells. Eur J Pharmacol 2011;650:145-150.
35.
Nakashima M, Adachi S, Yasuda I, Yamauchi T, Kozawa O, Moriwaki H: Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation. Int J Oncol 2010;36:585-592.
36.
Makrodouli E, Oikonomou E, Koc M, Andera L, Sasazuki T, Shirasawa S, Pintzas A: BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study. Mol Cancer 2011;10:118.
37.
Abotchie PN, Vernon SW, Du XL: Gender differences in colorectal cancer incidence in the United States, 1975-2006. J Womens Health 2012;21:393-400.
38.
Amos-Landgraf JM, Heijmans J, Wielenga MC, Dunkin E, Krentz KJ, Clipson L, Ederveen AG, Groothuis PG, Mosselman S, Muncan V, Hommes DW, Shedlovsky A, Dove WF, van den Brink GR: Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones. Proc Natl Acad Sci USA 2014;111:16514-16519.
39.
Gonzalez-Montelongo MC, Marin R, Gomez T, Diaz M: Androgens differentially potentiate mouse intestinal smooth muscle by nongenomic activation of polyamine synthesis and Rho kinase activation. Endocrinology 2006;147:5715-5729.
40.
Song J, Kost CK Jr, Martin DS: Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway. Cardiovasc Res 2006;72:456-463.
41.
Vignozzi L, Morelli A, Filippi S, Ambrosini S, Mancina R, Luconi M, Mungai S, Vannelli GB, Zhang XH, Forti G, Maggi M: Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 2007;4:620-630; discussion 631-632.
42.
Lin MT, Lin BR, Chang CC, Chu CY, Su HJ, Chen ST, Jeng YM, Kuo ML: IL-6 induces AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway. Int J Cancer 2007;120:2600-2608.
43.
Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121-124.
44.
Tabur S, Oztuzcu S, Oguz E, Korkmaz H, Eroglu S, Ozkaya M, Demiryurek AT: Association of Rho/Rho-kinase gene polymorphisms and expressions with obesity-related metabolic syndrome. Eur Rev Med Pharmacol Sci 2015;19:1680-1688.
45.
Zhao R, Liu K, Huang Z, Wang J, Pan Y, Huang Y, Deng X, Liu J, Qin C, Cheng G, Hua L, Li J, Yin C: Genetic variants in caveolin-1 and RhoA/ROCK1 are associated with clear cell renal cell carcinoma risk in a Chinese population. PloS One 2015;10:e0128771.
46.
Kale VP, Hengst JA, Desai DH, Amin SG, Yun JK: The regulatory roles of ROCK and MRCK kinases in the plasticity of cancer cell migration. Cancer Lett 2015;361:185-196.
47.
Morgan-Fisher M, Wewer UM, Yoneda A: Regulation of ROCK activity in cancer. J Histochem Cytochem 2013;61:185-198.
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