Association of RAPH1 expression with cervical cancer progression and aggressiveness

Objective: The gene known as Ras association (RalGDS/AF-6) and pleckstrin homology domains 1 (RAPH1) play a role in cellular motility and lamelipodial protrusion, raising the possibility that it may contribute to development of cervical carcinoma and aggressive invasion by tumor cells. Materials and Methods: RAPH1 expression was analyzed in 153 cervical tissue samples at the mRNA level using quantitative RT-PCR and at the protein level using immunohistochemistry. Correlations were explored between expression and clinicopathological features of tumors. Results: Levels of RAPH1 mRNA were significantly higher in carcinoma tissues than in precancerous squamous intraepithelial lesions (SIL) or normal tissue (both p < 0.05). The percentage of RAPH1-positive samples increased progressively from normal tissue (10.0%) and low-grade SIL (31.3%) to high-grade SIL (45.8%) and carcinoma tissue (72.3%; Χ² CMH = 30.0, p < 0.001). RAHP1 expression positively correlated with grade of tumor differentiation (p = 0.04), vascular invasion (p < 0.001), interstitial invasive depth (p < 0.01), and tumor size (p < 0.01). Conclusions: RAPH1 expression is associated with cervical cancer development and aggressive behavior.

RAPH1; Cervical cancer; Carcinogenesis; Tumor development.

[1] Ferlay J., Shin H.R., Bray F., Forman D., Mathers C., Parkin D.M.: “Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008”. Int. J. Cancer, 2011, 127, 2893.

[2] Chen W., Zheng R., Baade P.D., Zhang S., Zeng H., Bray F., et al.: Cancer statistics in China, 2015. CA Cancer J Clin, 2016,66:115-32.

[3] Li J., Mei J., Wang X., Hu L., Lin Y., Yang P.: “Human papillomavirus type-specific prevalence in women with cervical intraepithelial neoplasm in western China”. J. Clin. Microbiol., 2012, 50, 1079.

[4] Krause M., Leslie J.D., Stewart M., Lafuente E.M., Valderrama F., Jagannathan R., et al.: “Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics”. Dev. Cell., 2004, 7, 571.

[5] Yoshinaga S., Ohkubo T., Sasaki S., Nuriya M., Ogawa Y., Yasui M., et al.: “A phosphatidylinositol lipids system, lamellipodin, and Ena/VASP regulate dynamic morphology of multipolar migrating cells in the developing cerebral cortex”. J. Neurosci., 2012, 32, 11643.

[6] Yamazaki D., Kurisu S., Takenawa T.: “Regulation of cancer cell motility through actin reorganization”. Cancer Sci., 2005, 6, 379.

[7] Eppert K., Wunder J.S., Aneliunas V., Tsui L.C., Scherer S.W., Andrulis I.L.: “Altered expression and deletion of RMO1 in osteosarcoma”. Int. J. Cancer, 2005, 114, 738.

[8] Dahl E., Sadr-Nabavi A., Klopocki E., Betz B., Grube S., Kreutzfeld R., et al.: “Systematic identification and molecular characterization of genes differentially expressed in breast and ovarian cancer”. J. Pathol., 2005, 205, 21.

[9] Livak K.J., Schmittgen T.D.: “Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method”. Methods, 2001, 25, 402.

[10] Li J., Jia H., Xie L., Wang X., He H., Lin Y., et al.: “Correlation of inhibitor of differentiation 1 expression to tumor progression, poor differentiation and aggressive behaviors in cervical carcinoma”. Gynecol. Oncol., 2009, 114, 89.

[11] Xie L., Li J., Zhang Y., Liu B., Peng X., Lin Y., et al.: “Inhibitors of Differentiation-1 Promotes Nitrosopyrrolidine induced Transformation of HPV 16-immortalized cervical epithelial cell”. Cancer Sci., 2014, 105, 506.

[12] Batistela M.S., Boberg D.R., Andrade F.A., Pecharki M., de S F Ribeiro E.M., Cavalli I.J., et al.: “Amplification and deletion of the RAPH1 gene in breast cancer patients”. Mol. Biol. Rep., 2013, 40, 6613