The potential role of the paxillin paralog Hic-5 in progression of hepatocellular carcinoma

Main Article Content

Wen-Sheng Wu Jia-Ru WU Chi-Tan Hu Ren-In You

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer worldwide. The poor prognosis of HCC is due to high recurrence rate mainly caused by intrahepatic metastasis. Paxillin was known to be a central adaptor protein for mediating focal adhesion (FA) signal required for HCC progression. However, target therapy aiming at paxillin seems unfeasible due to its ubiquitous tissue expression and essential biological functions. Within the paxillin superfamily, hydrogen peroxide inducible clone-5 (Hic-5) is the most homologous to paxillin. This review summarises the recent findings relevant to the differential biochemical and biological roles of Hic-5 and paxillin. Given the structure similarity between Hic-5 and paxillin, Hic-5 shares many of the characteristics of paxillin, including the localization of Hic-5 at focal adhesions and similar FA binding factors.  However, some of the regulatory mechanisms and molecular functions of Hic-5 are rather different from those of paxillin. These might explain the differential roles of both adaptors in regulating various pathophysiological processes. Interestingly, both adaptors might play distinct but complementary roles in tumor progression. Due to the more limited tissue distribution of Hic-5, it can be a more suitable therapeutic target for preventing HCC progression.


 

Article Details

How to Cite
WU, Wen-Sheng et al. The potential role of the paxillin paralog Hic-5 in progression of hepatocellular carcinoma. Medical Research Archives, [S.l.], v. 6, n. 3, mar. 2018. ISSN 2375-1924. Available at: <https://journals.ke-i.org/index.php/mra/article/view/1702>. Date accessed: 22 july 2018. doi: https://doi.org/10.18103/mra.v6i3.1702.
Section
Research Articles

References

1. Bosch, F.X., Ribes, J., Diaz, M., and Cleries, R. (2004). Primary liver cancer: worldwide incidence and trends. Gastroenterology 127, S5-S16.
2. El-Serag, H.B., Davila, J.A., Petersen, N.J., and McGlynn, K.A. (2003). The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139, 817-823.
3. Tang, Z.Y., Ye, S.L., Liu, Y.K., Qin, L.X., Sun, H.C., Ye, Q.H., Wang, L., Zhou, J., Qiu, S.J., Li, Y., Ji, X.N., Liu, H., Xia, J.L., Wu, Z.Q., Fan, J., Ma, Z.C., Zhou, X.D., Lin, Z.Y., and Liu, K.D. (2004). A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 130, 187-196.
4. Fornaro, L., Vivaldi, C., Caparello, C., Sacco, R., Rotella, V., Musettini, G., Luchi, S., Baldini, E.E., Falcone, A., and Masi, G. (2014). Dissecting signaling pathways in hepatocellular carcinoma: new perspectives in medical therapy. Future Oncol 10, 285-304.
5. Moeini, A., Cornella, H., and Villanueva, A. (2012). Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer 1, 83-93.
6. Mazzocca, A., Antonaci, S., and Giannelli, G. (2012). The TGF-beta signaling pathway as a pharmacological target in a hepatocellular carcinoma. Curr Pharm Des 18, 4148-4154.
7. Goyal, L., Muzumdar, M.D., and Zhu, A.X. (2013). Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 19, 2310-2318.
8. Giordano, S., and Columbano, A. (2013). Met as a therapeutic target in HCC: facts and hopes. J Hepatol 60, 442-452.
9. Bronte, F., Bronte, G., Cusenza, S., Fiorentino, E., Rolfo, C., Cicero, G., Bronte, E., Di Marco, V., Firenze, A., Angarano, G., Fontana, T., and Russo, A. (2014). Targeted therapies in hepatocellular carcinoma. Curr Med Chem 21, 966-974.
10. Zhang, X., Cheng, S.L., Bian, K., Wang, L., Zhang, X., Yan, B., Jia, L.T., Zhao, J., Gammoh, N., Yang, A.G., and Zhang, R. (2014). MicroRNA-26a promotes anoikis in human hepatocellular carcinoma cells by targeting alpha5 integrin. Oncotarget.
11. Fu, Y., Feng, M.X., Yu, J., Ma, M.Z., Liu, X.J., Li, J., Yang, X.M., Wang, Y.H., Zhang, Y.L., Ao, J.P., Xue, F., Qin, W., Gu, J., Xia, Q., and Zhang, Z.G. (2014). DNA methylation-mediated silencing of matricellular protein dermatopontin promotes hepatocellular carcinoma metastasis by alpha3beta1 integrin-Rho GTPase signaling. Oncotarget 5, 6701-6715.
12. Patman, G. (2014). Liver: loss of integrin beta1 impairs liver regeneration and HCC progression. Nat Rev Gastroenterol Hepatol 11, 392.
13. Bogorad, R.L., Yin, H., Zeigerer, A., Nonaka, H., Ruda, V.M., Zerial, M., Anderson, D.G., and Koteliansky, V. (2014). Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice. Nat Commun 5, 3869.
14. Hu, C.T., Wu, J.R., Cheng, C.C., Wang, S., Wang, H.T., Lee, M.C., Wang, L.J., Pan, S.M., Chang, T.Y., and Wu, W.S. (2011). Reactive oxygen species-mediated PKC and integrin signaling promotes tumor progression of human hepatoma HepG2. Clin Exp Metastasis 28, 851-863.
15. Wu, Y., Qiao, X., Qiao, S., and Yu, L. (2011). Targeting integrins in hepatocellular carcinoma. Expert Opin Ther Targets 15, 421-437.
16. Wang, S.M., Ooi, L.L., and Hui, K.M. (2011). Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. Clin Cancer Res 17, 6040-6051.
17. Lee, T.K., Poon, R.T., Yuen, A.P., Man, K., Yang, Z.F., Guan, X.Y., and Fan, S.T. (2006). Rac activation is associated with hepatocellular carcinoma metastasis by up-regulation of vascular endothelial growth factor expression. Clin Cancer Res 12, 5082-5089.
18. Fujii, T., Koshikawa, K., Nomoto, S., Okochi, O., Kaneko, T., Inoue, S., Yatabe, Y., Takeda, S., and Nakao, A. (2004). Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J Hepatol 41, 104-111.
19. Yao, W.L., Ko, B.S., Liu, T.A., Liang, S.M., Liu, C.C., Lu, Y.J., Tzean, S.S., Shen, T.L., and Liou, J.Y. (2014). Cordycepin suppresses integrin/FAK signaling and epithelial-mesenchymal transition in hepatocellular carcinoma. Anticancer Agents Med Chem 14, 29-34.
20. Ding, J., Huang, S., Wu, S., Zhao, Y., Liang, L., Yan, M., Ge, C., Yao, J., Chen, T., Wan, D., Wang, H., Gu, J., Yao, M., Li, J., Tu, H., and He, X. (2010). Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol 12, 390-399.
21. Huang, J., Zheng, D.L., Qin, F.S., Cheng, N., Chen, H., Wan, B.B., Wang, Y.P., Xiao, H.S., and Han, Z.G. (2010). Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. J Clin Invest 120, 223-241.
22. Jia, Y.L., Shi, L., Zhou, J.N., Fu, C.J., Chen, L., Yuan, H.F., Wang, Y.F., Yan, X.L., Xu, Y.C., Zeng, Q., Yue, W., and Pei, X.T. (2011). Epimorphin promotes human hepatocellular carcinoma invasion and metastasis through activation of focal adhesion kinase/extracellular signal-regulated kinase/matrix metalloproteinase-9 axis. Hepatology 54, 1808-1818.
23. Cortese, R., Almendros, I., Wang, Y., and Gozal, D. (2014). Tumor circulating DNA profiling in xenografted mice exposed to intermittent hypoxia. Oncotarget.
24. Cao, J., Chen, Y., Fu, J., Qian, Y.W., Ren, Y.B., Su, B., Luo, T., Dai, R.Y., Huang, L., Yan, J.J., Wu, M.C., Yan, Y.Q., and Wang, H.Y. (2013). High expression of proline-rich tyrosine kinase 2 is associated with poor survival of hepatocellular carcinoma via regulating phosphatidylinositol 3-kinase/AKT pathway. Ann Surg Oncol 20 Suppl 3, S312-323.
25. Ng, L., Tung-Ping Poon, R., Yau, S., Chow, A., Lam, C., Li, H.S., Chung-Cheung Yau, T., Law, W.L., and Pang, R. (2013). Suppression of actopaxin impairs hepatocellular carcinoma metastasis through modulation of cell migration and invasion. Hepatology 58, 667-679.
26. Mitra, S.K., Hanson, D.A., and Schlaepfer, D.D. (2005). Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6, 56-68.
27. Deakin, N.O., and Turner, C.E. (2008). Paxillin comes of age. J Cell Sci 121, 2435-2444.
28. Bi, Y., Han, Y., Bi, H., Gao, F., and Wang, X. (2014). miR-137 impairs the proliferative and migratory capacity of human non-small cell lung cancer cells by targeting paxillin. Hum Cell 27, 95-102.
29. Li, H.G., Xie, D.R., Shen, X.M., Li, H.H., Zeng, H., and Zeng, Y.J. (2005). Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma. World J Gastroenterol 11, 1445-1451.
30. Hu, C.T., Cheng, C.C., Pan, S.M., Wu, J.R., and Wu, W.S. (2013). PKC mediates fluctuant ERK-paxillin signaling for hepatocyte growth factor-induced migration of hepatoma cell HepG2. Cell Signal 25, 1457-1467.
31. Ching, Y.P., Leong, V.Y., Lee, M.F., Xu, H.T., Jin, D.Y., and Ng, I.O. (2007). P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation. Cancer Res 67, 3601-3608.
32. Shibanuma, M., Mashimo, J., Kuroki, T., and Nose, K. (1994). Characterization of the TGF beta 1-inducible hic-5 gene that encodes a putative novel zinc finger protein and its possible involvement in cellular senescence. J Biol Chem 269, 26767-26774.
33. Deakin, N.O., Pignatelli, J., and Turner, C.E. (2012). Diverse roles for the paxillin family of proteins in cancer. Genes Cancer 3, 362-370.
34. Tumbarello, D.A., Brown, M.C., Hetey, S.E., and Turner, C.E. (2005). Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. J Cell Sci 118, 4849-4863.
35. Sun, C.K., Ng, K.T., Lim, Z.X., Cheng, Q., Lo, C.M., Poon, R.T., Man, K., Wong, N., and Fan, S.T. (2011). Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition. PLoS One 6, e18878.
36. Brown, M.C., and Turner, C.E. (2004). Paxillin: adapting to change. Physiol Rev 84, 1315-1339.
37. Nishiya, N., Shirai, T., Suzuki, W., and Nose, K. (2002). Hic-5 interacts with GIT1 with a different binding mode from paxillin. J Biochem 132, 279-289.
38. Nishiya, N., Iwabuchi, Y., Shibanuma, M., Cote, J.F., Tremblay, M.L., and Nose, K. (1999). Hic-5, a paxillin homologue, binds to the protein-tyrosine phosphatase PEST (PTP-PEST) through its LIM 3 domain. J Biol Chem 274, 9847-9853.
39. Thomas, S.M., Hagel, M., and Turner, C.E. (1999). Characterization of a focal adhesion protein, Hic-5, that shares extensive homology with paxillin. J Cell Sci 112 ( Pt 2), 181-190.
40. Liu, S., Thomas, S.M., Woodside, D.G., Rose, D.M., Kiosses, W.B., Pfaff, M., and Ginsberg, M.H. (1999). Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature 402, 676-681.
41. Shibanuma, M., Mori, K., and Nose, K. (2012). HIC-5: A Mobile Molecular Scaffold Regulating the Anchorage Dependence of Cell Growth. Int J Cell Biol 2012, 426138.
42. Brugnera, E., Haney, L., Grimsley, C., Lu, M., Walk, S.F., Tosello-Trampont, A.C., Macara, I.G., Madhani, H., Fink, G.R., and Ravichandran, K.S. (2002). Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol 4, 574-582.
43. Liu, Z.X., Yu, C.F., Nickel, C., Thomas, S., and Cantley, L.G. (2002). Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin-focal adhesion kinase association. J Biol Chem 277, 10452-10458.
44. Turner, C.E., Brown, M.C., Perrotta, J.A., Riedy, M.C., Nikolopoulos, S.N., McDonald, A.R., Bagrodia, S., Thomas, S., and Leventhal, P.S. (1999). Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling. J Cell Biol 145, 851-863.
45. West, K.A., Zhang, H., Brown, M.C., Nikolopoulos, S.N., Riedy, M.C., Horwitz, A.F., and Turner, C.E. (2001). The LD4 motif of paxillin regulates cell spreading and motility through an interaction with paxillin kinase linker (PKL). J Cell Biol 154, 161-176.
46. Zhao, Z.S., Manser, E., Loo, T.H., and Lim, L. (2000). Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol Cell Biol 20, 6354-6363.
47. Matsuya, M., Sasaki, H., Aoto, H., Mitaka, T., Nagura, K., Ohba, T., Ishino, M., Takahashi, S., Suzuki, R., and Sasaki, T. (1998). Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions. J Biol Chem 273, 1003-1014.
48. Osada, M., Ohmori, T., Yatomi, Y., Satoh, K., Hosogaya, S., and Ozaki, Y. (2001). Involvement of Hic-5 in platelet activation: integrin alphaIIbbeta3-dependent tyrosine phosphorylation and association with proline-rich tyrosine kinase 2. Biochem J 355, 691-697.
49. Wang, Y., and Gilmore, T.D. (2003). Zyxin and paxillin proteins: focal adhesion plaque LIM domain proteins go nuclear. Biochim Biophys Acta 1593, 115-120.
50. Woods, A.J., Roberts, M.S., Choudhary, J., Barry, S.T., Mazaki, Y., Sabe, H., Morley, S.J., Critchley, D.R., and Norman, J.C. (2002). Paxillin associates with poly(A)-binding protein 1 at the dense endoplasmic reticulum and the leading edge of migrating cells. J Biol Chem 277, 6428-6437.
51. Shibanuma, M., Kim-Kaneyama, J.R., Ishino, K., Sakamoto, N., Hishiki, T., Yamaguchi, K., Mori, K., Mashimo, J., and Nose, K. (2003). Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal. Mol Biol Cell 14, 1158-1171.
52. Shibanuma, M., Mori, K., Kim-Kaneyama, J.R., and Nose, K. (2005). Involvement of FAK and PTP-PEST in the regulation of redox-sensitive nuclear-cytoplasmic shuttling of a LIM protein, Hic-5. Antioxid Redox Signal 7, 335-347.
53. Kasai, M., Guerrero-Santoro, J., Friedman, R., Leman, E.S., Getzenberg, R.H., and DeFranco, D.B. (2003). The Group 3 LIM domain protein paxillin potentiates androgen receptor transactivation in prostate cancer cell lines. Cancer Res 63, 4927-4935.
54. Yang, L., Guerrero, J., Hong, H., DeFranco, D.B., and Stallcup, M.R. (2000). Interaction of the tau2 transcriptional activation domain of glucocorticoid receptor with a novel steroid receptor coactivator, Hic-5, which localizes to both focal adhesions and the nuclear matrix. Mol Biol Cell 11, 2007-2018.
55. Chodankar, R., Wu, D.Y., Schiller, B.J., Yamamoto, K.R., and Stallcup, M.R. (2014). Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner. Proc Natl Acad Sci U S A 111, 4007-4012.
56. Shibanuma, M., Kim-Kaneyama, J.R., Sato, S., and Nose, K. (2004). A LIM protein, Hic-5, functions as a potential coactivator for Sp1. J Cell Biochem 91, 633-645.
57. Ghogomu, S.M., van Venrooy, S., Ritthaler, M., Wedlich, D., and Gradl, D. (2006). HIC-5 is a novel repressor of lymphoid enhancer factor/T-cell factor-driven transcription. J Biol Chem 281, 1755-1764.
58. Kim, K., Jr., Shibanuma, M., and Nose, K. (2002). Transcriptional activation of the c-fos gene by a LIM protein, Hic-5. Biochem Biophys Res Commun 299, 360-365.
59. Nose, K. (2002). [Regulation of gene expression by active oxygen species]. Yakugaku Zasshi 122, 773-780.
60. Lei, X.F., Kim-Kaneyama, J.R., Arita-Okubo, S., Offermanns, S., Itabe, H., Miyazaki, T., and Miyazaki, A. (2014). Identification of Hic-5 as a novel scaffold for the MKK4/p54 JNK pathway in the development of abdominal aortic aneurysms. J Am Heart Assoc 3, e000747.
61. Usuki, F., Fujita, E., and Sasagawa, N. (2008). Methylmercury activates ASK1/JNK signaling pathways, leading to apoptosis due to both mitochondria- and endoplasmic reticulum (ER)-generated processes in myogenic cell lines. Neurotoxicology 29, 22-30.
62. Funahashi, Y., Wang, Z., O'Malley, K.J., Tyagi, P., DeFranco, D.B., Gingrich, J.R., Takahashi, R., Majima, T., Gotoh, M., and Yoshimura, N. (2015). Influence of E. coli-induced prostatic inflammation on expression of androgen-responsive genes and transforming growth factor beta 1 cascade genes in rats. Prostate 75, 381-389.
63. Li, X., Martinez-Ferrer, M., Botta, V., Uwamariya, C., Banerjee, J., and Bhowmick, N.A. (2011). Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness. Oncogene 30, 167-177.
64. Akiyama, N., Matsuo, Y., Sai, H., Noda, M., and Kizaka-Kondoh, S. (2000). Identification of a series of transforming growth factor beta-responsive genes by retrovirus-mediated gene trap screening. Mol Cell Biol 20, 3266-3273.
65. Wu, R.F., Xu, Y.C., Ma, Z., Nwariaku, F.E., Sarosi, G.A., Jr., and Terada, L.S. (2005). Subcellular targeting of oxidants during endothelial cell migration. J Cell Biol 171, 893-904.
66. Desai, L.P., Zhou, Y., Estrada, A.V., Ding, Q., Cheng, G., Collawn, J.F., and Thannickal, V.J. (2014). Negative regulation of NADPH oxidase 4 by hydrogen peroxide-inducible clone 5 (Hic-5) protein. J Biol Chem 289, 18270-18278.
67. Pignatelli, J., Tumbarello, D.A., Schmidt, R.P., and Turner, C.E. (2012). Hic-5 promotes invadopodia formation and invasion during TGF-beta-induced epithelial-mesenchymal transition. J Cell Biol 197, 421-437.
68. Wang, H., Song, K., Sponseller, T.L., and Danielpour, D. (2005). Novel function of androgen receptor-associated protein 55/Hic-5 as a negative regulator of Smad3 signaling. J Biol Chem 280, 5154-5162.
69. Wang, H., Song, K., Krebs, T.L., Yang, J., and Danielpour, D. (2008). Smad7 is inactivated through a direct physical interaction with the LIM protein Hic-5/ARA55. Oncogene 27, 6791-6805.
70. Shola, D.T., Wang, H., Wahdan-Alaswad, R., and Danielpour, D. (2012). Hic-5 controls BMP4 responses in prostate cancer cells through interacting with Smads 1, 5 and 8. Oncogene 31, 2480-2490.
71. Kim-Kaneyama, J.R., Suzuki, W., Ichikawa, K., Ohki, T., Kohno, Y., Sata, M., Nose, K., and Shibanuma, M. (2005). Uni-axial stretching regulates intracellular localization of Hic-5 expressed in smooth-muscle cells in vivo. J Cell Sci 118, 937-949.
72. Nishiya, N., Tachibana, K., Shibanuma, M., Mashimo, J.I., and Nose, K. (2001). Hic-5-reduced cell spreading on fibronectin: competitive effects between paxillin and Hic-5 through interaction with focal adhesion kinase. Mol Cell Biol 21, 5332-5345.
73. Mitra, S.K., and Schlaepfer, D.D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18, 516-523.
74. Ninio-Many, L., Grossman, H., Shomron, N., Chuderland, D., and Shalgi, R. (2013). microRNA-125a-3p reduces cell proliferation and migration by targeting Fyn. J Cell Sci 126, 2867-2876.
75. Wade, R., Brimer, N., Lyons, C., and Vande Pol, S. (2011). Paxillin enables attachment-independent tyrosine phosphorylation of focal adhesion kinase and transformation by RAS. J Biol Chem 286, 37932-37944.
76. Mori, K., Hirao, E., Toya, Y., Oshima, Y., Ishikawa, F., Nose, K., and Shibanuma, M. (2009). Competitive nuclear export of cyclin D1 and Hic-5 regulates anchorage dependence of cell growth and survival. Mol Biol Cell 20, 218-232.
77. Noguchi, F., Inui, S., Nakajima, T., and Itami, S. (2012). Hic-5 affects proliferation, migration and invasion of B16 murine melanoma cells. Pigment Cell Melanoma Res 25, 773-782.
78. Deakin, N.O., and Turner, C.E. (2011). Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Mol Biol Cell 22, 327-341.
79. Aissaoui, H., Prevost, C., Boucharaba, A., Sanhadji, K., Bordet, J.C., Negrier, C., and Boukerche, H. (2014). MDA-9/Syntenin is essential for Factor VIIa-induced Signaling, Migration, and metastasis in melanoma Cells. J Biol Chem.
80. Kratimenos, P., Koutroulis, I., Marconi, D., Syriopoulou, V., Delivoria-Papadopoulos, M., Chrousos, G.P., and Theocharis, S. (2014). Multi-targeted molecular therapeutic approach in aggressive neuroblastoma: the effect of Focal Adhesion Kinase-Src-Paxillin system. Expert Opin Ther Targets 18, 1395-1406.
81. Avraamides, C., Bromberg, M.E., Gaughan, J.P., Thomas, S.M., Tsygankov, A.Y., and Panetti, T.S. (2007). Hic-5 promotes endothelial cell migration to lysophosphatidic acid. Am J Physiol Heart Circ Physiol 293, H193-203.
82. Nakamura, K., Yano, H., Uchida, H., Hashimoto, S., Schaefer, E., and Sabe, H. (2000). Tyrosine phosphorylation of paxillin alpha is involved in temporospatial regulation of paxillin-containing focal adhesion formation and F-actin organization in motile cells. J Biol Chem 275, 27155-27164.
83. Deakin, N.O., Ballestrem, C., and Turner, C.E. (2012). Paxillin and Hic-5 interaction with vinculin is differentially regulated by Rac1 and RhoA. PLoS One 7, e37990.
84. Liu, R.F., Xu, X., Huang, J., Fei, Q.L., Chen, F., Li, Y.D., and Han, Z.G. (2013). Down-regulation of miR-517a and miR-517c promotes proliferation of hepatocellular carcinoma cells via targeting Pyk2. Cancer Lett 329, 164-173.
85. Geng, W., Ng, K.T., Sun, C.K., Yau, W.L., Liu, X.B., Cheng, Q., Poon, R.T., Lo, C.M., Man, K., and Fan, S.T. (2011). The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma. PLoS One 6, e27362.
86. Li, Q., Liu, G., Shao, D., Wang, J., Yuan, H., Chen, T., Zhai, R., Ni, W., and Tai, G. (2015). Mucin1 mediates autocrine transforming growth factor beta signaling through activating the c-Jun N-terminal kinase/activator protein 1 pathway in human hepatocellular carcinoma cells. Int J Biochem Cell Biol 59, 116-125.
87. Dhanasekaran, R., Nakamura, I., Hu, C., Chen, G., Oseini, A.M., Seven, E.S., Miamen, A.G., Moser, C.D., Zhou, W., vanKuppevelt, T.H., vanDeursen, J., Mounajjed, T., Fernandez-Zapico, M.E., and Roberts, L.R. (2014). Activation of the TGFbeta/SMAD transcriptional pathway underlies a novel tumor promoting role of sulfatase1 in hepatocellular carcinoma. Hepatology.
88. Reichl, P., Dengler, M., van Zijl, F., Huber, H., Fuhrlinger, G., Reichel, C., Sieghart, W., Peck-Radosavljevic, M., Grubinger, M., and Mikulits, W. (2014). Signaling of Axl via 14-3-3zeta activates autocrine transforming growth factor-beta signaling in hepatocellular carcinoma. Hepatology.
89. Wu J.R., Hu C.T., You R.I., Pan S.M., Cheng C.C., Lee M.C., Wu C.C., Chang Y.J., Lin S.C., Chen C.S., Lin T.Y., Wu W.S. (2015) Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression. Oncotarget 6, 32526-32544.
90. Ren T., Zhang H., Wang J., Zhu J., Jin M., Wu Y., Guo X., Ji L., Huang Q, Zhang H., Yang H., Xing J. (2017) MCU-dependent mitochondrial Ca 2+inhibits NAD/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells. Oncogene 36, 5897-5909.
91. Hu C.T., Wu J.R., Cheng C.C., Wu W.S. (2017) The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches.
Cancers (Basel), 9(6) pii: E58.

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.