壹、 Trip6 蛋白質在小鼠腦中之表現
甲狀腺素受體作用蛋白質 6 (Thyroid receptor-interacting protein 6, Trip6)是一種焦點連接(focal adhesion)分子，它調控一些細胞機制
如：細胞之間的連接(cell adhesion)、細胞的遷移(cell migration)以及
基因轉錄的活化 (gene transactivation)。過去研究指出 Trip6 屬於幹
細胞性(stemness)的基因，在不同的幹細胞中具有較高的表現量。為了探究Trip6 在神經幹細胞所扮演的角色，我們分別檢測了 Trip6 蛋白質在胚胎與成年小鼠大腦中的表現量。發現 Trip6 的 mRNA 主要在胚胎小鼠的腦中有表現，但在成年小鼠腦中則比較低或偵測不到。其蛋白質也只可以在胚胎小鼠的大腦中被偵測到，成年小鼠則否。另外我們在胚胎與成年小鼠的大腦組織切片中，以不同的細胞標誌與 Trip6 進行組織免疫螢光染色。包括幹細胞的標誌 Sox2、增殖中細胞的標誌 Ki67、室管膜細胞的標誌 S100β、神經母細胞的標誌 DCX、神經元的標誌 MAP2、星狀細胞的標誌 GFAP 以及小膠質細胞的標誌(Iba1)。我們發現 Trip6 主要表達在胚胎小鼠的腦室區(ventricular zone, VZ)以及出生後小鼠的腦室下區(subventricular zone, SVZ)內的神經幹細胞(neural stem cells, NSC)中。這樣的結果支持Trip6 可能在調控幹細胞的特性中是一個重要的關鍵。

貳、建立人類惡性腫瘤之斑馬魚異體移植模式
神經膠質母細胞瘤是成人最常見且高侵略性的原發惡性腦腫瘤。它的侵襲力和耐傳統療法使其成為極易復發的惡性腫瘤。Rac蛋白質屬於Rho GTP酶亞家族，其主要功能包括調節細胞運動，增殖和存活。為了探究Rac蛋白質是否可以作為膠質母細胞瘤的新治療標靶，特別是對於神經膠質母細胞瘤幹細胞，我們利用其類癌幹細胞株建立了斑馬魚的異體移植模式來研究抑制Rac蛋白質對於神經膠質母細胞瘤的致癌性影響。
我們將表達控制組的shRNA或者是針對Rac蛋白質做抑制的shRNA序列和綠螢光蛋白的神經膠質母細胞瘤細胞株U251-MG和U373-MG培養於低分化培養液中，以形成腫瘤細胞球(tumorspheroids)。這些體外培養的球體細胞有著幹細胞的特性。我們將這些細胞以顯微注射的方式注射進入受精後兩天大的血管紅螢光轉基因斑馬魚Tg(kdr: mCherry)的卵黃囊。觀察發現注入的癌細胞誘導了血管新生作用的發生，而表達shRacs細胞萎縮且並未引發血管新生作用。另外，注射shRacs細胞的魚隻生存率也較高。
從我們的研究結果，Rac蛋白質會誘導膠質瘤幹細胞引發血管新生作用，並且可做為一個生物標誌。因此，Rac蛋白質可能可以進一步應用在神經膠質母細胞瘤的標靶治療上。
另一方面，我們也利用注射肝癌細胞株Hep3B進入受精後兩天大的斑馬魚卵黃囊中，來觀察Hep3B細胞的遷移現象，此模式約有20%的魚隻可觀察到細胞遷移。

I. The Expression Pattern of Trip6 in Mouse Brain
Trip6 (Thyroid receptor-interacting protein 6) is a focal adhesion molecule and its function is related to cell adhesion, cell migration and gene transactivation. Trip6 has been identified as a “stemness” gene which expresses higher in different lineage of stem cells. To investigate the role of Trip6 in neural stem cells, we examined the expression level of Trip6 in the brains of embryonic and adult mice, and found that the mRNA of Trip6 is detected in the embryonic mouse brain but low or undetectable in the adult mice brain. Similarly, the protein level of Trip6 is only detected in the embryonic mouse brains by western blot. We also performed double immunofluorecence with Trip6 and different cellular markers, including, stem cells marker- Sox2, proliferating cells marker- Ki67, ependymal cells marker- S100β, neuroblast marker- DCX, neuron maker- MAP2, astrocytes marker- GFAP and microglia marker- Iba1.We found that Trip6 was expressed by neural stem cells in the ventricular zone and subventricular zone of embryonic and postnatal mouse brains, respectively. Taken together, Trip6 may play an important role in regulation of neural stem cell (NSC) properties.

II. Establishing Zebrafish Xenotransplantation Model of Human Malignant Tumors
Glioblastoma is the most common and aggressive malignant primary brain tumor in adults. Its invasiveness and resistance to traditional therapies make it a highly recurrent malignant disease with poor prognosis. Rac proteins belong to the Rho small GTPase subfamily, which major functions include regulation of cell movement, proliferation, and survival. To investigate whether Rac proteins can serve as new therapeutic targets for glioblastoma, especially for glioblastoma stem cells, we established a zebrafish xenotransplantation model to study the effects of Rac proteins in glioblastoma.
Glioblastoma cell lines U373 and U251 expressing short hairpin RNA targeting Rac proteins or control RNA sequence and green fluorescence protein were generated and cultured in low differentiating medium to form tumorspheroids. These spheroid cells harbor stem cell properties and mimic stem cells in vitro. We injected these cells to egg yolk of zebrafish Tg(kdr: mCherry) on 2 post-fertilization-day stage(pfd). The behaviors of the injected cells were then monitored every day by the confocal microscope.
We observed that the cells expressing control scramble RNA sequence induced angiogenesis in the egg yolk of the fish, while the cells expressing shRacs shrank inside the fish and did not induce angiogenesis. The overall survival rates of fishes were also higher in the fishes injected shRac cells instead of fishes with control scramble RNA cells.
From our results, we conclude that Rac proteins induce angiogenesis of glioblastoma stem cells and serve as a poor prognosis marker. Therefore, Rac proteins could further be the potential therapeutic targets of glioblastoma and its stem cells.
On the other hand, we also inject the hepatocellular carcinoma cell line- Hep3B into egg yolk of zebrafish on 2 pfd stage to observe the migration of Hep3B cells. We have successfully established the in vivo migration/metastasis model of Hep3B cells in zebrafish of which the metastasis rate is about 20%.

Abdel-Latif, D., Steward, M., Macdonald, D.L., Francis, G.A., Dinauer, M.C., and Lacy, P. (2004). Rac2 is critical for neutrophil primary granule exocytosis. Blood 104, 832-839.

Aspenstrom, P., Fransson, A., and Saras, J. (2004). Rho GTPases have diverse effects on the organization of the actin filament system. The Biochemical journal 377, 327-337.

Azim, A.C., Cao, H., Gao, X., Joo, M., Malik, A.B., van Breemen, R.B., Sadikot, R.T., Park, G., and Christman, J.W. (2007). Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages. American journal of physiology Lung cellular and molecular physiology 293, L668-673.

Batista, C.M., Mariano, E.D., Barbosa, B.J., Morgalla, M., Marie, S.K., Teixeira, M.J., and Lepski, G. (2014). Adult neurogenesis and glial oncogenesis: when the process fails. BioMed research international 2014, 438639.

Chan, A.Y., Coniglio, S.J., Chuang, Y.Y., Michaelson, D., Knaus, U.G., Philips, M.R., and Symons, M. (2005). Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene 24, 7821-7829.

Chastre, E., Abdessamad, M., Kruglov, A., Bruyneel, E., Bracke, M., Di Gioia, Y., Beckerle, M.C., van Roy, F., and Kotelevets, L. (2009). TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23, 916-928.

Colman, H., Zhang, L., Sulman, E.P., McDonald, J.M., Shooshtari, N.L., Rivera, A., Popoff, S., Nutt, C.L., Louis, D.N., Cairncross, J.G., et al. (2010). A multigene predictor of outcome in glioblastoma. Neuro-oncology 12, 49-57.

Corotto, F.S., Henegar, J.A., and Maruniak, J.A. (1993). Neurogenesis persists in the subependymal layer of the adult mouse brain. Neuroscience letters 149, 111-114.

de Almeida Sassi, F., Lunardi Brunetto, A., Schwartsmann, G., Roesler, R., and Abujamra, A.L. (2012). Glioma revisited: from neurogenesis and cancer stem cells to the epigenetic regulation of the niche. Journal of oncology 2012, 537861.

Ehm, O., Goritz, C., Covic, M., Schaffner, I., Schwarz, T.J., Karaca, E., Kempkes, B., Kremmer, E., Pfrieger, F.W., Espinosa, L., et al. (2010). RBPJkappa-dependent signaling is essential for long-term maintenance of neural stem cells in the adult hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 13794-13807.

Englund, C., Fink, A., Lau, C., Pham, D., Daza, R.A., Bulfone, A., Kowalczyk, T., and Hevner, R.F. (2005). Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 25, 247-251.

Eriksson, A., Cao, R., Roy, J., Tritsaris, K., Wahlestedt, C., Dissing, S., Thyberg, J., and Cao, Y. (2003). Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. Circulation 107, 1532-1538.

Ferri, A.L., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., Ottolenghi, S., Pandolfi, P.P., Sala, M., DeBiasi, S., et al. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 131, 3805-3819.

Fortin Ensign, S.P., Mathews, I.T., Symons, M.H., Berens, M.E., and Tran, N.L. (2013). Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression. Frontiers in oncology 3, 241.

Galli, R., Binda, E., Orfanelli, U., Cipelletti, B., Gritti, A., De Vitis, S., Fiocco, R., Foroni, C., Dimeco, F., and Vescovi, A. (2004). Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer research 64, 7011-7021.

Galuppo, R., McCall, A., and Gedaly, R. (2013). The role of bridging therapy in hepatocellular carcinoma. International journal of hepatology 2013, 419302.

Gemma, C., and Bachstetter, A.D. (2013). The role of microglia in adult hippocampal neurogenesis. Frontiers in cellular neuroscience 7, 229.

Gong, C., Wang, T.W., Huang, H.S., and Parent, J.M. (2007). Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 1803-1811.

Gonzales-Roybal, G., and Lim, D.A. (2013). Chromatin-based epigenetics of adult subventricular zone neural stem cells. Frontiers in genetics 4, 194.

Gotz, M., and Huttner, W.B. (2005). The cell biology of neurogenesis. Nature reviews Molecular cell biology 6, 777-788.

Grandbarbe, L. (2003). Delta-Notch signaling controls the generation of neurons/glia from neural stem cells in a stepwise process. Development 130, 1391-1402.

Haataja, L., Groffen, J., and Heisterkamp, N. (1997). Characterization of RAC3, a Novel Member of the Rho Family. Journal of Biological Chemistry 272, 20384-20388.

Hadjipanayis, C.G., and Van Meir, E.G. (2009). Tumor initiating cells in malignant gliomas: biology and implications for therapy. Journal of molecular medicine 87, 363-374.

Hai, H., Tamori, A., and Kawada, N. (2014). Role of hepatitis B virus DNA integration in human hepatocarcinogenesis. World journal of gastroenterology : WJG 20, 6236-6243.

Hevner, R.F., Shi, L., Justice, N., Hsueh, Y., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A.M., Campagnoni, A.T., and Rubenstein, J.L. (2001). Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29, 353-366.

Higashi, M., Ishikawa, C., Yu, J., Toyoda, A., Kawana, H., Kurokawa, K., Matsuda, M., Kitagawa, M., and Harigaya, K. (2009). Human Mena Associates with Rac1 Small GTPase in Glioblastoma Cell Lines. PloS one 4.

Hoelzinger, D.B., Nakada, M., Demuth, T., Rosensteel, T., Reavie, L.B., and Berens, M.E. (2008). Autotaxin: a secreted autocrine/paracrine factor that promotes glioma invasion. Journal of neuro-oncology 86, 297-309.

Johansson, C.B., Momma, S., Clarke, D.L., Risling, M.r., Lendahl, U., and Frise´n, J. (1999). Identification of a neural stem cell in the adult mammalian central nervous system. Cell Press 96, 25–34.

Kaneko, N., Kako, E., and Sawamoto, K. (2013). Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives. Frontiers in cellular neuroscience 7, 235.

Kasai, T., Chen, L., Mizutani, A., Kudoh, T., Murakami, H., Fu, L., and Seno, M. (2014). Cancer stem cells converted from pluripotent stem cells and the cancerous niche. Journal of stem cells & regenerative medicine 10, 2-7.

Katoh, H., Hiramoto, K., and Negishi, M. (2006). Activation of Rac1 by RhoG regulates cell migration. Journal of cell science 119, 56-65.

Kong, X., Ma, M.Z., Zhang, Y., Weng, M.Z., Gong, W., Guo, L.Q., Zhang, J.X., Wang, G.D., Su, Q., Quan, Z.W., et al. (2014). Differentiation therapy: sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma. BMC complementary and alternative medicine 14, 254.
Kwiatkowska, A., Didier, S., Fortin, S., Chuang, Y., White, T., Berens, M.E., Rushing, E., Eschbacher, J., Tran, N.L., Chan, A., et al. (2012). The small GTPase RhoG mediates glioblastoma cell invasion. Molecular cancer 11, 65.

Lai, Y.J., Chen, C.S., Lin, W.C., and Lin, F.T. (2005). c-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration. Molecular and cellular biology 25, 5859-5868.

Lai, Y.J., Lin, V.T., Zheng, Y., Benveniste, E.N., and Lin, F.T. (2010). The adaptor protein TRIP6 antagonizes Fas-induced apoptosis but promotes its effect on cell migration. Molecular and cellular biology 30, 5582-5596.

Lai, Y.J., Lin, W.C., and Lin, F.T. (2007). PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration. The Journal of biological chemistry 282, 24381-24387.

Lee, J. (2013). Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 17, 375-383.

Lee, J.S., Lee, J.S., Wagoner-Johnson, A., and Murphy, W.L. (2009). Modular peptide growth factors for substrate-mediated stem cell differentiation. Angewandte Chemie 48, 6266-6269.

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. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 5082-5089.

Liebano, R.E., and Machado, A.F. (2014). Vascular Endothelial Growth Factor Release Following Electrical Stimulation in Human Subjects. Advances in wound care 3, 98-103.

Lin, M.E., Herr, D.R., and Chun, J. (2010). Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins & other lipid mediators 91, 130-138.

Lin, V.T., and Lin, F.T. (2011). TRIP6: an adaptor protein that regulates cell motility, antiapoptotic signaling and transcriptional activity. Cellular signalling 23, 1691-1697.

Lin, V.T., Lin, V.Y., Lai, Y.J., Chen, C.S., Liu, K., Lin, W.C., and Lin, F.T. (2013). TRIP6 regulates p27 KIP1 to promote tumorigenesis. Molecular and cellular biology 33, 1394-1409.

Liu, H., and Zhang, S.C. (2011). Specification of neuronal and glial subtypes from human pluripotent stem cells. Cellular and molecular life sciences : CMLS 68, 3995-4008.

Lloyd, R.V., Hardin, H., Montemayor-Garcia, C., Rotondo, F., Syro, L.V., Horvath, E., and Kovacs, K. (2013). Stem cells and cancer stem-like cells in endocrine tissues. Endocrine pathology 24, 1-10.

Loirand, G., Sauzeau, V., and Pacaud, P. (2013). Small G proteins in the cardiovascular system: physiological and pathological aspects. Physiological reviews 93, 1659-1720.

Luskin, M.B. (1993). Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11, 173-189.

Mack, N.A., Whalley, H.J., Castillo-Lluva, S., and Malliri, A. (2011). The diverse roles of Rac signaling in tumorigenesis. Cell Cycle 10, 1571-1581.

Maher, E.A., Furnari, F.B., Bachoo, R.M., Rowitch, D.H., Louis, D.N., Cavenee, W.K., and DePinho, R.A. (2001). Malignant glioma: genetics and biology of a grave matter. Genes & development 15, 1311-1333.

Malaguti, M., Nistor, P.A., Blin, G., Pegg, A., Zhou, X., and Lowell, S. (2013). Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin. eLife.
MAO, L., and WANG, J.Q. (2003). Mao-Adult neural stem_progenitor cells in neurodegenerative repair. Acta Physiologica 55, 233-244.

Mayor, R., and Theveneau, E. (2014). The role of the non-canonical Wnt-planar cell polarity pathway in neural crest migration. The Biochemical journal 457, 19-26.

Meng, W., and Takeichi, M. (2009). Adherens junction: molecular architecture and regulation. Cold Spring Harbor perspectives in biology 1, a002899.

Ming, G.L., and Song, H. (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687-702.

Murga, C., Zohar, M., Teramoto, H., and Gutkind, J.S. (2002). Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene 21, 207-216.

Murthy, K.K., Clark, K., Fortin, Y., Shen, S.H., and Banville, D. (1999). ZRP-1, a Zyxin-related Protein, Interacts with the Second PDZ Domain of the Cytosolic Protein Tyrosine Phosphatase hPTP1E. Journal of Biological Chemistry 274, 20679-20687.

Nadarajah, B., Brunstrom, J.E., Grutzendler, J., Wong, R.O., and Pearlman, A.L. (2001). Two modes of radial migration in early development of the cerebral cortex. Nature neuroscience 4, 143-150.

NIH (2009). StemCellBasics.

Ojha, R., Jha, V., Singh, S.K., and Bhattacharrya, S. (2014). Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer. Biochimica et biophysica acta.

Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R.C., and Melton, D.A. (2002). "Stemness": transcriptional profiling of embryonic and adult stem cells. Science 298, 597-600.
Ridley, A.J., Paterson, H.F., Johnston, C.L., and Hall, A. (1992). The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell Press 70, 401-410.

Roberts, D.D. (2011). Activate Rac to rescue new vessels. Blood 117, 1444-1445.

Ross, S.E., Greenberg, M.E., and Stiles, C.D. (2003). Basic Helix-Loop-Helix Factors in Cortical Development. Neuron 39, 13-25.

Rousso, D.L., Pearson, C.A., Gaber, Z.B., Miquelajauregui, A., Li, S., Portera-Cailliau, C., Morrisey, E.E., and Novitch, B.G. (2012). Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. Neuron 74, 314-330.

Seki, T., and Arai, Y. (1993). Highly polysialylated neural cell adhesion molecule (NCAM-H) is expressed by newly generated granule cells in the dentate gyrus of the adult rat. The Journal of Neuroscience 13, 2351-2358.

Shahar, T., Nossek, E., Steinberg, D.M., Rozovski, U., Blumenthal, D.T., Bokstein, F., Sitt, R., Freedman, S., Corn, B.W., Kanner, A.A., et al. (2012). The impact of enrollment in clinical trials on survival of patients with glioblastoma. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 19, 1530-1534.

Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., and Dirks, P.B. (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.

Singla, S., Hochwald, S.N., and Kuvshinoff, B. (2014). Evolving Ablative Therapies for Hepatic Malignancy. BioMed research international 2014, 230174.

Soga, N., Connolly, J.O., Chellaiah, M., Kawamura, J., and Hruska, K.A. (2001). Rac regulates vascular endothelial growth factor stimulated motility. Cell communication & adhesion 8, 1-13.

Spassky, N., Merkle, F.T., Flames, N., Tramontin, A.D., Garcia-Verdugo, J.M., and Alvarez-Buylla, A. (2005). Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 25, 10-18.

Stiles, C.D., and Rowitch, D.H. (2008). Glioma stem cells: a midterm exam. Neuron 58, 832-846.

Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., and Honjo, T. (2001). Tanigaki-Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Cell Press 29, 45-55.

Verhaak, R.G., Hoadley, K.A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M.D., Miller, C.R., Ding, L., Golub, T., Mesirov, J.P., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell 17, 98-110.

Vincent, S., Jeanteur, P., and Fort, P. (1992). Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Molecular and cellular biology 12, 3138-3148.

Walker, M.P., Zhang, M., Le, T.P., Wu, P., Laine, M., and Greene, G.L. (2011). RAC3 is a pro-migratory co-activator of ERalpha. Oncogene 30, 1984-1994.

Wang, T.W., Stromberg, G.P., Whitney, J.T., Brower, N.W., Klymkowsky, M.W., and Parent, J.M. (2006). Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones. The Journal of comparative neurology 497, 88-100.

Wang, T.W., Zhang, H., Gyetko, M.R., and Parent, J.M. (2011). Hepatocyte growth factor acts as a mitogen and chemoattractant for postnatal subventricular zone-olfactory bulb neurogenesis. Molecular and cellular neurosciences 48, 38-50.

Wang, T.W., Zhang, H., and Parent, J.M. (2005). Retinoic acid regulates postnatal neurogenesis in the murine subventricular zone-olfactory bulb pathway. Development 132, 2721-2732.

Wang, Y., and Gilmore, T.D. (2001). LIM domain protein Trip6 has a conserved nuclear export signal, nuclear targeting sequences, and multiple transactivation domains. Biochimica et biophysica acta 1538, 260-272.

Wheeler, A.P., Wells, C.M., Smith, S.D., Vega, F.M., Henderson, R.B., Tybulewicz, V.L., and Ridley, A.J. (2006). Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. Journal of cell science 119, 2749-2757.

Williams, J.M., Chen, G.-C., Zhu2, L., and Rest, R.F. (1998). Using the yeast two-hybrid system to identify human epithelial cell proteins that bind gonococcal Opa proteins: intracellular gonococci bind pyruvate kinase via their Opa proteins and require host pyruvate for growth. Molecular Microbiology 27, 171–186.

Wong, S.Y., and Kumar, S. (2014). Matrix regulation of tumor-initiating cells. Progress in molecular biology and translational science 126, 243-256.

Worley, M.J., Nieman, G.S., Geddes, K., and Heffron, F. (2006). Salmonella typhimurium disseminates within its host by manipulating the motility of infected cells. Proceedings of the National Academy of Sciences of the United States of America 103, 17915-17920.

Xu, J., Lai, Y.J., Lin, W.C., and Lin, F.T. (2004). TRIP6 enhances lysophosphatidic acid-induced cell migration by interacting with the lysophosphatidic acid 2 receptor. The Journal of biological chemistry 279, 10459-10468.

Yang, W.H., Lan, H.Y., Huang, C.H., Tai, S.K., Tzeng, C.H., Kao, S.Y., Wu, K.J., Hung, M.C., and Yang, M.H. (2012). RAC1 activation mediates Twist1-induced cancer cell migration. Nature cell biology 14, 366-374.

Ying, M., Wang, S., Sang, Y., Sun, P., Lal, B., Goodwin, C.R., Guerrero-Cazares, H., Quinones-Hinojosa, A., Laterra, J., and Xia, S. (2011). Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 30, 3454-3467.

Zappone, M.V., Galli, R., Catena, R., Meani, N., De Biasi, S., Mattei, E., Tiveron, C., Vescovi, A.L., Lovell-Badge, R., Ottolenghi, S., et al. (2000). Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367-2382.

Zhang, J., Woodhead, G.J., Swaminathan, S.K., Noles, S.R., McQuinn, E.R., Pisarek, A.J., Stocker, A.M., Mutch, C.A., Funatsu, N., and Chenn, A. (2010). Cortical neural precursors inhibit their own differentiation via N-cadherin maintenance of beta-catenin signaling. Developmental cell 18, 472-479.

Zhao, Y., Alakhova, D.Y., and Kabanov, A.V. (2013). Can nanomedicines kill cancer stem cells? Advanced drug delivery reviews 65, 1763-1783.