Novel Homeodomain Transcription Factor Nkx2.2 in the Brain Tumor Development

Author(s): Mubeena P.M. Mariyath, Mehdi H. Shahi*, Shirin Farheen, Mohd Tayyab, Nabeela Khanam, Asif Ali

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 5 , 2020

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Graphical Abstract:


Background: Complex central nervous system (CNS) is made up of neuronal cells and glial cells. Cells of central nervous system are able to regenerate after injury and during repairing. Sonic hedgehog pathway initiated by Shh-N a glycoprotein plays vital role in CNS patterning growth, development and now tumorigenesis. Nkx2.2 homeodomain transcription factor is an effecter molecule, which is positively regulated by Shh during normal growth. Nkx2.2 is essential for V3 domain specification during neural tube patterning at embryonic stage. MBP + oligodendrocytes are differentiated from progenitor cells which express Olig2. Nx2.2 is co-expressed with Olig2 in oligodendrocytes and is essential for later stage of oligodendrocyte maturation.

Objective: This review paper explores the potential role of Nkx2.2 transcription factor in glioblastoma development.

Conclusion: Shh pathway plays a vital role in oligodendrocytes differentiation and Nkx2.2 transcription factor is essential for oligodendrocytes differentiation and maturation. Intriguingly, down regulation of Nkx2.2 transcription factor with aberrant Shh signaling pathway is reported in glioma samples. So here it is suggested that Nkx2.2 expression pattern could be used as a potential biomarker for the early diagnosis of glioma.

Keywords: Sonic hedgehog, Nkx2.2, Pax6, Olig2, oligodendrocytes, glioblastoma.

Gawlik-rzemieniewska, N.; Bednarek, I. The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells. Cancer Biol. Ther., 2016, 17, 1-10.
Briscoe, J.; Sussel, L.; Serup, P.; Connor, D. H. Homeobox gene Nkx2 . 2 and Speci ® cation of neuronal identity by graded sonic hedgehog signalling. 1999, 398, 622-627.
Briscoe, J.; Pierani, A.; Jessell, T.M.; Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell, 2000, 101, 435-445.
Gama, A.M.D.; Geng, Y.; Couto, J.A.; Martin, B.; Boyle, E.A.; Lacoursiere, C.M.; Hossain, A.; Nicole, E.; Barry, B.; Kwiatkowski, D.J. mTOR pathway mutations cause hemimegalencephaly and focal cortical dysplasia alissa. Ann. Neurol., 2016, 77, 720-725.
Jiang, Y.; Sheng, H.; Meng, L.; Yue, H.; Li, B.; Zhang, A.; Dong, Y. RBM5 inhibits tumorigenesis of gliomas through inhibition of Wnt / β -catenin signaling and induction of apoptosis; Biomed. Central, 2017, pp. 1-8.
U, J. B.; Ericson, J. The specification of neuronal identity by graded sonic hedgehog signalling. Cell Dev. Biol., 1999, 10, 353-362.
Shahi, M.H.; Díaz, E. Transcription factor targets as treatment for medulloblastoma; Brain Tumors-Current and Emerging Therapeutic Strategies, 2010, pp. 209-224.
Shahi, M.H.; Lorente, A.; Castresana, J.S. Hedgehog signalling in medulloblastoma, glioblastoma and neuroblastoma. Oncol. Rep., 2008, 19, 681-688.
Marigo, V.; Roberts, D.J.; Lee, S.M.; Tsukurov, O.; Levi, T.; Gastier, J.M.; Epstein, D.J.; Gilbert, D.J.; Copeland, N.G.; Seidman, C.E. Cloning, expression, and chromosomal location of SHH and IHH: Two human homologues of the drosophila segment polarity gene hedgehog. Genomics, 1995, 28, 44-51.
Nüsslein-Volhard, C.; Wieschaus, E. Mutations affecting segment number and polarity in drosophila. Nature, 1980, 287, 795-801.
Sansom, S.N.; Livesey, F.J. Gradients in the brain: The control of the development of form and function in the cerebral cortex. Cold Spring Harborperspectives Biol., 2009, 1, 1-16.
Porter, J.A.; Ekker, S.C.; Park, W.J.; Von Kessler, D.P.; Young, K.E.; Chen, C.H.; Ma, Y.; Woods, A.S.; Cotter, R.J.; Koonin, E.V.; Beachy, P.A. Hedgehog patterning activity : Role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. 1996, 86, 21-34.
Pepinsky, R.B. Zeng, C.; Wen, D.; Rayhorn, P.; Baker, D.P.; Williams, K.P.; Bixler, S.A.; Ambrose, C.M.; Garber, E.A.; Miatkowski, K.; Taylor, F.R. Identification of a palmitic acid-modified form of human sonic hedgehog. J. Biol. Chem., 1998, 273, 14037-14045.
Goodrich, L.V.; Jung, D.; Higgins, K.M.; Scott, M.P. Overexpression of ptc1 inhibits induction of shh target genes and prevents normal patterning in the neural tube. Dev. Biol., 1999, 211, 323-334.
Stone, D.M.; Hynes, M.; Armanini, M.; Swanson, T.A.; Gu, Q.; Johnson, R.L.; Scott, M.P.; Pennica, D.; Goddard, A.; Phillips, H.; Noll, M. The tumour-suppressor gene patched encodes a candidate receptor for sonic hedgehog. Nature, 1996, 384, 129-134.
Hahn, H.; Christiansen, J.; Wicking, C.; Zaphiropoulos, P.G.; Chidambaram, A.; Gerrard, B.; Vorechovsky, I.; Bale, A.E.; Toftgard, R.; Dean, M.; Wainwright, B. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J. Biol. Chem., 1996, 271, 12125-12129.
Yoon, J.W.; Kita, Y.; Frank, D.J.; Majewski, R.R.; Konicek, B.A.; Nobrega, M.A.; Jacob, H.; Walterhouse, D.; Iannaccone, P. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J. Biol. Chem., 2002, 277, 5548-5555.
Shahi, M.H.; Afzal, M.; Sinha, S.; Eberhart, C.G.; Rey, J. a; Fan, X.; Castresana, J. S. Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma. BMC Cancer, 2010, 10, 614-634.
Watada, H.; Mirmira, R.G.; Kalamaras, J.; German, M.S. Intramolecular control of transcriptional activity by the NK2-specific domain in nk-2 homeodomain proteins. Proc. Natl. Acad. Sci. USA, 2000, 97, 9443-9448.
Bhat, S.; Kabekkodu, S.P.; Varghese, V.K.; Chakrabarty, S.; Mallya, S.P.; Rotti, H.; Pandey, D.; Kushtagi, P.; Satyamoorthy, K. Aberrant gene-specific DNA methylation signature analysis in cervical cancer. Tumour Biol., 2017, 39, 1-16.
Dayer, D.; Tabar, M.H.; Moghimipour, E.; Tabandeh, M.R.; Ghadiri, A.A.; Bakhshi, E.A.; Orazizadeh, M.; Ghafari, M.A. Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. Cytotherapy, 2016, 18, 937-946.
Mitutsova, V.; Yeo, W.W.Y.; Davaze, R.; Franckhauser, C.; Hani, E-H.; Abdullah, S.; Mollard, P.; Schaeffer, M.; Fernandez, A.; Lamb, N.J.C. Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice. Stem Cell Res. Ther., 2017, 8, 86-100.
Kim, Y.; Nirenberg, M. Drosophila NK-homeobox genes. Proc. Natl. Acad. Sci. USA, 1989, 86, 7716-7720.
Lints, T.J.; Parsons, L.M.; Hartley, L.; Lyons, I.; Harvey, R.P. Nkx-2. 5 : A novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development, 1993, 119, 419-431.
Dna, N. -. Drosophila NK-homeobox genes. Biochemistry, 1989, 86, 7716-7720.
Hessabi, B.; Schmidt, I.; Walther, R. The homeodomain of Nkx2.2 carries two cooperatively acting nuclear localization signals. Biochem. Biophys. Res. Commun., 2000, 270, 695-700.
Sun, T.; Dong, H.; Wu, L.; Kane, M.; Rowitch, D.H.; Stiles, C.D. Cross-repressive interaction of the Olig2 and Nkx2.2 transcription factors in developing neural tube associated with formation of a specific physical complex. J. Neurosci., 2003, 23, 9547-9556.
Briscoe, J. Morphogens, modeling and patterning the neural tube: An interview with james briscoe. BMC Biol., 2015, 13, 1-5.
Son, H.Y.; Hwangbo, Y.; Yoo, S.K.; Im, S.W.; Kwak, S.J.; Park, M.S.; Kwak, S.H.; Cho, S.W.; Ryu, J.S.; Kim, J.; Jung, Y.S. Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer. Nat. Commun., 2017, 8, 1-12.
Griesing, S.; Kajino, T.; Tai, M.C.; Liu, Z.; Nakatochi, M.; Shimada, Y.; Suzuki, M.; Takahashi, T. Thyroid transcription factor-1-regulated microRNA-532-5p targets KRAS and MKL2 Oncogenes and induces apoptosis in lung adenocarcinoma cells. Cancer Sci., 2017, 108, 1394-1404.
Smith, R.; Owen, L.A.; Trem, D.J.; Wong, J.S.; Whangbo, J.S.; Golub, T.R.; Lessnick, S.L. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell, 2006, 9, 405-416.
Hung, Y.P.; Fletcher, C.D.M.; Hornick, J.L. Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: Imperfect specificity for Ewing Sarcoma. Mod. Pathol., 2016, 29, 370-380.
Lu, X.; Tang, L.; Li, K.; Zheng, J.; Zhao, P.; Tao, Y.; Li, L-X. Contribution of NKX2-3 polymorphisms to inflammatory bowel diseases: A meta-analysis of 35358 subjects. Sci. Rep., 2014, 4, 1-9.
Xu, J.H.; Gu, J.Y.; Guo, Y.H.; Zhang, H.; Qiu, X.B.; Li, R.G.; Shi, H.Y.; Liu, H.; Yang, X.X.; Xu, Y.J.; Qu, X.K. Prevalence and spectrum of NKX2-5 mutations associated with sporadic adult-onset dilated cardiomyopathy. Int. Heart J., 2017, 58, 1-9.
Wang, J.; Zhang, D.F.; Sun, Y.M.; Li, R.G.; Qiu, X.B.; Qu, X.K.; Liu, X.; Fang, W.Y.; Yang, Y.Q. NKX2-6 Mutation predisposes to familial atrial fibrillation. Int. J. Mole. Med., 2014, 34, 1581-1590.
Wang, J.; Mao, J.H.; Ding, K.K.; Xu, W.J.; Liu, X.Y.; Qiu, X.B.; Li, R.G.; Qu, X.K.; Xu, Y.J.; Huang, R.T.; Xue, S. A novel NKX2.6 mutation associated with congenital ventricular septal defect. Pediatr. Cardiol., 2014, 36, 646-656.
Qi, Y.; Cai, J.; Wu, Y.; Wu, R.; Lee, J.; Fu, H.; Rao, M.; Sussel, L. Control of oligodendrocyte differentiation by the Nkx2. 2 Homeodomain Transcription Factor. Development, 2001, 128, 2723-2733.
Tanaka, T.; Yoshida, S. Mechanisms of remyelination : Recent insight from experimental models. Biomol. Concepts, 2014, 5, 289-298.
Samanta, J.; Kessler, J.A. Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development, 2004, 131, 4131-4142.
Shimizu, T.; Kagawa, T.; Wada, T.; Muroyama, Y.; Takada, S.; Ikenaka, K. Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Dev. Biol., 2005, 282, 397-410.
Park, H-C.; Appel, B. Delta-notch signaling regulates oligodendrocyte specification. Development (Cambridge, England), 2003, 130, 3747-3755.
Murray, K.; Calaora, V.; Rottkamp, C.; Guicherit, O.; Dubois-dalcq, M. Sonic hedgehog is a potent inducer of rat oligodendrocyte development from cortical precursors in vitro. Mol. Cell. Neurosci., 2002, 19, 320-332.
Fancy, S.P.J.; Zhao, C.; Franklin, R.J.M. Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. Mol. Cell. Neurosci., 2004, 27, 247-254.
Douarin, N.M. Le. Oligodendrocyte precursors originate from both the dorsal and the ventral parts of the spinal cord. Neuron, 1995, 15, 1299-1310.
Fu, H.; Qi, Y.; Tan, M.; Cai, J.; Takebayashi, H.; Nakafuku, M. Dual origin of spinal oligodendrocyte progenitors and evidence for the cooperative role of olig2 and Nkx2. 2 in the control of oligodendrocyte differentiation. Development, 2002, 129, 681-693.
Affeldt, B.M.; Obenaus, A.; Chan, J.; Pardo, A.C. Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury. Int. J. Dev. Neurosci., 2017, 61, 1-11.
Kremer, D.; Cui, Q.L.; Göttle, P.; Kuhlmann, T.; Hartung, H.P.; Antel, J.; Küry, P. CXCR7 is involved in human oligodendroglial precursor cell maturation. PLoS One, 2016, 11, 1-12.
Tochitani, S.; Hayashizaki, Y. Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation. Biochem. Biophys. Res. Commun., 2008, 372, 691-696.
Zhou, Q.; Choi, G.; Anderson, D.J. The bHLH transcription factor olig2 promotes oligodendrocyte differentiation in collaboration with Nkx2. 2. Neuron, 2001, 31, 791-807.
Rodrigues, G.M.; Gaj, T.; Adil, M.M.; Wahba, J.; Rao, A.T.; Lorbeer, F.K.; Kulkarni, R.U.; Diogo, M.M.; Cabral, J.M.; Miller, E.W.; Hockemeyer, D. Defined and scalable differentiation of human oligodendrocyte precursors from pluripotent stem cells in a 3D culture system. Stem Cell Reports, 2017, 8, 1-14.
Lee, S.; Lee, B.; Ruiz, E.C.; Pfaff, S.L. Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Gener Dev., 2005, 19, 282-294.
Holz, A.; Kollmus, H.; Ryge, J.; Niederkofler, V.; Dias, J.; Ericson, J.; Stoeckli, E.T.; Kiehn, O.; Arnold, H-H. The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance. Development (Cambridge, England), 2010, 137, 4249-4260.
Ericson, J.; Morton, S.; Kawakami, A.; Roelink, H.; Jessell, T.M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity. Cell, 1996, 87, 661-673.
Jarrar, W.; Vauti, F.; Arnold, H-H.; Holz, A. Generation of a Nkx2.2(Cre) knock-in mouse line: Analysis of cell lineages in the central nervous system. Differentiation, 2015, 89, 1-7.
Chow, B.A.Y.; Division, P.D.; Biology, C. Cell cycle control by oncogenes and tumor suppressors : Driving the transformation of normal cells into cancerous cells appropriately drive progression from one cell cycle stage to the next. Nature Education, 2010, 1205, 1-4.
Hoshino, T.W.C. Review of basic concepts of cell kinetics as applied to brain tumors. J. Neurosurg., 1975, 42, 123-131.
Dunn, G.P.; Rinne, M.L.; Wykosky, J.; Genovese, G.; Quayle, S.N.; Dunn, I.F.; Agarwalla, P.K.; Chheda, M.G.; Campos, B.; Wang, A. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev., 2012, 26, 756-784.
Mattern, R-H.; Read, S.B.; Pierschbacher, M.D.; Sze, C-I.; Eliceiri, B.P.; Kruse, C.A. Glioma cell integrin expression and their interactions with integrin antagonists. Cancer Ther., 2005, 3A, 325-340.
Shahi, M.H.; Rey, J.A.; Castresana, J.S. The sonic hedgehog-GLI1 signaling pathway in brain tumor development. Expert Opin. Ther. Targets, 2012, 16, 1227-1238.
Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol., 2007, 17, 165-172.
Shahi, M.H.; Farheen, S.; Mariyath, M.P.M.; Castresana, J.S. Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance. Tumor Biol., 2016, 37, 15107-15114.
Balbous, A.; Renoux, B.; Cortes, U.; Milin, S.; Guilloteau, K.; Tripiana, C.; Legigan, T.; Rivet, P.; Boissonnade, O.; Karayan-tapon, L. Selective release of a cyclopamine glucuronide prodrug toward stem-like cancer cell inhibition in glioblastoma. Mol. Cancer Ther., 2014, 13, 2159-2170.
Song, L.; Wang, W.; Liu, D.I.; Zhao, Y.; He, J.; Wang, X.; Dai, Z.; Zhang, H.; Li, X. Targeting of sonic hedgehog - Gli signaling : A potential therapeutic target for patients with breast cancer. Oncol. Lett., 2016, 12, 1027-1033.
Han, L.; Ma, J.; Duan, W.; Zhang, L.; Yu, S.; Xu, Q.; Lei, J.; Li, X.; Wang, Z.; Wu, Z. Pancreatic stellate cells contribute pancreatic cancer pain via activation of shh signaling pathway. Oncotarget, 2016, 7, 18146-18158.
Muraguchi, T.; Tanaka, S.; Yamada, D.; Tamase, A.; Nakada, M.; Nakamura, H.; Hoshii, T.; Ooshio, T.; Tadokoro, Y.; Naka, K. NKX2.2 suppresses self-renewal of glioma-initiating cells. Cancer Res., 2011, 71, 1135-1145.
Genethliou, N.; Panayiotou, E.; Panayi, H.; Orford, M.; Mean, R.; Lapathitis, G.; Malas, S. Spatially distinct functions of PAX6 and NKX2.2 during gliogenesis in the ventral spinal cord. Biochem. Biophys. Res. Commun., 2009, 382, 69-73.

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Year: 2020
Published on: 04 June, 2020
Page: [335 - 340]
Pages: 6
DOI: 10.2174/1568009618666180102111539
Price: $65

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