[en] Leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) is an endogenous feedback regulator of receptor tyrosine kinases (RTKs) and was recently shown to inhibit growth of different types of malignancies. Additionally, this multifaceted RTK inhibitor was reported to be a tumor suppressor, a stem cell regulator, and a modulator of different cellular phenotypes. This mini-review provides a concise and up-to-date summary about the known functions of LRIG1 and its related family members, with a special emphasis on underlying molecular mechanisms and the opportunities for harnessing its therapeutic potential against cancer.
Disciplines :
Oncology
Author, co-author :
Neirinckx, Virginie; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg.
Hedman, Hakan; Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, 90187 Umeå, Sweden.
NICLOU, Simone P. ; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 1526, Luxembourg, K.G. Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, 5020 Bergen, Norway. Electronic address: simone.niclou@lih.lu.
External co-authors :
yes
Language :
English
Title :
Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy.
[1] Gschwind, A., Fischer, O.M., Ullrich, A., The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat. Rev. Cancer 4 (2004), 361–370.
[4] Levitzki, A., Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu. Rev. Pharmacol. Toxicol. 53 (2013), 161–185.
[5] Jackman, D., Pao, W., Riely, G.J., Engelman, J.A., Kris, M.G., Janne, P.A., Lynch, T., Johnson, B.E., Miller, V.A., Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 28 (2010), 357–360.
[6] Kobayashi, S., Boggon, T.J., Dayaram, T., Janne, P.A., Kocher, O., Meyerson, M., Johnson, B.E., Eck, M.J., Tenen, D.G., Halmos, B., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352 (2005), 786–792.
[7] Pao, W., Miller, V.A., Politi, K.A., Riely, G.J., Somwar, R., Zakowski, M.F., Kris, M.G., Varmus, H., Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med., 2, 2005, e73.
[8] Pao, W., Wang, T.Y., Riely, G.J., Miller, V.A., Pan, Q., Ladanyi, M., Zakowski, M.F., Heelan, R.T., Kris, M.G., Varmus, H.E., KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med., 2, 2005, e17.
[9] Sequist, L.V., Waltman, B.A., Dias-Santagata, D., Digumarthy, S., Turke, A.B., Fidias, P., Bergethon, K., Shaw, A.T., Gettinger, S., Cosper, A.K., Akhavanfard, S., Heist, R.S., Temel, J., Christensen, J.G., Wain, J.C., Lynch, T.J., Vernovsky, K., Mark, E.J., Lanuti, M., Iafrate, A.J., Mino-Kenudson, M., Engelman, J.A., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med., 3(75), 2011, 75ra26.
[10] Bivona, T.G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., Moonsamy, P., Dahlman, K., Miller, V.A., Costa, C., Hannon, G., Sawyers, C.L., FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471 (2011), 523–526.
[11] Niederst, M.J., Engelman, J.A., Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal., 6, 2013, re6.
[12] Ma, Y., Tang, N., Thompson, R.C., Mobley, B.C., Clark, S.W., Sarkaria, J.N., Wang, J., InsR/IGF1R pathway mediates resistance to EGFR inhibitors in glioblastoma. Clin. Cancer Res. 22 (2016), 1767–1776.
[13] Akhavan, D., Pourzia, A.L., Nourian, A.A., Williams, K.J., Nathanson, D., Babic, I., Villa, G.R., Tanaka, K., Nael, A., Yang, H., Dang, J., Vinters, H.V., Yong, W.H., Flagg, M., Tamanoi, F., Sasayama, T., James, C.D., Kornblum, H.I., Cloughesy, T.F., Cavenee, W.K., Bensinger, S.J., Mischel, P.S., De-repression of PDGFRbeta transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. Cancer Discov. 3 (2013), 534–547.
[14] Brandman, O., Meyer, T., Feedback loops shape cellular signals in space and time. Science 322 (2008), 390–395.
[15] Ostman, A., Bohmer, F.D., Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 11 (2001), 258–266.
[16] Mohapatra, B., Ahmad, G., Nadeau, S., Zutshi, N., An, W., Scheffe, S., Dong, L., Feng, D., Goetz, B., Arya, P., Bailey, T.A., Palermo, N., Borgstahl, G.E., Natarajan, A., Raja, S.M., Naramura, M., Band, V., Band, H., Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases. Biochim. Biophys. Acta 1833 (2013), 122–139.
[17] Goh, L.K., Sorkin, A., Endocytosis of receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol., 5, 2013, a017459.
[18] Donzelli, S., Cioce, M., Muti, P., Strano, S., Yarden, Y., Blandino, G., MicroRNAs: non-coding fine tuners of receptor tyrosine kinase signalling in cancer. Semin. Cell Dev. Biol. 50 (2016), 133–142.
[21] Segatto, O., Anastasi, S., Alema, S., Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors. J. Cell Sci. 124 (2011), 1785–1793.
[22] Nilsson, J., Vallbo, C., Guo, D., Golovleva, I., Hallberg, B., Henriksson, R., Hedman, H., Cloning, characterization, and expression of human LIG1. Biochem. Biophys. Res. Commun. 284 (2001), 1155–1161.
[23] Gur, G., Rubin, C., Katz, M., Amit, I., Citri, A., Nilsson, J., Amariglio, N., Henriksson, R., Rechavi, G., Hedman, H., Wides, R., Yarden, Y., LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 23 (2004), 3270–3281.
[24] Laederich, M.B., Funes-Duran, M., Yen, L., Ingalla, E., Wu, X., Carraway, K.L. 3rd, Sweeney, C., The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J. Biol. Chem. 279 (2004), 47050–47056.
[25] Wong, V.W., Stange, D.E., Page, M.E., Buczacki, S., Wabik, A., Itami, S., van de Wetering, M., Poulsom, R., Wright, N.A., Trotter, M.W., Watt, F.M., Winton, D.J., Clevers, H., Jensen, K.B., Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14 (2012), 401–408.
[26] Powell, A.E., Wang, Y., Li, Y., Poulin, E.J., Means, A.L., Washington, M.K., Higginbotham, J.N., Juchheim, A., Prasad, N., Levy, S.E., Guo, Y., Shyr, Y., Aronow, B.J., Haigis, K.M., Franklin, J.L., Coffey, R.J., The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149 (2012), 146–158.
[27] Ledda, F., Bieraugel, O., Fard, S.S., Vilar, M., Paratcha, G., Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF. J. Neurosci. 28 (2008), 39–49.
[28] Shattuck, D.L., Miller, J.K., Laederich, M., Funes, M., Petersen, H., Carraway, K.L. 3rd, Sweeney, C., LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy. Mol. Cell. Biol. 27 (2007), 1934–1946.
[29] Rondahl, V., Holmlund, C., Karlsson, T., Wang, B., Faraz, M., Henriksson, R., Hedman, H., Lrig2-deficient mice are protected against PDGFB-induced glioma. PLoS One, 8, 2013, e73635.
[30] Alsina, F.C., Hita, F.J., Fontanet, P.A., Irala, D., Hedman, H., Ledda, F., Paratcha, G., Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling. EMBO Rep. 17 (2016), 601–616.
[31] Lindquist, D., Kvarnbrink, S., Henriksson, R., Hedman, H., LRIG and cancer prognosis. Acta Oncol. 53 (2014), 1135–1142.
[32] Simion, C., Cedano-Prieto, M.E., Sweeney, C., The LRIG family: enigmatic regulators of growth factor receptor signaling. Endocr. Relat. Cancer 21 (2014), R431–R443.
[33] Wang, Y., Poulin, E.J., Coffey, R.J., LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. Br. J. Cancer 108 (2013), 1765–1770.
[34] Mandai, K., Guo, T., Hillaire, C. St, Meabon, J.S., Kanning, K.C., Bothwell, M., Ginty, D.D., LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development. Neuron 63 (2009), 614–627.
[35] Mi, S., Lee, X., Shao, Z., Thill, G., Ji, B., Relton, J., Levesque, M., Allaire, N., Perrin, S., Sands, B., Crowell, T., Cate, R.L., McCoy, J.M., Pepinsky, R.B., LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7 (2004), 221–228.
[36] Kim, S., Burette, A., Chung, H.S., Kwon, S.K., Woo, J., Lee, H.W., Kim, K., Kim, H., Weinberg, R.J., Kim, E., NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nat. Neurosci. 9 (2006), 1294–1301.
[37] Kuja-Panula, J., Kiiltomaki, M., Yamashiro, T., Rouhiainen, A., Rauvala, H., AMIGO, a transmembrane protein implicated in axon tract development, defines a novel protein family with leucine-rich repeats. J. Cell Biol. 160 (2003), 963–973.
[38] Ozkan, E., Carrillo, R.A., Eastman, C.L., Weiszmann, R., Waghray, D., Johnson, K.G., Zinn, K., Celniker, S.E., Garcia, K.C., An extracellular interactome of immunoglobulin and LRR proteins reveals receptor-ligand networks. Cell 154 (2013), 228–239.
[39] de Wit, J., Ghosh, A., Specification of synaptic connectivity by cell surface interactions. Nat. Rev. Neurosci. 17 (2016), 22–35.
[40] Meabon, J.S., de Laat, R., Ieguchi, K., Serbzhinsky, D., Hudson, M.P., Huber, B.R., Wiley, J.C., Bothwell, M., Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling. Mol. Cell. Neurosci. 70 (2016), 1–10.
[41] Meabon, J.S., De Laat, R., Ieguchi, K., Wiley, J.C., Hudson, M.P., Bothwell, M., LINGO-1 protein interacts with the p75 neurotrophin receptor in intracellular membrane compartments. J. Biol. Chem. 290 (2015), 9511–9520.
[42] Inoue, H., Lin, L., Lee, X., Shao, Z., Mendes, S., Snodgrass-Belt, P., Sweigard, H., Engber, T., Pepinsky, B., Yang, L., Beal, M.F., Mi, S., Isacson, O., Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson's disease models. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 14430–14435.
[43] Mosyak, L., Wood, A., Dwyer, B., Buddha, M., Johnson, M., Aulabaugh, A., Zhong, X., Presman, E., Benard, S., Kelleher, K., Wilhelm, J., Stahl, M.L., Kriz, R., Gao, Y., Cao, Z., Ling, H.P., Pangalos, M.N., Walsh, F.S., Somers, W.S., The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J. Biol. Chem. 281 (2006), 36378–36390.
[44] Zhao, H., Tanegashima, K., Ro, H., Dawid, I.B., Lrig3 regulates neural crest formation in Xenopus by modulating Fgf and Wnt signaling pathways. Development 135 (2008), 1283–1293.
[45] Wu, M., Huang, C., Gan, K., Huang, H., Chen, Q., Ouyang, J., Tang, Y., Li, X., Yang, Y., Zhou, H., Zhou, Y., Zeng, Z., Xiao, L., Li, D., Tang, K., Shen, S., Li, G., LRRC4, a putative tumor suppressor gene, requires a functional leucine-rich repeat cassette domain to inhibit proliferation of glioma cells in vitro by modulating the extracellular signal-regulated kinase/protein kinase B/nuclear factor-kappaB pathway. Mol. Biol. Cell 17 (2006), 3534–3542.
[46] Morrison, M.M., Williams, M.M., Vaught, D.B., Hicks, D., Lim, J., McKernan, C., Aurisicchio, L., Ciliberto, G., Simion, C., Sweeney, C., Cook, R.S., Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth. Oncogene 35 (2016), 1143–1152.
[47] Rafidi, H., Mercado, F. 3rd, Astudillo, M., Fry, W.H., Saldana, M., Carraway, K.L. 3rd, Sweeney, C., Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3). J. Biol. Chem. 288 (2013), 21593–21605.
[48] Goldoni, S., Iozzo, R.A., Kay, P., Campbell, S., McQuillan, A., Agnew, C., Zhu, J.X., Keene, D.R., Reed, C.C., Iozzo, R.V., A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity. Oncogene 26 (2007), 368–381.
[49] Johansson, M., Oudin, A., Tiemann, K., Bernard, A., Golebiewska, A., Keunen, O., Fack, F., Stieber, D., Wang, B., Hedman, H., Niclou, S.P., The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status. Neuro-Oncology 15 (2013), 1200–1211.
[50] Yi, W., Holmlund, C., Nilsson, J., Inui, S., Lei, T., Itami, S., Henriksson, R., Hedman, H., Paracrine regulation of growth factor signaling by shed leucine-rich repeats and immunoglobulin-like domains 1. Exp. Cell Res. 317 (2011), 504–512.
[52] Thien, C.B., Langdon, W.Y., Cbl: many adaptations to regulate protein tyrosine kinases. Nat. Rev. Mol. Cell Biol. 2 (2001), 294–307.
[53] Thien, C.B., Walker, F., Langdon, W.Y., RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are insufficient for cell transformation. Mol. Cell 7 (2001), 355–365.
[55] Ghiglione, C., Amundadottir, L., Andresdottir, M., Bilder, D., Diamonti, J.A., Noselli, S., Perrimon, N., Carraway, I.K., Mechanism of inhibition of the Drosophila and mammalian EGF receptors by the transmembrane protein Kekkon 1. Development 130 (2003), 4483–4493.
[57] Xiao, Q., Tan, Y., Guo, Y., Yang, H., Mao, F., Xie, R., Wang, B., Lei, T., Guo, D., Soluble LRIG2 ectodomain is released from glioblastoma cells and promotes the proliferation and inhibits the apoptosis of glioblastoma cells in vitro and in vivo in a similar manner to the full-length LRIG2. PLoS One, 9, 2014, e111419.
[58] van Erp, S., van den Heuvel, D.M., Fujita, Y., Robinson, R.A., Hellemons, A.J., Adolfs, Y., Van Battum, E.Y., Blokhuis, A.M., Kuijpers, M., Demmers, J.A., Hedman, H., Hoogenraad, C.C., Siebold, C., Yamashita, T., Pasterkamp, R.J., Lrig2 negatively regulates ectodomain shedding of axon guidance receptors by ADAM proteases. Dev. Cell 35 (2015), 537–552.
[59] Guo, D., Yang, H., Guo, Y., Xiao, Q., Mao, F., Tan, Y., Wan, X., Wang, B., Lei, T., LRIG3 modulates proliferation, apoptosis and invasion of glioblastoma cells as a potent tumor suppressor. J. Neurol. Sci. 350 (2015), 61–68.
[60] Jensen, K.B., Watt, F.M., Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 11958–11963.
[61] Jensen, K.B., Collins, C.A., Nascimento, E., Tan, D.W., Frye, M., Itami, S., Watt, F.M., Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 4 (2009), 427–439.
[63] Kretzschmar, K., Weber, C., Driskell, R.R., Calonje, E., Watt, F.M., Compartmentalized epidermal activation of beta-catenin differentially affects lineage reprogramming and underlies tumor heterogeneity. Cell Rep. 14 (2016), 269–281.
[64] Powell, A.E., Vlacich, G., Zhao, Z.Y., McKinley, E.T., Washington, M.K., Manning, H.C., Coffey, R.J., Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. Am. J. Physiol. Gastrointest. Liver Physiol. 307 (2014), G16–G23.
[65] Poulin, E.J., Powell, A.E., Wang, Y., Li, Y., Franklin, J.L., Coffey, R.J., Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine. Stem Cell Res. 13 (2014), 422–430.
[66] Kondo, J., Powell, A.E., Wang, Y., Musser, M.A., Southard-Smith, E.M., Franklin, J.L., Coffey, R.J., LRIG1 regulates ontogeny of smooth muscle-derived subsets of interstitial cells of Cajal in mice. Gastroenterology 149 (2015), 407–419 (e408).
[67] Nakamura, T., Hamuro, J., Takaishi, M., Simmons, S., Maruyama, K., Zaffalon, A., Bentley, A.J., Kawasaki, S., Nagata-Takaoka, M., Fullwood, N.J., Itami, S., Sano, S., Ishii, M., Barrandon, Y., Kinoshita, S., LRIG1 inhibits STAT3-dependent inflammation to maintain corneal homeostasis. J. Clin. Invest. 124 (2014), 385–397.
[68] Quist, S.R., Eckardt, M., Kriesche, A., Gollnick, H.P., Expression of stem cell markers in skin and adnexal malignancies. Br. J. Dermatol., 2016.
[69] Frances, D., Sharma, N., Pofahl, R., Maneck, M., Behrendt, K., Reuter, K., Krieg, T., Klein, C.A., Haase, I., Niemann, C., A role for Rac1 activity in malignant progression of sebaceous skin tumors. Oncogene 34 (2015), 5505–5512.
[73] Das, B.C., Tyagi, A., Vishnoi, K., Mahata, S., Verma, G., Srivastava, Y., Masaldan, S., Roy, B.G., Bharti, A.C., Cervical cancer stem cells selectively overexpress HPV oncoprotein E6 that controls stemness and self renewal through upregulation of HES1. Clin. Cancer Res., 2016.
[74] Miller, J.K., Shattuck, D.L., Ingalla, E.Q., Yen, L., Borowsky, A.D., Young, L.J., Cardiff, R.D., Carraway, K.L. 3rd, Sweeney, C., Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer Res. 68 (2008), 8286–8294.
[75] Bai, L., McEachern, D., Yang, C.Y., Lu, J., Sun, H., Wang, S., LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFalpha expression and receptor tyrosine kinase signaling. Cancer Res. 72 (2012), 1229–1238.
[76] Yokdang, N., Hatakeyama, J., Wald, J.H., Simion, C., Tellez, J.D., Chang, D.Z., Swamynathan, M.M., Chen, M., Murphy, W.J., Carraway Iii, K.L., Sweeney, C., LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene, 2015.
[77] Yang, W.M., Yan, Z.J., Ye, Z.Q., Guo, D.S., LRIG1, a candidate tumour-suppressor gene in human bladder cancer cell line BIU87. BJU Int. 98 (2006), 898–902.
[78] Sheu, J.J., Lee, C.C., Hua, C.H., Li, C.I., Lai, M.T., Lee, S.C., Cheng, J., Chen, C.M., Chan, C., Chao, S.C., Chen, J.Y., Chang, J.Y., Lee, C.H., LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene 33 (2014), 1375–1384.
[79] Mao, F., Wang, B., Xiao, Q., Xi, G., Sun, W., Zhang, H., Ye, F., Wan, F., Guo, D., Lei, T., Chen, X., A role for LRIG1 in the regulation of malignant glioma aggressiveness. Int. J. Oncol. 42 (2013), 1081–1087.
[80] Lu, L., Teixeira, V.H., Yuan, Z., Graham, T.A., Endesfelder, D., Kolluri, K., Al-Juffali, N., Hamilton, N., Nicholson, A.G., Falzon, M., Kschischo, M., Swanton, C., Wright, N.A., Carroll, B., Watt, F.M., George, J.P., Jensen, K.B., Giangreco, A., Janes, S.M., LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development. J. Pathol. 229 (2013), 608–620.
[81] Lamouille, S., Xu, J., Derynck, R., Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15 (2014), 178–196.
[82] De Craene, B., Berx, G., Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13 (2013), 97–110.
[83] Zhang, X., Song, Q., Wei, C., Qu, J., LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells. Cell Stress Chaperones 20 (2015), 631–641.
[84] Wang, Y., Shi, C., Lu, Y., Poulin, E.J., Franklin, J.L., Coffey, R.J., Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia. Am. J. Pathol. 185 (2015), 1123–1134.
[85] Kou, C., Zhou, T., Han, X., Zhuang, H., Qian, H., LRIG1, a 3p tumor suppressor, represses EGFR signaling and is a novel epigenetic silenced gene in colorectal cancer. Biochem. Biophys. Res. Commun. 464 (2015), 519–525.
[86] Lando, M., Fjeldbo, C.S., Wilting, S.M., B, C.S., Aarnes, E.K., Forsberg, M.F., Kristensen, G.B., Steenbergen, R.D., Lyng, H., Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer. Epigenetics 10 (2015), 970–980.
[87] Thomasson, M., Wang, B., Hammarsten, P., Dahlman, A., Persson, J.L., Josefsson, A., Stattin, P., Granfors, T., Egevad, L., Henriksson, R., Bergh, A., Hedman, H., LRIG1 and the liar paradox in prostate cancer: a study of the expression and clinical significance of LRIG1 in prostate cancer. Int. J. Cancer 128 (2011), 2843–2852.
[88] Krig, S.R., Frietze, S., Simion, C., Miller, J.K., Fry, W.H., Rafidi, H., Kotelawala, L., Qi, L., Griffith, O.L., Gray, J.W., Carraway, K.L. III, Sweeney, C., Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERalpha-positive breast cancer. Mol. Cancer Res. 9 (2011), 1406–1417.
[89] Wang, S., Li, N., Yousefi, M., Nakauka-Ddamba, A., Li, F., Parada, K., Rao, S., Minuesa, G., Katz, Y., Gregory, B.D., Kharas, M.G., Yu, Z., Lengner, C.J., Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat. Commun., 6, 2015, 6517.
[90] Li, N., Yousefi, M., Nakauka-Ddamba, A., Li, F., Vandivier, L., Parada, K., Woo, D.H., Wang, S., Naqvi, A.S., Rao, S., Tobias, J., Cedeno, R.J., Minuesa, G., Y, K., Barlowe, T.S., Valvezan, A., Shankar, S., Deering, R.P., Klein, P.S., Jensen, S.T., Kharas, M.G., Gregory, B.D., Yu, Z., Lengner, C.J., The Msi family of RNA-binding proteins function redundantly as intestinal oncoproteins. Cell Rep. 13 (2015), 2440–2455.
[91] Bai, L., Smith, D.C., Wang, S., Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol. Ther. 144 (2014), 82–95.
[92] Li, F., Ye, Z.Q., Guo, D.S., Yang, W.M., Suppression of bladder cancer cell tumorigenicity in an athymic mouse model by adenoviral vector-mediated transfer of LRIG1. Oncol. Rep. 26 (2011), 439–446.
[93] Li, F., Yang, W., Guo, D., Hu, Z., Xu, H., Ye, Z., LRIG1 combined with cisplatin enhances bladder cancer lesions via a novel pathway. Oncol. Rep. 25 (2011), 1629–1637.
