LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer

Lindquist,David; Alsina,Fernando  C.; Herdenberg,Carl; Larsson,Catharina; Höppener,Jo; Wang,Na; Paratcha,Gustavo; Tarján,Miklós; Tot,Tibor; Henriksson,Roger; Hedman,Håkan

doi:10.3892/ijo.2018.4273

LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer

Authors:
- David Lindquist
- Fernando C. Alsina
- Carl Herdenberg
- Catharina Larsson
- Jo Höppener
- Na Wang
- Gustavo Paratcha
- Miklós Tarján
- Tibor Tot
- Roger Henriksson
- Håkan Hedman
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Affiliations: Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, SE-90187 Umeå, Sweden, Institute of Cell Biology and Neuroscience (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Buenos Aires 1121, Argentina, Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, 171 76 Stockholm, Sweden, University Medical Center Utrecht, Division of Biomedical Genetics and Laboratory of Translational Immunology, 3508 GA Utrecht, The Netherlands, Department of Pathology and Clinical Cytology, Central Hospital Falun, 791 82 Falun, Sweden
Published online on: February 9, 2018 https://doi.org/10.3892/ijo.2018.4273
Pages: 1189-1197
Copyright: © Lindquist et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
2	DeLellis R and Williams ED: Tumours of the thyroid and parathyroid. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. DeLellis R and Williams ED: 8. IARC Press; pp. 51–56. 2004
3	Romei C, Fugazzola L, Puxeddu E, Frasca F, Viola D, Muzza M, Moretti S, Nicolosi ML, Giani C, Cirello V, et al: Modifications in the papillary thyroid cancer gene profile over the last 15 years. J Clin Endocrinol Metab. 97:E1758–E1765. 2012. View Article : Google Scholar : PubMed/NCBI
4	Romei C, Ciampi R and Elisei R: A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 12:192–202. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, Sherman SI, Lee JE and Evans DB: RET proto-oncogene: A review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 15:531–544. 2005. View Article : Google Scholar : PubMed/NCBI
6	Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H and Fagin JA: Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 57:1690–1694. 1997.PubMed/NCBI
7	Agrawal N, A R, Aksoy BA, Ally A, Arachchi H, Asa SL, Auman JT, Balasundaram M, Balu S, Baylin SB and Behera M: Integrated genomic characterization of papillary thyroid carcinoma. Cell. 159:676–690. 2014. View Article : Google Scholar :
8	Network CGAR; Cancer Genome Atlas Research Network: Integrated genomic characterization of papillary thyroid carcinoma. Cell. 159:676–690. 2014. View Article : Google Scholar : PubMed/NCBI
9	Guo D, Holmlund C, Henriksson R and Hedman H: The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics. 84:157–165. 2004. View Article : Google Scholar : PubMed/NCBI
10	Holmlund C, Nilsson J, Guo D, Starefeldt A, Golovleva I, Henriksson R and Hedman H: Characterization and tissue-specific expression of human LRIG2. Gene. 332:35–43. 2004. View Article : Google Scholar : PubMed/NCBI
11	Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R and Hedman H: Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun. 284:1155–1161. 2001. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Poulin EJ and Coffey RJ: LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. Br J Cancer. 108:1765–1770. 2013. View Article : Google Scholar : PubMed/NCBI
13	Lindquist D, Kvarnbrink S, Henriksson R and Hedman H: LRIG and cancer prognosis. Acta Oncol. 53:1135–1142. 2014. View Article : Google Scholar : PubMed/NCBI
14	Krig SR, Frietze S, Simion C, Miller JK, Fry WH, Rafidi H, Kotelawala L, Qi L, Griffith OL, Gray JW, et al: Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERα-positive breast cancer. Mol Cancer Res. 9:1406–1417. 2011. View Article : Google Scholar : PubMed/NCBI
15	Willis S, Villalobos VM, Gevaert O, Abramovitz M, Williams C, Sikic BI and Leyland-Jones B: Single Gene Prognostic Biomarkers in Ovarian Cancer: A Meta-Analysis. PLoS One. 11:e01491832016. View Article : Google Scholar : PubMed/NCBI
16	Lindström AK, Ekman K, Stendahl U, Tot T, Henriksson R, Hedman H and Hellberg D: LRIG1 and squamous epithelial uterine cervical cancer: Correlation to prognosis, other tumor markers, sex steroid hormones, and smoking. Int J Gynecol Cancer. 18:312–317. 2008. View Article : Google Scholar
17	Tanemura A, Nagasawa T, Inui S and Itami S: LRIG-1 provides a novel prognostic predictor in squamous cell carcinoma of the skin: Immunohistochemical analysis for 38 cases. Dermatol Surg. 31:423–430. 2005. View Article : Google Scholar : PubMed/NCBI
18	Lindquist D, Näsman A, Tarján M, Henriksson R, Tot T, Dalianis T and Hedman H: Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropha-ryngeal cancer. Br J Cancer. 110:1793–1800. 2014. View Article : Google Scholar : PubMed/NCBI
19	Sheu JJ, Lee CC, Hua CH, Li CI, Lai MT, Lee SC, Cheng J, Chen CM, Chan C, Chao SC, et al: LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. Oncogene. 33:1375–1384. 2014. View Article : Google Scholar
20	Kvarnbrink S, Karlsson T, Edlund K, Botling J, Lindquist D, Jirström K, Micke P, Henriksson R, Johansson M and Hedman H: LRIG1 is a prognostic biomarker in non-small cell lung cancer. Acta Oncol. 54:1113–1119. 2015. View Article : Google Scholar : PubMed/NCBI
21	Yang B, Dai C, Tan R, Zhang B, Meng X, Ye J, Wang X, Wei L, He F and Chen Z: Lrig1 is a positive prognostic marker in hepatocellular carcinoma. Onco Targets Ther. 9:7071–7079. 2016. View Article : Google Scholar : PubMed/NCBI
22	Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, Amariglio N, Henriksson R, Rechavi G, Hedman H, et al: LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 23:3270–3281. 2004. View Article : Google Scholar : PubMed/NCBI
23	Laederich MB, Funes-Duran M, Yen L, Ingalla E, Wu X, Carraway KL III and Sweeney C: The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem. 279:47050–47056. 2004. View Article : Google Scholar : PubMed/NCBI
24	Miller JK, Shattuck DL, Ingalla EQ, Yen L, Borowsky AD, Young LJ, Cardiff RD, Carraway KL III and Sweeney C: Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. Cancer Res. 68:8286–8294. 2008. View Article : Google Scholar : PubMed/NCBI
25	Stutz MA, Shattuck DL, Laederich MB, Carraway KL III and Sweeney C: LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene. 27:5741–5752. 2008. View Article : Google Scholar : PubMed/NCBI
26	Shattuck DL, Miller JK, Laederich M, Funes M, Petersen H, Carraway KL III and Sweeney C: LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy. Mol Cell Biol. 27:1934–1946. 2007. View Article : Google Scholar :
27	Ledda F, Bieraugel O, Fard SS, Vilar M and Paratcha G: Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF. J Neurosci. 28:39–49. 2008. View Article : Google Scholar : PubMed/NCBI
28	Rondahl V, Holmlund C, Karlsson T, Wang B, Faraz M, Henriksson R and Hedman H: Lrig2-deficient mice are protected against PDGFB-induced glioma. PLoS One. 8:e736352013. View Article : Google Scholar : PubMed/NCBI
29	Alsina FC, Hita FJ, Fontanet PA, Irala D, Hedman H, Ledda F and Paratcha G: Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling. EMBO Rep. 17:601–616. 2016. View Article : Google Scholar : PubMed/NCBI
30	Nilsson J, Starefeldt A, Henriksson R and Hedman H: LRIG1 protein in human cells and tissues. Cell Tissue Res. 312:65–71. 2003.PubMed/NCBI
31	Rossel M, Pasini A, Chappuis S, Geneste O, Fournier L, Schuffenecker I, Takahashi M, van Grunsven LA, Urdiales JL, Rudkin BB, et al: Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. Oncogene. 14:265–275. 1997. View Article : Google Scholar : PubMed/NCBI
32	Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, et al: Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 267:381–383. 1995. View Article : Google Scholar : PubMed/NCBI
33	Wang N, Kjellin H, Sofiadis A, Fotouhi O, Juhlin CC, Bäckdahl M, Zedenius J, Xu D, Lehtiö J and Larsson C: Genetic and epigenetic background and protein expression profiles in relation to telomerase activation in medullary thyroid carcinoma. Oncotarget. 7:21332–21346. 2016.PubMed/NCBI
34	Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S, Ozawa K, Inui S, Nakata A, Takagi T, et al: Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett. 521:67–71. 2002. View Article : Google Scholar : PubMed/NCBI
35	Acton DS, Velthuyzen D, Lips CJ and Höppener JW: Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. Oncogene. 19:3121–3125. 2000. View Article : Google Scholar : PubMed/NCBI
36	van Veelen W, van Gasteren CJ, Acton DS, Franklin DS, Berger R, Lips CJ and Höppener JW: Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer Res. 68:1329–1337. 2008. View Article : Google Scholar : PubMed/NCBI
37	Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI
38	Guo D, Nilsson J, Haapasalo H, Raheem O, Bergenheim T, Hedman H and Henriksson R: Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors. Acta Neuropathol. 111:238–246. 2006. View Article : Google Scholar : PubMed/NCBI
39	Hedman H, Lindström AK, Tot T, Stendahl U, Henriksson R and Hellberg D: LRIG2 in contrast to LRIG1 predicts poor survival in early-stage squamous cell carcinoma of the uterine cervix. Acta Oncol. 49:812–815. 2010. View Article : Google Scholar : PubMed/NCBI
40	Holmlund C, Haapasalo H, Yi W, Raheem O, Brännström T, Bragge H, Henriksson R and Hedman H: Cytoplasmic LRIG2 expression is associated with poor oligodendroglioma patient survival. Neuropathology. 29:242–247. 2009. View Article : Google Scholar
41	Muller S, Lindquist D, Kanter L, Flores-Staino C, Henriksson R, Hedman H and Andersson S: Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma. Int J Oncol. 42:247–252. 2013. View Article : Google Scholar
42	Neirinckx V, Hedman H and Niclou SP: Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy. Biochim Biophys Acta. 1868:109–116. 2017.PubMed/NCBI