Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis

Fujitomo,Takashi; Daigo,Yataro; Matsuda,Koichi; Ueda,Koji; Nakamura,Yusuke

doi:10.3892/ijo.2014.2418

Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis

Authors:
- Takashi Fujitomo
- Yataro Daigo
- Koichi Matsuda
- Koji Ueda
- Yusuke Nakamura
View Affiliations

Affiliations: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, Laboratory for Biomarker Development, Center for Genomic Medicine, RIKEN, Yokohama 230-0045, Japan
Published online on: May 6, 2014 https://doi.org/10.3892/ijo.2014.2418
Pages: 147-156

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

On the basis of the gene expression profiles of 120 lung cancer cases using a cDNA microarray containing 27,648 genes or expressed sequence tags (ESTs), we identified LRRC42 (Leucine-rich repeat containing 42) to be significantly upregulated in the majority of lung cancers. Northern blot analysis demonstrated that LRRC42 was expressed only in testis among normal tissues examined. Knockdown of LRRC42 expression by siRNA against LRRC42 significantly suppressed the growth of lung cancer cells. On the other hand, stable induction of LRRC42 expression significantly promoted cell growth. LRRC42, which was found to localize in the nucleus of mammalian cells, is likely to interact with and stabilize GATAD2B (GATA zinc finger domain-containing 2B) and MBD3 (Methyl-CpG-binding domain protein 3) proteins that could contribute to lung cancer cell proliferation partly through the regulation of p21Waf1/Cip1. Our findings suggest that LRRC42 overexpression as well as its interaction with LRRC42-GATAD2B might play essential roles in lung carcinogenesis, and be a promising molecular target for lung cancer therapy.

View Figures

View References

1.	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
2.	Daigo Y, Takano A, Teramoto K, Chung S and Nakamura Y: A systematic approach to the development of novel therapeutics for lung cancer using genomic analyses. Clin Pharmacol Ther. 94:218–223. 2013. View Article : Google Scholar : PubMed/NCBI
3.	Inoue A, Saijo Y, Maemondo M, et al: Severe acute interstitial pneumonia and gefitinib. Lancet. 361:137–139. 2003. View Article : Google Scholar : PubMed/NCBI
4.	Sandomenico C, Costanzo R, Carillio G, et al: Bevacizumab in non small cell lung cancer: development, current status and issues. Curr Med Chem. 19:961–971. 2012. View Article : Google Scholar : PubMed/NCBI
5.	Daigo Y and Nakamura Y: From cancer genomics to thoracic oncology: discovery of new biomarkers and therapeutic targets for lung and esophageal carcinoma. Gen Thorac Cardiovasc Surg. 56:43–53. 2008. View Article : Google Scholar : PubMed/NCBI
6.	Kikuchi T, Daigo Y, Katagiri T, et al: Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene. 22:2192–2205. 2003. View Article : Google Scholar : PubMed/NCBI
7.	Kakiuchi S, Daigo Y, Tsunoda T, Yano S, Sone S and Nakamura Y: Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice. Mol Cancer Res. 1:485–499. 2003.PubMed/NCBI
8.	Kakiuchi S, Daigo Y, Ishikawa N, et al: Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). Hum Mol Genet. 13:3029–3043. 2004. View Article : Google Scholar
9.	Kikuchi T, Daigo Y, Ishikawa N, et al: Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. Int J Oncol. 28:799–805. 2006.PubMed/NCBI
10.	Taniwaki M, Daigo Y, Ishikawa N, et al: Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer. Int J Oncol. 29:567–575. 2006.PubMed/NCBI
11.	Bella J, Hindle KL, McEwan PA and Lovell SC: The leucine-rich repeat structure. Cell Mol Life Sci. 65:2307–2333. 2008. View Article : Google Scholar : PubMed/NCBI
12.	Chai L, Dai L, Che Y, et al: LRRC19, a novel member of the leucine-rich repeat protein family, activates NF-κB and induces expression of proinflammatory cytokines. Biochem Biophys Res Commun. 388:543–548. 2009.PubMed/NCBI
13.	Kajava AV: Structural diversity of leucine-rich repeat proteins. J Mol Biol. 277:519–527. 1998. View Article : Google Scholar : PubMed/NCBI
14.	Pancer Z and Cooper MD: The evolution of adaptive immunity. Annu Rev Immunol. 24:497–518. 2006. View Article : Google Scholar
15.	Feng Q, Cao R, Xia L, Erdjument-Bromage H, Tempst P and Zhang Y: Identification and functional characterization of the p66/p68 components of the MeCP1 complex. Mol Cell Biol. 22:536–546. 2002. View Article : Google Scholar
16.	Ciavarella S, Milano A, Dammacco F and Silverstris F: Targeted therapies in cancer. BioDrugs. 24:77–88. 2010. View Article : Google Scholar
17.	Suzuki C, Daigo Y, Ishikawa N, et al: ANLN plays a critical role in human lung carcinogenesis through the activation of RHOA and by involvement in the phosphoinositide 3-kinase/AKT pathway. Cancer Res. 65:11314–11325. 2005. View Article : Google Scholar : PubMed/NCBI
18.	Ishikawa N, Daigo Y, Takano A, et al: Characterization of SEZ6L2 cell-surface protein as a novel prognostic marker for lung cancer. Cancer Sci. 97:737–745. 2006. View Article : Google Scholar : PubMed/NCBI
19.	Kato T, Sato N, Takano A, et al: Activation of placenta-specific transcription factor distal-less homeobox 5 predicts clinical outcome in primary lung cancer patients. Clin Cancer Res. 14:2363–2370. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Dunleavy EM, Roche D, Tagami H, et al: HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell. 137:485–497. 2009. View Article : Google Scholar : PubMed/NCBI
21.	Hirata D, Yamabuki T, Miki D, et al: Involvement of epithelial cell transforming sequence-2 oncoantigen in lung and esophageal cancer progression. Clin Cancer Res. 15:256–266. 2009. View Article : Google Scholar : PubMed/NCBI
22.	Sato N, Koinuma J, Fujita M, et al: Activation of WD repeat and high-mobility group box DNA binding protein 1 in pulmonary and esophageal carcinogenesis. Clin Cancer Res. 16:226–239. 2010. View Article : Google Scholar : PubMed/NCBI
23.	Sato N, Koinuma J, Ito T, et al: Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis. Genes Chromosomes Cancer. 49:353–367. 2010.PubMed/NCBI
24.	Nguyen MH, Koinuma J, Ueda K, et al: Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Cancer Res. 70:5337–5347. 2010. View Article : Google Scholar
25.	Takano A, Ishikawa N, Nishino R, et al: Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Res. 69:6694–6703. 2009. View Article : Google Scholar : PubMed/NCBI
26.	Sato N, Yamabuki T, Takano A, et al: Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy. Cancer Res. 70:5326–5336. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Mizukami Y, Kono K, Daigo Y, et al: Detection of novel cancer-testis antigen-specific T-cell responses in TIL, regional lymph nodes, and PBL in patients with esophageal squamous cell carcinoma. Cancer Sci. 99:1448–1454. 2008. View Article : Google Scholar : PubMed/NCBI
28.	Harao M, Hirata S, Irie A, et al: HLA-A2-restricted CTL epitopes of a novel lung cancer-associated cancer testis antigen, cell division cycle associated 1, can induce tumor-reactive CTL. Int J Cancer. 123:2616–2625. 2008. View Article : Google Scholar : PubMed/NCBI
29.	Kono K, Mizukami Y, Daigo Y, et al: Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer. Cancer Sci. 100:1502–1509. 2009. View Article : Google Scholar
30.	Yokomine K, Senju S, Nakatsura T, et al: The forkhead Box M1 transcription factor as a candidate of target for anti-cancer immunotherapy. Int J Cancer. 126:2153–2163. 2010.PubMed/NCBI
31.	Tomita Y, Imai K, Senju S, et al: A novel tumor-associated antigen, cell division cycle 45-like can induce cytotoxic T-lymphocytes reactive to tumor cells. Cancer Sci. 102:697–705. 2011. View Article : Google Scholar
32.	Aragaki M, Takahashi K, Akiyama H, et al: Characterization of a cleavage stimulation factor, 3′ pre-RNA, subunit 2, 64 kDa (CSTF2) as a therapeutic target for lung cancer. Clin Cancer Res. 17:5889–5900. 2011.
33.	Nishino R, Takano A, Oshita H, et al: Identification of Epstein-Barr virus-induced gene 3 as a novel serum and tissue biomarker and a therapeutic target for lung cancer. Clin Cancer Res. 17:6272–6286. 2011. View Article : Google Scholar
34.	Masuda K, Takano A, Oshita H, et al: Chondrolectin is a novel diagnostic biomarker and a therapeutic target for lung cancer. Clin Cancer Res. 17:7712–7722. 2011. View Article : Google Scholar : PubMed/NCBI
35.	Fujitomo T, Daigo Y, Matsuda K, Ueda K and Nakamura Y: Critical function for nuclear envelope protein TMEM209 in human pulmonary carcinogenesis. Cancer Res. 72:4110–4118. 2012. View Article : Google Scholar : PubMed/NCBI
36.	Koinuma J, Akiyama H, Fujita M, et al: Characterization of an Opa interacting protein 5 involved in lung and esophageal carcinogenesis. Cancer Sci. 103:577–586. 2012. View Article : Google Scholar : PubMed/NCBI
37.	Nguyen MH, Ueda K, Nakamura Y and Daigo Y: Identification of a novel oncogene, MMS22L, involved in lung and esophageal carcinogenesis. Int J Oncol. 41:1285–1296. 2012.
38.	Oshita H, Nishino R, Takano A, et al: RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer. Mol Cancer Res. 11:937–951. 2013. View Article : Google Scholar : PubMed/NCBI
39.	Tong ZB, Nelson LM and Dean J: Mater encodes a maternal protein in mice with a leucine-rich repeat domain homologous to porcine ribonuclease inhibitor. Mamm Genome. 11:281–287. 2000. View Article : Google Scholar : PubMed/NCBI
40.	Mutai H, Toyoshima Y, Sun W, Hattori N, Tanaka S and Shiota K: PAL31, a novel nuclear protein, expressed in the developing brain. Biochem Biophys Res Commun. 274:427–433. 2000. View Article : Google Scholar : PubMed/NCBI
41.	Bilder D and Perrimon N: Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature. 403:676–680. 2000. View Article : Google Scholar : PubMed/NCBI
42.	Linhoff MW, Harton JA, Cressman DE, Martin BK and Ting JP: Two distinct domains within CIITA mediate self-association: involvement of the GTP-binding and leucine-rich repeat domains. Mol Cell Biol. 21:3001–3011. 2001. View Article : Google Scholar : PubMed/NCBI
43.	Inohara N, Koseki T, del Peso L, et al: Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem. 274:14560–14567. 1999. View Article : Google Scholar : PubMed/NCBI
44.	Wu H, Maciejewski MW, Marintchev A, Benashski SE, Mullen GP and King SM: Solution structure of a dynein motor domain associated light chain. Nat Struct Biol. 7:575–579. 2000. View Article : Google Scholar
45.	Xu P, Mitchelhill KI, Kobe B, Kemp BE and Zot HG: The myosin-I-binding protein Acan125 binds the SH3 domain and belongs to the superfamily of leucine-rich repeat proteins. Proc Natl Acad Sci USA. 94:3685–3690. 1997. View Article : Google Scholar : PubMed/NCBI
46.	Brackertz M, Boeke J, Zhang R and Renkawitz R: Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3. J Biol Chem. 277:40958–40966. 2002. View Article : Google Scholar : PubMed/NCBI
47.	Noh EJ, Lim DS and Lee JS: A novel role for methyl CpG-binding domain protein 3, a component of the histone deacetylase complex, in regulation of cell cycle progression and cell death. Biochem Biophys Res Commun. 378:332–337. 2009. View Article : Google Scholar : PubMed/NCBI
48.	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
49.	Wu S, Cetinkaya C, Munoz-Alonso MJ, et al: Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene. 22:351–360. 2003. View Article : Google Scholar : PubMed/NCBI
50.	Reese KJ, Lin S, Verona RI, Schultz RM and Bartolomei MS: Maintenance of paternal methylation and repression of the imprinted H19 gene requires MBD3. PLoS Genet. 3:e1372007. View Article : Google Scholar : PubMed/NCBI