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Chondrolectin Is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer

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Chondrolectin Is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer Published OnlineFirst October 20, 2011; DOI: 10.1158/1078-0432.CCR-11-0619 Clinical Cancer Imaging, Diagnosis, Prognosis Research Chondrolectin Is a Novel Diagnostic Biomarker and a Therapeutic Target for Lung Cancer Ken Masuda1,4, Atsushi Takano1,2,3, Hideto Oshita1, Hirohiko Akiyama5, Eiju Tsuchiya6, Nobuoki Kohno4, Yusuke Nakamura1, and Yataro Daigo1,2,3 Abstract Purpose: This study aims to identify molecules that might be useful as diagnostic/prognostic biomarkers and as targets for the development of new molecular therapies for lung cancer. Experimental Design: We screened for genes that were highly transactivated in a large proportion of 120 lung cancers by means of a cDNA microarray representing 27,648 genes and found chondrolectin (CHODL) as a candidate. Tumor tissue microarray was applied to examine the expression of CHODL protein and its clinicopathologic significance in archival non–small cell lung cancer (NSCLC) tissues from 295 patients. A role of CHODL in cancer cell growth and/or survival was examined by siRNA experiments. Cellular invasive effect of CHODL on mammalian cells was examined by Matrigel assays. Results: Immunohistochemical staining revealed that strong positivity of CHODL protein was associated with shorter survival of patients with NSCLC (P ¼ 0.0006), and multivariate analysis confirmed it to be an independent prognostic factor. Treatment of lung cancer cells with siRNAs against CHODL suppressed growth of the cancer cells. Furthermore, induction of exogenous expression of CHODL conferred growth and invasive activity of mammalian cells. Conclusions: CHODL is likely to be a prognostic biomarker in the clinic and targeting CHODL might be a strategy for the development of anticancer drugs. Clin Cancer Res; 17(24); 7712–22. Ó2011 AACR. Introduction molecule inhibitors of EGFR tyrosine kinase, such as gefi- tinib and erlotinib, have been investigated in clinical Lung cancer is one of the most common causes of cancer trials and/or were approved for clinical use. These agents death in the world, and non–small cell lung cancer are effective in the treatment of advanced NSCLC to a certain (NSCLC) accounts for nearly 80% of those cases (1, 2). In extent, but a proportion of patients who could receive a the last 2 decades, several newly developed cytotoxic agents survival benefit is still limited (4, 5). Hence, new therapeutic including paclitaxel, docetaxel, gemcitabine, vinorelbine, strategies, such as the development of more selective and and irinotecan have emerged to offer multiple therapeutic effective molecular targeted agents against lung cancer are choices for patients with advanced NSCLC; however, each eagerly awaited. of the new regimens can provide only modest improve- Genome-wide cDNA microarray analysis of cancers ments in survival and quality of life compared with tradi- enabled us to obtain their comprehensive gene expression tional cisplatin-based therapies (3). Recently, molecular profiles and to compare the gene expression levels with targeted agents, including anti-EGFR or anti-VEGF mono- clinicopathologic and biologic information of cancers (6). clonal antibody, cetuximab or bevacizumab, and small- This approach is also useful to identify unknown molecules involved in the carcinogenic pathway. Through the gene expression profile analysis of 120 lung cancers on a cDNA Authors' Affiliations: 1Laboratory of Molecular Medicine, Human Genome microarray consisting of 27,648 genes or expressed Center, Institute of Medical Science, The University of Tokyo, Tokyo; sequence tags (EST) coupled with purification of cancer 2Department of Medical Oncology; and 3Cancer Center, Shiga University of Medical Science, Otsu; 4Department of Molecular and Internal Medicine, cell population by laser microdissection, and subsequent Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima; comparison of the data with the expression profile of 31 5Department of Thoracic Surgery, Saitama Cancer Center, Saitama; and 6Kanagawa Cancer Center Research Institute, Yokohama, Japan normal human tissues, we identified a number of potential molecular targets for cancer diagnosis, treatment, and/or Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). choice of therapy (6–11). To verify the biologic and clinico- pathologic significance of the respective gene products, we Corresponding Author: Yataro Daigo, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, have also been carrying out high-throughput screening of Japan. Phone: 81-3-5449-5457; Fax: 81-3-5449-5406; E-mail: loss-of-function effects by means of the RNA interference [email protected] technique as well as tumor tissue microarray analysis of doi: 10.1158/1078-0432.CCR-11-0619 clinical lung cancer materials (12–41). This systematic Ó2011 American Association for Cancer Research. approach identified a set of molecules that seem to fall into 7712 Clin Cancer Res; 17(24) December 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst October 20, 2011; DOI: 10.1158/1078-0432.CCR-11-0619 CHODL as a Novel Cancer Biomarker mas (SCC; LU61, NCI-H520, NCI-H1703, NCI-H2170, and Translational Relevance SK-MES-1), 1 large cell carcinoma (LCC; LX1), and 4 small cell lung cancers (DMS114, DMS273, SBC-3, and SBC-5). A Because there is a significant association of CHODL human bronchial epithelial cell line (BEAS-2B) was used as a positivity with poor clinical outcome of lung cancer control (Supplementary Table S1). All cells were grown in patients, CHODL positivity in resected specimens could monolayers in appropriate media supplemented with 10% be an index that provides valuable information to phy- fetal calf serum (FCS) and were maintained at 37 Cinan sicians in applying adjuvant therapy and intensive fol- atmosphere of humidified air with 5% CO . Primary lung low-up to the patients who are likely to relapse. Because 2 cancers were obtained with informed consent along with CHODL encodes a cancer-testis antigen, it may be useful adjacent normal lung tissue samples from patients, as for screening of human leukocyte antigen–restricted described previously (7, 11). All tumors were staged on the epitope peptides for cancer vaccine that can induce basis of the pathologic tumor-node-metastasis (pTNM) clas- specific immune responses by cytotoxic T cells against sification of the Unio Internationale Contra Cancrum (Ital- CHODL-positive cancers. Because CHODL plays impor- ian; UICC; ref. 44). Formalin-fixed primary NSCLCs and tant roles in cancer proliferation and invasion, targeting adjacent normal lung tissue samples used for immunostain- CHODL function by small-molecule compounds could ing on tissue microarrays had been obtained from 295 be a new therapeutic strategy that is expected to have a patients undergoing curative surgery at Saitama Cancer powerful anticancer activity with a minimal risk of Center (Saitama, Japan). To be eligible for this study, tumor adverse effects. samples were selected from patients who fulfilled all of the following criteria: (i) patients suffered from primary NSCLC with confirmed stage (only pT1 to pT3, pN0 to pN2, and pM0), (ii) patients underwent curative surgery but did not the category of cancer-testis antigens and in which upregu- receive any preoperative treatment, (iii) among them lation is a frequent and important feature of the malignant NSCLC patients with lymph node metastasis–positive nature of human cancer. These molecules identified can be tumors (pN1 and pN2) were treated with platinum-based regarded as potential targets for the development of highly adjuvant chemotherapies after surgery, whereas patients sensitive and specific biomarkers as well as being useful in with pN0 did not receive adjuvant chemotherapies, and (iv) the development of small molecular compounds, antibo- patients whose clinical follow-up data were available. This dies, and cancer vaccines that could have a more specific and study and the use of all clinical materials mentioned were efficient anticancer effect with minimal risk of adverse approved by individual institutional ethics committees. effects (12–41). Among them, Chondrolectin (CHODL) was commonly overexpressed in the great majority of lung Semiquantitative reverse transcriptase PCR analysis cancers. Total RNA was extracted from cultured cells and clini- CHODL, a human ortholog of mouse chondrolectin cal tissues with Trizol reagent (Life Technologies, Inc.) (chodl) encodes a single-pass transmembrane protein with according to the manufacturer’s protocol. Extracted one carbohydrate recognition domain of C-type lectins RNAs and normal human-tissue polyA RNAs were treated (42). C-type lectin family is classified into 17 groups accord- with DNase I (Roche Diagnostics) and then reverse tran- ing to their domain architecture. They are divided into 2 scribed using oligo (dT) primer and SuperScript II reverse major types: transmembrane C-type lectins and soluble transcriptase (Life Technologies, Inc.). Semiquantitative ones. These lectins have a wide variety of functions at reverse transcriptase PCR (RT-PCR) experiments were cytoplasm, cytoplasmic membrane, and extracellular space. carried out with synthesized CHODL gene–specific primers Mouse chodl was mainly expressed in embryonic tissues, (50-GGAAGGAAAGGAACTACGAAATC-30 and 50-GTTAA- and its expression level was tightly controlled during embry-
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