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Expression of DMBT1, a Candidate Tumor Suppressor Gene, Is Frequently Lost in Lung Cancer1

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Expression of DMBT1, a Candidate Tumor Suppressor Gene, Is Frequently Lost in Lung Cancer1 [CANCER RESEARCH 59, 1846–1851, April 15, 1999] Advances in Brief Expression of DMBT1, a Candidate Tumor Suppressor Gene, Is Frequently Lost in Lung Cancer1 Weiguo Wu, Bonnie L. Kemp, Monja L. Proctor, Adi F. Gazdar, John D. Minna, Waun Ki Hong, and Li Mao2 Departments of Thoracic/Head and Neck Medical Oncology [W. W., W. K. H., L. M.] and Pathology [B. L. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75235 [M. L. P., A. E. G., J. D. M.] Abstract long period of time, even with a successful, nationwide antismoking campaign. DMBT1 is a candidate tumor suppressor gene located at 10q25.3–26.1. DMBT1 was cloned through a representational differential analysis Homozygous deletion of the gene was found in a subset of medulloblas- that is used to identify potential homozygous deletions in target toma and glioblastoma multiforme; lack of expression was noted in the genomic DNA (6). The gene was localized to 10q25.3–q26.1, a region majority of these tumors. In adult tissues, DMBT1 is highly expressed only 3 in lung and small intestine tissues, indicating its important role in these with frequent LOH in many types of human cancers including lung organs. By analyzing lung cancer cell lines and primary lung tumors using cancer (7–10). Intragenic homozygous deletions of DMBT1 were reverse transcription-PCR, we found that 100% (20 of 20) of small cell found in 23–38% of medulloblastoma and glioblastoma multiforme lung cancer (SCLC) cell lines and 43% (6 of 14) of non-small cell lung cell lines and primary glioblastoma multiforme (6, 11). Interestingly, cancer (NSCLC) cell lines lacked DMBT1 expression. Furthermore, 45% loss of DMBT1 gene expression was found in 80% of these tumor cell (9 of 20) of the primary NSCLCs exhibited a markedly low level of gene lines (6). These data suggest that DMBT1 is a candidate tumor expression compared with corresponding normal lung tissues, indicating suppressor gene and may play an important role in brain tumorigen- that lack of gene expression also occurs in primary lung cancers. To esis. Deduced DMBT1 protein contains at least nine SRCR domains determine the potential mechanisms for lack of DMBT1 expression in lung that allow the gene to be classified as a new member of the SRCR cancer, we analyzed tumor cell lines for potential intragenic homozygous superfamily. Some members of this superfamily have been linked to deletions of the gene and found such homozygous deletions in 10% (4 of 40) of SCLC cell lines but in none of 14 NSCLC cell lines. Moreover, the initiation of cell proliferation and differentiation in immune system loss of expression could not be rescued by treatment with a demethylation tissue and other tissues (12–15) or have been associated with the agent (5-azacytidine) in two NSCLC cell lines lacking DMBT1 expression, polarity of epithelial cells (16). A leader sequence present in DMBT1 suggesting that de novo methylation of the promoter region of the gene is protein, together with the presence of SRCR, CUB, and ZP domains unlikely to play a role in inactivation of the gene. We then sequenced the and N-glycosylation sites, suggests that DMBT1 is likely a secreted or whole coding region of DMBT1 in 8 NSCLC cell lines that expressed membrane protein (12–17). In adult humans, DMBT1 is highly ex- DMBT1 and 20 primary NSCLCs. A potential point mutation at codon 52 pressed only in lung and small intestine, suggesting that the protein was detected in a NSCLC cell line and resulted in an amino acid change has an important role in these tissues (6). Furthermore, the gene is from serine to tryptophan. Three common polymorphisms were also located within one of the two minimally deleted regions at chromo- detected in tissues analyzed. Our data demonstrate that DMBT1 expres- some 10q identified in primary SCLCs (10), raising the possibility that sion is frequently lost in lung cancer due to gene deletion and to other not the gene may be also important in lung tumorigenesis. In this study, yet identified mechanisms, suggesting that inactivation of DMBT1 may play an important role in lung tumorigenesis. we investigated whether DMBT1 is altered in lung cancer and found an intragenic homozygous deletion of the gene in 10% of the SCLC Introduction cell lines tested and lack of the gene expression in all of the SCLC cell lines tested. Furthermore, more than 40% of NSCLC cell lines and Lung cancer is the leading cause of cancer-related death in the primary NSCLCs also lacked DMBT1 expression. The identification United States. More than 171,000 new cases are estimated to occur in of a potential point mutation in the gene in a NSCLC cell line further the United States in 1998 (1). Despite improvements in detection and supports the notion that DMBT1 may play an important role in lung treatment of the disease over the past two decades, the overall 5-year tumorigenesis. survival rate for patients with lung cancer is still ,15%. It is clear that cigarette smoking is a major cause of lung cancer and that smoking Materials and Methods cessation can reduce the risk for lung cancer development. However, genetic damage caused by cigarette smoking may still exist in former Cell Lines and Tissue Specimens. All of the lung cancer cell lines have smokers (2, 3). In fact, according to recent reports, about half of all been deposited in the American Type Culture Collection (Rockville, MD). The SCLC cell lines used in this study were NCI-H60, -H69, -H82, -H128, -H146, new patients with lung cancer in the United States are former smokers -H182, -H187, -H196, -H211, -H249, -H289, -H345, -H378, -H524, -H526, (4, 5), suggesting that lung cancer incidence may remain high for a -H711, -H719, -H735, -H738, -H740, -H748, -H841, -H847, -H865, -H889, -H1045, -H1092, -H1105, -H1184, -H1238, -H1284, -H1304, -H1417, -H1450, Received 12/14/98; accepted 3/2/99. -H1514, -H1522, -H1618, -H1672, -H1688, -H1882, -H1963, -H2081, -H2107, The costs of publication of this article were defrayed in part by the payment of page -H2141, -H2171, and -H2227. The NSCLC cell lines used were NCI-H460, charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. -H157, -H226, -H1792, -H522, -H292, -H1944, -H1648, A549, -H727, S966, 1 Supported in part by American Cancer Society Grant RPG-98-054, National Cancer A427, Calu-1, and SK-Mes-1. These cell lines were grown in RPMI 1640 with Institute Grants PO1 CA74173 and Lung SPORE Grant CA 70907, and NIH Fellowship 10% fetal bovine serum. Primary NSCLC samples and corresponding normal Training Grant T32 CA 66187. W. K. H. is an American Cancer Society Clinical Research Professor. 2 To whom requests for reprints should be addressed, at Molecular Biology Labora- 3 The abbreviations used are: LOH, loss of heterozygosity; SCLC, small cell lung tory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas cancer; NSCLC, non-small cell lung cancer; RT-PCR, reverse transcription-PCR; STS, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: specific tag sequence; SRCR, scavenger receptor cysteine-rich; CUB, complement sub- (713) 792-6363; Fax: (713) 796-8865; E-mail: [email protected]. components Clr/Cls, Uegf, Bmp1; ZP, zona pellucida. 1846 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1999 American Association for Cancer Research. EXPRESSION OF DMBT1 IN LUNG CANCER lung tissues were obtained from surgical resection specimens collected by the DNA polymerase (Life Technologies, Inc.). DNA was amplified for 35 cycles Department of Pathology at M. D. Anderson Cancer Center and stored at at 95°C for 30 s, 56–60°C for 60 s, and 70°C for 60 s, followed by a 5-min 280°C until the experiment. extension at 70°C in a temperature cycler (Hybaid; Omnigene) in 500-ml DNA and RNA Extraction and cDNA Synthesis. Genomic DNA was plastic tubes. PCR products were separated on a 7% polyacrylamide-urea- isolated from SCLC and NSCLC cell lines by proteinase-K digestion (0.1 formamide gel and then exposed to X-ray film. LOH was defined as a .50% mg/ml) at 50°C overnight, followed by phenol/chloroform extraction and reduction of intensity by visual inspection in one of the two alleles as ethanol precipitation. For fresh tissues, samples were sectioned using a cryostat compared with that seen in the corresponding normal control. microtome. Selected sections were stained with H&E and reviewed for the presence of tumor cells. Only tumor samples containing about 70% or more Results tumor cells and normal lung tissues without tumor cells were used for DNA extraction. The proteinase-K digestion and DNA purification methods are the To determine the expression pattern of the DMBT1 gene in lung same as those used for cell lines. For total RNA extraction from cell lines, the cancer, we analyzed 20 SCLC cell lines, 14 NSCLC cell lines, and 20 cell pellets were quickly suspended in RNAzol B solution (Biotecx Labora- primary NSCLC tumors by RT-PCR. We used two primer sets to tories, Inc., Houston, TX) to lyse the cells. For fresh tissue samples, 20–50 mg amplify DMBT1 cDNA fragments separately at two different regions of tissue were mechanically homogenized in 1 ml of RNAzol B solution to verify expression status. The two fragments (165 and 909 bp) were m (Biotecx Laboratories, Inc., Houston, TX). Five g of total RNA from each located at the 59 end and the 39 end of the coding sequences, respec- sample were then used to synthesize single-strand cDNA using SUPER- tively.
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