Human Epididymis Protein 4 (HE4) Is a Secreted Glycoprotein that Is Overexpressed by Serous and Endometrioid Ovarian Carcinomas

Cancer Research - Tập 65 Số 6 - Trang 2162-2169 - 2005
Ronny Drapkin1,2, Hans Henning von Horsten3, Yafang Lin1, Samuel C. Mok4, Christopher P. Crum2, William R. Welch2, Jonathan L. Hecht5
11Department of Cancer Biology, Dana-Farber Cancer Institute;
22Department of Pathology, Division of Women's and Perinatal Pathology and
35Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas
43Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Brigham and Women's Hospital;
54Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and

Tóm tắt

Abstract Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.

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Tài liệu tham khảo

Jemal A, Tiwari RC, Murray T, et al. American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin 2004; 54: 8–29.

Stewart BW, Kleihues P (editors): WHO world cancer report. Lyon (France): IARC Press; 2003.

Drapkin R, Hecht JL. The origins of ovarian cancer: hurdles and progress. Women's Oncol Rev 2002; 2: 261–8.

Ozols RF, Bookman MA, Connolly DC, et al. Focus on epithelial ovarian cancer. Cancer Cell 2004; 5: 19–24.

Schummer M, Ng WV, Bumgarner RE, et al. Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Gene 1999; 238: 375–85.

Ono K, Tanaka T, Tsunoda T, et al. Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res 2000; 60: 5007–11.

Wong KK, Cheng RS, Mok SC. Identification of differentially expressed genes from ovarian cancer cells by MICROMAX cDNA microarray system. Biotechniques 2001; 30: 670–5.

Schaner ME, Ross DT, Ciaravino G, et al. Gene expression patterns in ovarian carcinomas. Mol Biol Cell 2003; 14: 4376–86.

Welsh JB, Zarrinkar PP, Sapinoso LM, et al. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci U S A 2001; 98: 1176–81.

Welsh JB, Sapinoso LM, Kern SG, et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci U S A 2003; 100: 3410–5.

Hough CD, Sherman-Baust CA, Pizer ES, et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 2000; 60: 6281–7.

Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ. Coordinately up-regulated genes in ovarian cancer. Cancer Res 2001; 61: 3869–76.

Shridhar V, Lee J, Pandita A, et al. Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res 2001; 61: 5895–904.

Santin AD, Zhan F, Bellone S, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer 2004; 112: 14–25.

Tonin PN, Hudson TJ, Rodier F, et al. Microarray analysis of gene expression mirrors the biology of an ovarian cancer model. Oncogene 2001; 20: 6617–26.

Sawiris GP, Sherman-Baust CA, Becker KG, Cheadle C, Teichberg D, Morin PJ. Development of a highly specialized cDNA array for the study and diagnosis of epithelial ovarian cancer. Cancer Res 2002; 62: 2923–8.

Cecco LD, Marchionni L, Gariboldi M, et al. Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2. Oncogene 2004; 23: 8171–83.

Tapper J, Kettunen E, El-Rifai W, Seppala M, Andersson LC, Knuutila S. Changes in gene expression during progression of ovarian carcinoma. Cancer Genet Cytogenet 2001; 128: 1–6.

Wang K, Gan L, Jeffery E, et al. Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. Gene 1999; 229: 101–8.

Drapkin R, Crum CP, Hecht JL. Expression of candidate tumor markers in ovarian carcinoma and benign ovary: evidence for a link between epithelial phenotype and neoplasia. Hum Pathol 2004; 35: 1014–21.

Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod 1991; 45: 350–7.

Kirchhoff C. Molecular characterization of epididymal proteins. Rev Reprod 1998; 3: 86–95.

Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene 2002; 21: 2768–73.

Clauss A, Lilja H, Lundwall A. A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein. Biochem J 2002; 368: 233–42.

Sonoda G, Palazzo J, du Manoir S, et al. Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas. Genes Chromosomes Cancer 1997; 20: 320–8.

Kiechle M, Jacobsen A, Schwarz-Boeger U, Hedderich J, Pfisterer J, Arnold N. Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation. Cancer 2001; 91: 534–40.

Iwabuchi H, Sakamoto M, Sakunaga H, et al. Genetic analysis of benign, low-grade, and high-grade ovarian tumors. Cancer Res 1995; 55: 6172–80.

Zhou C, Smith JL, Liu J. Role of BRCA1 in cellular resistance to paclitaxel and ionizing radiation in an ovarian cancer cell line carrying a defective BRCA1. Oncogene 2003; 22: 2396–404.

Yuan Y, Kim WH, Han HS, et al. Establishment and characterization of human ovarian carcinoma cell lines. Gynecol Oncol 1997; 66: 378–87.

Richardson RT, Sivashanmugam P, Hall SH, et al. Cloning and sequencing of human Eppin: a novel family of protease inhibitors expressed in the epididymis and testis. Gene 2001; 270: 93–102.

Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 2001; 105: 149–60.

Cao QJ, Jones JG, Li M. Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors. Int J Gynecol Pathol 2001; 20: 346–52.

Terry KL, Sluss PM, Skates SJ, et al. Blood and urine markers for ovarian cancer: a comprehensive review. Dis Markers 2004; 20: 53–70.

Feeley KM, Wells M. Precursor lesions of ovarian epithelial malignancy. Histopathology 2001; 38: 87–95.

Okamura H, Katabuchi H. Detailed morphology of human ovarian surface epithelium focusing on its metaplastic and neoplastic capability. Ital J Anat Embryol 2001; 106: 263–76.

Roland IH, Yang WL, Yang DH, et al. Loss of surface and cyst epithelial basement membranes and preneoplastic morphologic changes in prophylactic oophorectomies. Cancer 2003; 98: 2607–23.

Orntoft TF, Vestergaard EM. Clinical aspects of altered glycosylation of glycoproteins in cancer. Electrophoresis 1999; 20: 362–71.

Dwek MV, Brooks SA. Harnessing changes in cellular glycosylation in new cancer treatment strategies. Curr Cancer Drug Targets 2004; 4: 425–42.

Hakomori S. Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci U S A 2002; 99: 10231–3.

Hellstrom I, Raycraft J, Hayden-Ledbetter M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res 2003; 63: 3695–700.

Bast RC Jr. Status of tumor markers in ovarian cancer screening. J Clin Oncol 2003; 21: 200–5.

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Cancer Research

Tập 65 Số 6

2162-2169

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