keratan-sulfate and Ovarian-Neoplasms

The AT-hook transcription factor HMGA2 is an oncogene involved in the tumorigenesis of many malignant neoplasms. HMGA2 overexpression is common in both early and late-stage high-grade ovarian serous papillary carcinoma. To test whether HMGA2 participates in the initiation of ovarian cancer and promotion of aggressive tumor growth, we examined the oncogenic properties of HMGA2 in ovarian surface epithelial (OSE) cell lines. We found that introduction of HMGA2 overexpression was sufficient to induce OSE transformation in vitro. HMGA2-mediated OSE transformation resulted in tumor formation in the xenografts of nude mice. By silencing HMGA2 in HMGA2-overexpressing OSE and ovarian cancer cell lines, the aggressiveness of tumor cell growth behaviors was partially suppressed. Global gene profiling analyses revealed that HMGA2-mediated tumorigenesis was associated with expression changes of target genes and microRNAs that are involved in epithelial-to-mesenchymal transition (EMT). Lumican, a tumor suppressor that inhibits EMT, was found to be transcriptionally repressed by HMGA2 and was frequently lost in human high-grade serous papillary carcinoma. Our findings show that HMGA2 overexpression confers a powerful oncogenic signal in ovarian cancers through the modulation of EMT genes.

Topics: Animals; Case-Control Studies; Cell Line, Transformed; Cell Transformation, Neoplastic; Chondroitin Sulfate Proteoglycans; Cystadenocarcinoma, Papillary; Cystadenocarcinoma, Serous; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; HMGA2 Protein; Humans; Keratan Sulfate; Lumican; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; RNA, Small Interfering; Transfection; Transplantation, Heterologous

A previously developed method for the structural fingerprinting of keratan sulfates (Brown et al., Glycobiology, 5, 311-317, 1995) has been adapted for use with oligosaccharides fluorescently labeled with 2-aminobenzoic acid following keratanase II digestion. The oligosaccharides are separated by high-pH anion-exchange chromatography on a Dionex AS4A-SC column. This methodology permits quantitative analysis of labeled oligosaccharides which can be detected at the sub-nanogram ( approximately 100 fmol) level. Satisfactory calibration of this method can be achieved using commercial keratan sulfate standards. Keratan sulfates from porcine brain phosphocan and human ovarian tumors have been examined using this methodology, and their structural features are discussed.

Topics: Acetylglucosaminidase; Animals; Brain Neoplasms; Carbohydrate Sequence; Cattle; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Chromatography, Liquid; Female; Fluorometry; Humans; Keratan Sulfate; Molecular Sequence Data; Oligosaccharides; ortho-Aminobenzoates; Ovarian Neoplasms; Swine