RESUMEN
BACKGROUND: Cisplatin is used as a key drug for ovarian yolk sac tumor (YST), but relapse may occur. Details of the molecular mechanism responsible for cisplatin resistance remain unclear. METHODS: We established cisplatin-resistant ovarian YST cells (NOY1-CR) from parent NOY1. To characterize these cells, we examined cross-resistance to other anticancer drugs. Then, cDNA microarray analysis was performed to quantify gene expression in NOY1 and NOY1-CR cells. The expression of several potential genes related to drug resistance was compared with parent cells by real-time PCR and Western blotting. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm the genetic association with drug resistance. RESULTS: The IC(50) for cisplatin of NOY1-CR was 22.3-fold higher than that for parent cells. NOY1-CR cells showed cross-resistance to some drugs, but not to VP-16 and bleomycin. Microarray analysis identified 315 up-regulated and 412 down-regulated genes in NOY1-CR cells. Knockdown of GSTA1, which was up-regulated in resistant cells, by GSTA1 siRNA restored cisplatin sensitivity in NOY1-CR cells. CONCLUSIONS: Our data suggest the molecular mechanisms of cisplatin resistance and show the potential for GSTA1 to become a novel therapeutic target for cisplatin-resistant ovarian YST.
Asunto(s)
Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Tumor del Seno Endodérmico/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Proteínas Reguladoras de la Apoptosis/metabolismo , Western Blotting , Línea Celular Tumoral , Tumor del Seno Endodérmico/genética , Femenino , Silenciador del Gen , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Humanos , Neoplasias Ováricas/genética , Reacción en Cadena de la Polimerasa , ARN Interferente PequeñoRESUMEN
OBJECTIVE: Ovarian clear cell carcinoma (CCC) is well known to be highly resistant to platinum-based chemotherapy. Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, is overexpressed in only CCC of epithelial ovarian carcinoma subtypes. The purpose of this study was to identify the role of GPC3 in ovarian CCC. METHODS: To evaluate the function of GPC3 in ovarian CCC cells, we generated an ovarian cancer cell line, KOC7C cells stably transfected with plasmids encompassing shRNA targeting GPC3 (shGPC cells), and compared cell growth and the colony-forming ability to control shRNA-transfected cells (shCon cells). RESULTS: We showed that shGPC3 cells significantly increased cell growth and the colony-forming potential compared with shCon cells in 1% serum containing medium with 100 ng/ml IGF-II. Furthermore, these effects were significantly attenuated by pretreatment with 1 µM wortmannin (an inhibitor of PI3K/Akt). CONCLUSIONS: We have demonstrated for the first time the presence of elevated levels of GPC3 protein associated with cell growth inhibition in CCC cells. Our data suggest that GPC3 has the potential to become a novel therapeutic target for ovarian CCC patients.
Asunto(s)
Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Glipicanos/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Adenocarcinoma de Células Claras/genética , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Femenino , Técnicas de Silenciamiento del Gen , Glipicanos/biosíntesis , Glipicanos/genética , Humanos , Inmunohistoquímica , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Ováricas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , TransfecciónRESUMEN
Perivascular epithelioid cell tumors (PEComa) are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelial cells. Although the uterine corpus seems to be one of the most prevalent sites of involvement, PEComa of the uterine cervix are very rare. Only four cervical PEComa cases have been described, and were treated with hysterectomy and radiotherapy.We report a case of a 24-year-old nulligravida woman who presented with acute abdominal pain and was diagnosed with a rupture of an ovarian chocolate cyst. Subsequent surgery revealed that the tumor arose in the uterus, and the histological diagnosis was uterine PEComa with low potential malignancy. Recurrent PEComa in the uterine cervix were excised twice, and she remains disease free 12 months after the last operation. To the best of our knowledge, this is the first report of recurrent cervical PEComa with fertility-preserving surgery. Estimating the malignant potential and appropriate surgery are essential for young patients with uterine PEComa.