TNF GENE REGULATION IN BREAST AND OVARY CANCER

越来越多的证据表明，肿瘤坏死因子-α可能在 一些恶性肿瘤的发病机制。看起来，生产的 肿瘤细胞产生的肿瘤坏死因子-α存在于一些人类癌症中，包括 卵巢癌和神经母细胞瘤。在人类卵巢癌中，肿瘤坏死因子-α具有 被认为是一种旁分泌和自分泌生长因子。肿瘤坏死因子-α 还可能增加对某些药物的化疗敏感性，包括紫杉醇和 顺铂，治疗卵巢癌最活跃的药物。 自分泌产生的肿瘤坏死因子-α对 肿瘤坏死因子-α对上皮性癌细胞增殖的抑制作用 然而，肿瘤坏死因子-α在恶性上皮细胞中的表达调控 人们对细胞知之甚少。此次续签是对 肿瘤坏死因子-α基因调控在人上皮癌中的研究进展 细胞。乳腺癌和卵巢癌自分泌肿瘤坏死因子-α模型的建立 在我们实验室中首次鉴定出来的产品将被利用。我们将研究 人上皮癌中肿瘤坏死因子-α基因调控的分子生物学研究 细胞通过对5‘侧翼区和3’区的研究 人类肿瘤坏死因子-α基因。早期反应基因，包括c-fos和 Jun家族似乎是上皮性肿瘤细胞的关键参与者 肿瘤坏死因子-α的调节。这些实验室研究将伴随着 通过对卵巢癌患者临床样本的研究， 探讨肿瘤坏死因子-α在卵巢癌发病机制中的重要性。 具体目标将是：1.调查肿瘤坏死因子的重要性- α5‘侧翼区在肿瘤坏死因子-α基因调控中的作用 报告基因在人乳腺癌细胞和卵巢癌细胞中的表达 和凝胶位移分析；2.研究AP-1基序的重要性 在控制人上皮癌细胞产生肿瘤坏死因子中的作用 正义和反义c-jun构建；3.评估c-jun的作用 肿瘤坏死因子-α3‘侧翼区对肿瘤坏死因子-α蛋白的调控 带有3‘侧翼区的人上皮性癌细胞的产生 报告基因构建；4.检测人上皮性卵巢癌 从我们的卵巢癌组织库中更好地定义 肿瘤坏死因子-α表达与卵巢癌病理生理的关系。已被占用 综上所述，这些研究将提供对肺炎的病理生物学的洞察力。 卵巢癌，可能为卵巢癌提供新的治疗策略 心理治疗。

There is growing evidence that TNF-alpha may play an important role in the pathogenesis of some malignancies. It appears that production of TNF-alpha by malignant cells occurs in some human cancers including ovarian cancer and neuroblastoma. In human ovarian cancer, TNF-alpha has been implicated as a paracrine and autocrine growth factor. TNF-alpha may also increase chemosensitivity to certain drugs including taxol and cisplatin, the most active drugs in the treatment of ovary cancer. Autocrine production of TNF-alpha produces resistance to the antiproliferative effects of TNF-alpha in epithelial cancer cells. However, the regulation of TNF-alpha expression in malignant epithelial cells is very poorly understood. This renewal represent extension of previous studies of TNF-alpha gene regulation in human epithelial cancer cells. Breast and ovary cancer models of autocrine TNF-alpha production first identified in our laboratory will be utilized. We will examine the molecular biology of TNF-alpha gene regulation in human epithelial cancer cells through studies of both the 5' flanking region and the 3' region of the human TNF-alpha gene. Early response genes, including c-fos and the jun family appear to be key participants in epithelial tumor cell regulation of TNF-alpha. These laboratory studies will be accompanied by studies of clinical samples from patients with ovarian carcinoma to examine the importance of TNF-alpha in ovarian cancer pathogenesis. The specific aims will be: 1. To investigate the importance of the TNF- alpha 5' flanking region in the regulation of TNF-alpha gene regulation in human breast and ovary cancer cells through reporter gene constructs and gel shift assays; 2. To investigate the importance of the AP-1 motif in the control of TNF production in human epithelial cancer cells with sense and antisense c-jun constructs; 3. To evaluate the role of the TNF-alpha 3' flanking region in the regulation of TNF-alpha protein production in human epithelial cancer cells with 3' flanking region reporter gene constructs; 4. To examine human epithelial ovarian cancers from our ovarian cancer tissue bank to better define the relationships between TNF-alpha expression and ovarian cancer pathophysiology. Taken together, these studies will provide insight into the pathobiology of ovarian cancer and possibly provide new strategies for ovarian cancer therapy.