Muthukumaran Neelakandan, Miletti-González Karl E, Ravindranath Abhilash K, Rodríguez-Rodríguez Lorna
Division of Gynecologic Oncology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Room 2009, 195 Little Albany Street, New Brunswick, 08901, USA.
Mol Cancer Res. 2006 Aug;4(8):511-20. doi: 10.1158/1541-7786.MCR-05-0232.
Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-alpha modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-alpha in CD44 expression of cancer cells. Recent clinical work using TNF-alpha inhibitors for the treatment of ovarian cancer makes the study of TNF-alpha interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-alpha on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-alpha differentially modulates the expression of CD44 in TNF-alpha-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-alpha up-regulation of CD44 expression was dependent on the activation of c-Jun NH(2)-terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-alpha failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.
慢性炎症与卵巢癌的病理生理学有关。肿瘤坏死因子-α（TNF-α）是一种主要的炎症细胞因子，在卵巢癌微环境中含量丰富。TNF-α调节正常T淋巴细胞中CD44的表达，而CD44与卵巢癌的发生和转移有关。然而，关于TNF-α在癌细胞CD44表达中的作用知之甚少。最近使用TNF-α抑制剂治疗卵巢癌的临床研究使得研究TNF-α与CD44的相互作用对于确定治疗的成败至关重要。我们研究了TNF-α对卵巢癌细胞活力、CD44表达以及体外迁移/侵袭的影响。我们的结果表明，TNF-α对TNF-α耐药的卵巢癌细胞中CD44的表达有不同的调节作用，影响其体外迁移、侵袭以及与透明质酸的结合。TNF-α对CD44表达的上调依赖于c-Jun氨基末端激酶（JNK）的激活，并且这种激活伴随着其侵袭表型的增加。相反，如果TNF-α未能诱导JNK磷酸化，最终结果是CD44表达和侵袭表型均下调。使用JNK抑制剂和TNF受体竞争性抑制剂证实了这些结果。
