Leong C T C, Ong C K, Tay S K, Huynh H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore, Singapore.
Oncogene. 2007 Feb 8;26(6):870-80. doi: 10.1038/sj.onc.1209836. Epub 2006 Jul 24.
Ovarian cancer is currently the second leading cause of gynecological malignancy and cisplatin or cisplatin-based regimens have been the standard of care for the treatment of advance epithelial ovarian cancers. However, the efficacy of cisplatin treatment is often limited by the development of drug resistance either through the inhibition of apoptotic genes or activation of antiapoptotic genes. We have previously reported the overexpression of human UO-44 (HuUO-44) in ovarian cancers and the HuUO-44 antisera markedly inhibited NIH-OVCAR3 ovarian cancer cell attachment and proliferation (Oncogene 23: 5707-5718, 2004). In the present study, we observed through the cancer cell line profiling array that the expression of HuUO-44 was suppressed in the ovarian cancer cell line (SKOV-3) after treatment with several chemotherapeutic drugs. Similarly, this suppression in HuUO-44 expression was also correlated to the cisplatin sensitivity in two other ovarian cancer cell lines NIH-OVCAR3 and OV-90 in a dose-dependent manner. To elucidate the function of HuUO-44 in cisplatin chemoresistance in ovarian cancer cell, small interfering RNAs (siRNAs) were employed to mediate HuUO-44 silencing in ovarian cancer cell line, NIH-OVCAR3. HuUO-44 RNA interference (RNAi) resulted in the inhibition of cell growth and proliferation. Importantly, HuUO-44 RNAi significantly increased sensitivity of NIH-OVCAR3 to cytotoxic stress induced by cisplatin (P<0.01). Strikingly, we have also demonstrated that overexpression of HuUO-44 significantly conferred cisplatin resistance in NIH-OVCAR3 cells (P<0.05). Taken together, UO-44 is involved in conferring cisplatin resistance; the described HuUO-44-specific siRNA oligonucleotides that can potently silence HuUO-44 gene expression may prove to be valuable pretreatment targets for antitumor therapy or other pathological conditions that involves aberrant HuUO-44 expression.
卵巢癌是目前妇科恶性肿瘤的第二大主要病因，顺铂或基于顺铂的治疗方案一直是晚期上皮性卵巢癌治疗的标准。然而，顺铂治疗的疗效常常受到耐药性发展的限制，这可能是通过抑制凋亡基因或激活抗凋亡基因实现的。我们之前报道过人UO-44（HuUO-44）在卵巢癌中过表达，且HuUO-44抗血清显著抑制NIH-OVCAR3卵巢癌细胞的黏附和增殖（《癌基因》23: 5707 - 5718, 2004）。在本研究中，我们通过癌细胞系分析阵列观察到，用几种化疗药物处理后，卵巢癌细胞系（SKOV-3）中HuUO-44的表达受到抑制。同样，在另外两种卵巢癌细胞系NIH-OVCAR3和OV-90中，HuUO-44表达的这种抑制也与顺铂敏感性呈剂量依赖性相关。为了阐明HuUO-44在卵巢癌细胞顺铂耐药中的作用，我们使用小干扰RNA（siRNA）介导卵巢癌细胞系NIH-OVCAR3中HuUO-44的沉默。HuUO-44 RNA干扰（RNAi）导致细胞生长和增殖受到抑制。重要的是，HuUO-44 RNAi显著增加了NIH-OVCAR3对顺铂诱导的细胞毒性应激的敏感性（P<0.01）。令人惊讶的是，我们还证明HuUO-44的过表达显著赋予了NIH-OVCAR3细胞顺铂耐药性（P<0.05）。综上所述，UO-44参与赋予顺铂耐药性；所描述的能有效沉默HuUO-44基因表达的HuUO-44特异性siRNA寡核苷酸可能被证明是抗肿瘤治疗或其他涉及异常HuUO-44表达的病理状况的有价值的预处理靶点。
