Shang Wen-Qing, Li Hui, Liu Li-Bing, Chang Kai-Kai, Yu Jia-Jun, Xie Feng, Li Ming-Qing, Yu Jin-Jin
Department of Obstetrics and Gynecology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, P.R. China.
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, P.R. China.
Oncol Rep. 2015 Dec;34(6):3007-16. doi: 10.3892/or.2015.4303. Epub 2015 Sep 22.
Receptor activator for nuclear factor κB ligand (RANKL) is a member of the tumor necrosis factor (TNF) family. The interaction between RANKL and its receptor RANK plays an important role in the development and function of diverse tissues. However, the expression and role of RANKL in cervical cancer are still unknown. In the present study, we found that RANKL and RANK were highly co-expressed in cervical cancer. HeLa and SiHa cells secreted soluble RANKL (sRANKL), expressed member RANKL (mRANKL) and RANK. Recombinant human RANKL protein had no effect on the viability of HeLa and SiHa cells. Yet, blocking RANKL with an anti-human RANKL neutralizing antibody (α-RANKL) or recombinant human osteoprotegrin (OPG) protein resulted in the downregulation of Ki-67 and B-cell lymphoma 2 (Bcl-2) expression and an increase in Fas and Fas ligand (FasL) expression, as well as a high level of viability and a low level of apoptosis in the HeLa and SiHa cells. In addition, α-RANKL led to a decrease in IL-8 secretion. Recombinant human IL-8 protein reversed the effect of α-RANKL on the expression of proliferation- and apoptosis‑related molecules, and proliferation and apoptosis in the HeLa and SiHa cells. The present study suggests that a high level of mRANKL/RANK expression in cervical cancer lesions plays an important role in the rapid growth of cervical cancer cells possibly through strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion, which may be a possible target for cervical cancer therapy.
核因子κB 配体受体激活剂（RANKL）是肿瘤坏死因子（TNF）家族的成员。RANKL与其受体RANK之间的相互作用在多种组织的发育和功能中发挥着重要作用。然而，RANKL在宫颈癌中的表达及作用仍不清楚。在本研究中，我们发现RANKL和RANK在宫颈癌中高度共表达。HeLa和SiHa细胞分泌可溶性RANKL（sRANKL），表达膜型RANKL（mRANKL）和RANK。重组人RANKL蛋白对HeLa和SiHa细胞的活力没有影响。然而，用抗人RANKL中和抗体（α-RANKL）或重组人骨保护素（OPG）蛋白阻断RANKL会导致HeLa和SiHa细胞中Ki-67和B细胞淋巴瘤2（Bcl-2）表达下调，Fas和Fas配体（FasL）表达增加，同时细胞活力升高，凋亡水平降低。此外，α-RANKL导致IL-8分泌减少。重组人IL-8蛋白逆转了α-RANKL对HeLa和SiHa细胞中增殖和凋亡相关分子表达以及增殖和凋亡的影响。本研究表明，宫颈癌病变中高水平的mRANKL/RANK表达可能通过加强宫颈癌细胞之间的对话和调节IL-8分泌在宫颈癌细胞的快速生长中起重要作用，这可能是宫颈癌治疗的一个潜在靶点。
