Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, China.
J Cell Physiol. 2012 Nov;227(11):3629-38. doi: 10.1002/jcp.24069.
High-mobility group box 1 (HMGB1), a nuclear and extracellular protein, is implicated in the development and progression of some types of cancers. However, no information is available to date regarding the function of HMGB1 in ovarian cancer. In this study, we performed cDNA microarray analysis and identified HMGB1 as a gene dramatically elevated in the highly invasive subclone S1 compared with the low invasive subclone S21 derived from the same cell line SKOV3. Then lentivirus vector with HMGB1 shRNA was constructed and infected the highly invasive cell line S1, A1, and HO8910PM. Real-time RT-PCR, Western blot, and IHC results confirmed the down-regulation of HMGB1 expression by its shRNA was about 80-90% at both the mRNA and protein levels. Knockdown of HMGB1 significantly suppressed ovarian cancer cell proliferation and induced cell cycle arrest at the G1/G0 phase, which was accompanied by decreased expressions of cyclin D1 and PCNA. Furthermore, knockdown of HMGB1 induced ovarian cancer cell apoptosis, which was mediated by increased expression of Bax and decreased expression of Bcl-2. Finally, knockdown of HMGB1 significantly inhibited ovarian cancer cell invasion and metastasis, which was regulated by decreased expressions of MMP2 and MMP9. Serum HMGB1 levels in patients with epithelial ovarian cancer were significantly higher than that in patients with benign ovarian tumor and healthy controls. These results indicate that HMGB1 is a newly identified gene associated with ovarian cancer growth and metastasis. HMGB1 may serve as a new therapeutic target for the treatment of ovarian cancer in the future.
高迁移率族蛋白 B1（HMGB1）是一种核蛋白和细胞外蛋白，与某些类型癌症的发展和进展有关。然而，目前尚无关于 HMGB1 在卵巢癌中的功能的信息。在这项研究中，我们进行了 cDNA 微阵列分析，发现与低侵袭性亚克隆 S21 相比，高侵袭性亚克隆 S1 中 HMGB1 基因显著升高，该亚克隆源自同一细胞系 SKOV3。然后构建了带有 HMGB1 shRNA 的慢病毒载体，并感染了高侵袭性细胞系 S1、A1 和 HO8910PM。实时 RT-PCR、Western blot 和 IHC 结果证实，其 shRNA 下调 HMGB1 表达约 80-90%，在 mRNA 和蛋白水平上均下调。HMGB1 的敲低显著抑制卵巢癌细胞增殖，并诱导细胞周期停滞在 G1/G0 期，伴随细胞周期蛋白 D1 和 PCNA 的表达降低。此外，HMGB1 的敲低诱导卵巢癌细胞凋亡，这是通过 Bax 表达增加和 Bcl-2 表达降低介导的。最后，HMGB1 的敲低显著抑制卵巢癌细胞侵袭和转移，这是通过 MMP2 和 MMP9 的表达降低来调节的。上皮性卵巢癌患者的血清 HMGB1 水平明显高于良性卵巢肿瘤患者和健康对照组。这些结果表明，HMGB1 是一个与卵巢癌生长和转移相关的新鉴定基因。HMGB1 可能成为未来治疗卵巢癌的新靶点。
