Bourgo Ryan J, Braden Wesley A, Wells Susanne I, Knudsen Erik S
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Mol Carcinog. 2009 Jan;48(1):45-55. doi: 10.1002/mc.20456.
High-risk human papilloma virus (HPV) encodes two oncoproteins, E6 and E7, which are vital to viral replication and contribute to the development of cervical cancer. HPV16 E7 can target over 20 cellular proteins, but is best known for inactivating the retinoblastoma (RB) tumor suppressor. RB functions by restraining cells from entering S-phase of the cell cycle, thus preventing aberrant proliferation. While it is well established that HPV16 E7 facilitates the degradation of the RB protein, the ability of the RB pathway to overcome E7 action is less well understood. In this study the RB-pathway was activated via the overexpression of the p16ink4a tumor suppressor or ectopic expression of an active allele of RB (PSM-RB). While p16ink4a had no influence on cell cycle progression, PSM-RB expression was sufficient to induce a cell cycle arrest in both SiHa and HeLa cells, HPV positive cervical cancer cell lines. Strikingly, this arrest led to the downregulation of E2F target gene expression, which was antagonized via enhanced HPV-E7 expression. Since downmodulation of E7 function is associated with chronic growth arrest and senescence, the effect of PSM-RB on proliferation and survival was evaluated. Surprisingly, sustained PSM-RB expression impeded the proliferation of SiHa cells, resulting in both cell cycle inhibition and cell death. From these studies we conclude that active RB expression can sensitize specific cervical cancer cells to cell cycle inhibition and cell death. Thus, targeted therapies involving activation of RB function may be effective in inducing cell death in cervical cancer.
高危型人乳头瘤病毒（HPV）编码两种癌蛋白E6和E7，它们对病毒复制至关重要，并促使宫颈癌的发生。HPV16 E7可作用于20多种细胞蛋白，但最广为人知的是其使视网膜母细胞瘤（RB）肿瘤抑制因子失活。RB通过抑制细胞进入细胞周期的S期发挥作用，从而防止异常增殖。虽然HPV16 E7促使RB蛋白降解这一点已得到充分证实，但RB通路克服E7作用的能力却鲜为人知。在本研究中，通过过表达p16ink4a肿瘤抑制因子或异位表达RB的活性等位基因（PSM-RB）激活RB通路。虽然p16ink4a对细胞周期进程没有影响，但PSM-RB的表达足以在SiHa和HeLa这两种HPV阳性宫颈癌细胞系中诱导细胞周期停滞。引人注目的是，这种停滞导致E2F靶基因表达下调，而HPV-E7表达增强可对抗这种下调。由于E7功能的下调与慢性生长停滞和衰老相关，因此评估了PSM-RB对增殖和存活的影响。令人惊讶的是，持续的PSM-RB表达阻碍了SiHa细胞的增殖，导致细胞周期抑制和细胞死亡。从这些研究中我们得出结论，活性RB的表达可使特定的宫颈癌细胞对细胞周期抑制和细胞死亡敏感。因此，涉及激活RB功能的靶向治疗可能有效诱导宫颈癌细胞死亡。
