- 作者列表："Lee H","Kim JW","Kim DK","Choi DK","Lee S","Yu JH","Kwon OB","Lee J","Lee DS","Kim JH","Min SH
:Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.
据报道，上皮性卵巢癌 (EOC) 的耐药性归因于癌症干细胞 (CSC) 的存在，因为在大多数癌症中，化疗后 CSC 仍然存在。为了克服这一局限性，需要新的治疗策略，通过靶向癌症干细胞 (CSCs) 来预防癌症复发和化疗耐药癌症。我们筛选了 FDA 批准的化合物库，发现了 4 种靶向卵巢 CSCs 的电压门控钙通道阻滞剂 (马尼地平、拉西地平、贝尼地平和洛美利嗪)。四种钙通道阻滞剂 (CCBs) 降低卵巢 CSCs 的球体形成、活力和增殖，诱导细胞凋亡。CCBs 破坏卵巢 CSCs 的干性，抑制 AKT 和 ERK 信号通路。在钙通道亚基基因中，3 个 L 型和 T 型钙通道基因在卵巢 CSCs 中过表达，钙通道基因的下调降低了卵巢 CSCs 的干细胞样特性。这三个基因的表达与患者组的生存率呈负相关。在与顺铂的联合治疗中，在抑制卵巢 CSCs 的活力和增殖方面显示出协同作用。此外，马尼地平和紫杉醇的组合使用在卵巢 CSCs 异种移植小鼠模型中表现出增强的作用。我们的结果表明，四种 CCBs 可能是预防卵巢癌复发的潜在治疗药物。
METHODS::Altered aerobic glycolysis is an important feature of cancer cell energy metabolism, known as the Warburg effect. Cervical cancer is one of the most common causes of cancer death in females. However, the roles of aerobic glycolysis in the development of cervical cancer are still poorly defined. Here, we identified a transcription factor (TF), ETS-related gene (ERG), as a new regulator of cancer progression and the glycolysis process in cervical cancer. In this study, we found that ectopic expression of ERG enhanced the capacity of aerobic glycolysis and increased glucose uptake, lactate production, and ATP generation. ERG overexpression increased and ERG knockdown decreased the anchorage independent cell growth and cell invasion in cervical cancer cells. Mechanistically, we propose that ERG regulates the expression of hexokinase 2 (HK2) and phosphoglycerate kinase 1 (PGK1) in the glycolytic pathway by directly binding to their promoters. A gain-of-function study showed that the knockdown or overexpression of HK2 and PGK1 abolished the increased or decreased aerobic glycolysis and cervical cancer progression induced by stable ectopic expression or depletion of ERG, respectively. Taken together, our findings suggest that ERG plays a potential role in the progression of cervical cancer, and could serve as a novel biomarker and potential therapeutic target in cervical cancer.
METHODS:INTRODUCTION:Australia has recently implemented major changes in cervical cancer prevention policies including introduction of primary human papillomavirus (HPV) screening starting at age 25, and replacement of the quadrivalent HPV vaccine with the nonavalent vaccine in the national school-based program. We assessed the feasibility and utility of conducting HPV testing in residual clinical specimens submitted for routine Chlamydia trachomatis screening, as a means of tracking HPV vaccine program impact among young sexually active women. METHODS:De-identified residual specimens from women aged 16-24 years submitted for chlamydia testing were collected from three pathology laboratories in Victoria and New South Wales. Limited demographic information, and chlamydia test results were also collected. Patient identifiers were sent directly from the laboratories to the National HPV Vaccination Program Register, to obtain HPV vaccination histories. Samples underwent HPV genotyping using Seegene Anyplex II HPV 28 assay. RESULTS:Between April and July 2018, 362 residual samples were collected, the majority (60.2%) of which were cervical swabs. Demographic data and vaccination histories were received for 357 (98.6%) women (mean age 21.8, SD 2.0). Overall, 65.6% of women were fully vaccinated, 9.8% partially, and 24.7% unvaccinated. The majority (86.0%) resided in a major city, 35.9% were classified in the upper quintile of socioeconomic advantage and chlamydia positivity was 7.8%.The prevalence of quadrivalent vaccine-targeted types (HPV6/11/16/18) was 2.8% (1.5-5.1%) overall with no differences by vaccination status (p = 0.729). The prevalence of additional nonavalent vaccine-targeted types (HPV31/33/45/52/58) was 19.3% (15.6-23.8%). One or more oncogenic HPV types were detected in 46.8% (95% CI 41.6-52.0%) of women. CONCLUSIONS:HPV testing of residual chlamydia specimens provides a simple, feasible method for monitoring circulating genotypes. Applied on a larger scale this method can be utilised to obtain a timely assessment of nonavalent vaccine impact among young women not yet eligible for cervical screening.
METHODS::Human papillomavirus (HPV) type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Our previous international epidemiological studies revealed that a HPV58E7 natural variant, T20I/G63S (designated as V1), was associated with a higher risk of cervical cancer. We recently showed that V1 possesses a greater ability to immortalise and transform primary cells, as well as degrading pRB more effectively than the prototype and other common variants. In this study, we performed a series of phenotypic and molecular assays using physiologically relevant in vitro and in vivo models to compare the oncogenicity of V1 with that of the prototype and other common natural variants. Through activation of AKT and K-Ras/ERK signalling pathways, V1 consistently showed greater oncogenicity compared with prototype and other variants, as demonstrated by increased cell proliferation, migration and invasion, as well as induction of larger tumours in athymic nude mice. This study complements our previous epidemiological and molecular observations pinpointing the higher oncogenicity of V1 compared with prototype and all other common variants. Since V1 is more commonly found in Eastern Asia, our report provides insight into the design of HPV-screening assays and selection of components for HPV vaccines in this region.IMPORTANCE Epidemiological studies have revealed that a wild type variant of HPV58 carrying an E7 variation, T20I/G63S (V1), is associated with a higher risk of cervical cancer. We previously reported that this increased oncogenicity could be the result of its greater ability to degrade pRB, thereby leading to an increased ability to grow in an anchorage-independent manner. In addition to this, this report further showed that this HPV variant induced activation of AKT and K-Ras/ERK signalling pathways, thereby, explaining its genuine oncogenicity in promoting cell proliferation, migration, invasion, and formation of tumours, all to a greater extent than prototype HPV58 and other common variants.