靶向 Claudin-2 治疗子宫内膜样癌的可能性。
- 作者列表："Okada T","Konno T","Kohno T","Shimada H","Saito K","Satohisa S","Saito T","Kojima T
:Claudin-2 (CLDN-2) is a leaky-type tight junction protein, and its overexpression increases tumorigenesis of some types of cancer cells. In the present study, to examine the possibility of targeting CLDN-2 in the therapy for endometrioid endometrial adenocarcinoma, we investigated the regulation and role of CLDN-2 in endometriosis and endometrioid endometrial adenocarcinoma. In endometrioid endometrial adenocarcinoma tissues, marked upregulation of CLDN-2 was observed together with malignancy, while in endometriosis tissues, a change in the localization of CLDN-2 was observed. In cells of the endometrial adenocarcinoma cell line Sawano, which highly express CLDN-2, downregulation of CLDN-2 induced by the siRNA upregulated the epithelial barrier and inhibited cell migration. Furthermore, the downregulation of CLDN-2 affected the cell cycle and inhibited cell proliferation. In Sawano cells cultured with high-glucose medium, CLDN-2 expression was downregulated at the mRNA and protein levels. The high-glucose medium upregulated the epithelial barrier, cell proliferation, and migration, and inhibited cell invasion. The histone deacetylase (HDAC) inhibitor tricostatin A (TSA), which has antitumor effects, downregulated CLDN-2 expression, cell proliferation, invasion, and migration, and upregulated the epithelial barrier. The mitochondrial respiration level, an indicator of cancer metabolism, was downregulated by CLDN-2 knockdown and upregulated by the high-glucose condition. Taken together, these results indicated that overexpression of CLDN-2 closely contributed to the malignancy of endometrioid endometrial adenocarcinoma. Downregulation of CLDN-2 via the changes of the glucose concentration and treatment with HDAC inhibitors may be important in the therapy for endometrial cancer.
Claudin-2 (CLDN-2) 是一种漏型紧密连接蛋白，其过表达增加了某些类型癌细胞的肿瘤发生。在本研究中，我们研究了 CLDN-2 在子宫内膜异位症和子宫内膜样腺癌中的调节和作用，以探讨靶向 CLDN-2 治疗子宫内膜样腺癌的可能性。在子宫内膜样腺癌组织中，观察到 CLDN-2 与恶性肿瘤一起显著上调，而在子宫内膜异位症组织中，观察到 CLDN-2 定位的变化。在高表达 CLDN-2 的子宫内膜腺癌细胞系 Sawano 的细胞中，siRNA 诱导的 CLDN-2 下调上调了上皮屏障并抑制了细胞迁移。此外，CLDN-2 的下调影响细胞周期，抑制细胞增殖。在高糖培养基培养的 Sawano 细胞中，CLDN-2 在 mRNA 和蛋白水平表达下调。高糖培养基上调上皮屏障、细胞增殖和迁移，抑制细胞侵袭。组蛋白去乙酰化酶 (HDAC) 抑制剂 tricostatin A (TSA) 具有抗肿瘤作用，下调 CLDN-2 表达、细胞增殖、侵袭和迁移，上调上皮屏障。线粒体呼吸水平是癌症代谢的指标，通过 CLDN-2 敲除下调，高糖条件下上调。总之，这些结果表明 CLDN-2 的过度表达与子宫内膜样腺癌的恶性程度密切相关。在子宫内膜癌的治疗中，通过葡萄糖浓度的变化和 HDAC 抑制剂的治疗下调 CLDN-2 可能是重要的。
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.