Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling

Oridonin, an ent-kaurane diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, has shown various pharmacological and physiological effects such as anti-tumor, anti-bacterial, and anti-inflammatory properties. However, the effect of oridonin on human ovarian cancer cell lines has not been determined. In this study, we demonstrated that oridonin inhibited ovarian cancer cell proliferation, migration and invasion in a dose-dependent manner. Furthermore, we showed oridonin inhibited tumor growth of ovarian cancer cells (SKOV3) in vivo. We then assessed mechanisms and found that oridonin specifically abrogated the phosphorylation/activation of mTOR signaling. In summary, our results indicate that oridonin is a potential inhibitor of ovarian cancer by blocking the mTOR signaling pathway.     

mTOR信号通路与胃癌的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）及其信号通路调控蛋白质的合成,细胞生长、迁移、凋亡以及血管形成等,该信号通路在胃癌中常被高度激活,并与胃癌的复发、转移等临床病理特性密切相关。雷帕霉素及其衍生物通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法。     

Ia期卵巢癌及对侧卵巢癌前病变的探讨

对Ｉａ期卵巢癌的对侧卵巢进行病理学检查并与非卵巢癌病例作对照。患者卵巢内包涵囊肿数及其浆液性分化频度明显高于对照组（Ｐ＜０．０１，后者ＯＲ＝１０．０，９５％可信区间＝１．２～７８．１）。研究组卵巢包涵囊肿随年龄而增多。认为卵巢内包涵囊肿可能在卵巢癌的发生中发挥重要作用。     

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a BRCA1/2 mutation. Inhibition of PARP, the key enzyme in base excision repair, is based on synthetic lethality whereby alternative DNA repair pathways in tumor cells that are deficient in homologous recombination is blocked, rendering them unviable and leading to cell death. The Australia New Zealand Gynaecological Oncology Group (ANZGOG) is the national gynecological cancer clinical trials organization for Australia and New Zealand. ANZGOG''s purpose is to improve outcomes and quality of life for women with gynecological cancer through cooperative clinical trials and undertaking multidisciplinary research into the causes, prevention and treatments of gynecological cancer. This review summarizes current ovarian cancer research and treatment approaches presented by Australian and New Zealand experts in the field at the 2020 ANZGOG webinar series entitled “Ovarian Cancer systems of Care”.     

mTOR功能及其抑制剂研究进展

哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin mTOR）是一种丝／苏氨酸蛋白激酶，mTOR在肿瘤细胞生长、增殖过程中起重要作用，mTOR信号通路活动异常与肿瘤的发生有密切关系，mTOR足肿瘤药物治疗作用的理想靶点，目前新的mTOR抑制剂不断出现。本文对mTOR蛋白的结构、功能和mTOR信号通路及其抑制剂进行了综述。     

哺乳动物雷帕霉素靶蛋白信号通路与大肠癌

哺乳动物雷帕霉素靶蛋白(mTOR)信号通路作为细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,调节细胞存活、增殖、转分化、迁移和细胞周期.mTOR这些调节机制的异常与大肠癌的发生和发展密切相关.目前mTOR抑制剂治疗大肠癌已处于临床试验中,并取得了一定的进展.     

Pathway Crosstalk Analysis Based on Protein-protein Network Analysis in Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death in women aged 35 to 74 years. Although there areseveral popular hypothesis of ovarian cancer pathogenesis, the genetic mechanisms are far from being clear.Recently, systems biology approaches such as network-based methods have been successfully applied to elucidatethe mechanisms of diseases. In this study, we constructed a crosstalk network among ovarian cancer relatedpathways by integrating protein-protein interactions and KEGG pathway information. Several significantpathways were identified to crosstalk with each other in ovarian cancer, such as the chemokine, Notch, Wnt andNOD-like receptor signaling pathways. Results from these studies will provide the groundwork for a combinationtherapy approach targeting multiple pathways which will likely be more effective than targeting one pathwayalone.     

Ovarian Cancer: Interplay of Vitamin D Signaling and miRNA Action

Increasing attention is being devoted to the mechanisms by which cells receive signals and then translatethese into decisions for growth, death, or migration. Recent findings have presented significant breakthroughsin developing a deeper understanding of the activation or repression of target genes and proteins in response tovarious stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanisticinsights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted natureof the pathways remains unclear. Although new layers of information are being added regarding mechanismsunderlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of thisresearch must be sequentially collected and re-interpreted. We divide this multi-component review into differentsegments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlledby tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression.Intra/inter-population variability is insufficiently studied and a better understanding of genetics of populationwill be helpful in getting a step closer to personalized medicine.     

Endometriosis and Ovarian Cancer: an Integrative Review (Endometriosis and Ovarian Cancer)

Despite being initially considered a benign disease, it is widely thought nowadays that endometriosis and especially ovarian endometriomas are neoplastic conditions with the potential to become malignant. This review was conducted to summarize, in a concise and systematic manner, the available scientific data relating endometriosis to ovarian cancer, published in the past five years. After reading abstracts and applying our predefined inclusion and exclusion criteria, a final list of 11 scientific papers was obtained and subjected to review. Endometriosis is associated with an increased risk of developing epithelial ovarian cancer (EOC), mainly of endometrioid and clear cell subtypes. This might be by virtue of the high estrogen concentration with the disease, which leads to malignant proliferation of endometriotic cysts, or be due to mutations in the ARID1A gene and consequent loss of BAF250a expression. The iron produced in the fluid of endometriotic cysts promotes oxidative stress, which in turn may cause genetic mutations and malignant progression of ovarian cysts.     

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market.Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3’-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.     

A Nationwide Population‐Based Retrospective Cohort Study of the Risk of Uterine,Ovarian and Breast Cancer in Women With Polycystic Ovary Syndrome

Background.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. We used a nationwide population-based retrospective cohort study to explore the relationship between PCOS and the subsequent development of gynecological cancers including uterine, breast, or ovarian cancer.

Methods.

We identified subjects who were diagnosed with PCOS between January 1, 2000, and December 31, 2004, in the Taiwan National Health Insurance (NHI) Research Database. A comparison cohort was constructed for patients without known PCOS who were also matched according to age. All PCOS and control patients were observed until diagnosed with breast cancer, ovarian cancer, or uterine cancer or until death, withdrawal from the NHI system, or December 31, 2009.

Results.

The PCOS cohort consisted of 3,566 patients, and the comparison cohort consisted of 14,264 matched control patients without PCOS. The adjusted hazard ratio (HR) of uterine cancer and breast cancer in subjects with PCOS were higher (HR: 8.42 [95% confidence interval: 1.62–43.89] and HR: 1.99 [95% confidence interval: 1.05–3.77], respectively) than that of the controls during the follow-up. With the Monte Carlo method, only the mean adjusted HR of 1,000 comparisons for developing uterine cancer during the follow-up period was greater for the PCOS group than for the control groups (HR: 4.71, 95% confidence interval: 1.57–14.11).

Conclusion.

PCOS might increase the risk of subsequent newly diagnosed uterine cancer. It is critical that further large-scale, well-designed studies be conducted to confirm the association between PCOS and gynecological cancer risk.     

Polycystic Ovary Syndrome and Risk of Endometrial Cancer: a Mini-Review

The polycystic ovary syndrome is the most common endocrinological disorder of reproductive age women with a prevalence of 5 to 8 %. The most common diagnostic criteria used for polycystic ovary syndrome are oligo- or an-ovulation, clinical and/ or biochemical signs of hyperandrogenism and polycystic ovaries. Hyperandrogenism results in increased estrogen levels and lack of cyclic progesterone due to anovulation and persistent stimulation of the endometrium may lead to endometrial hyperplasia or adenocarcinoma development. In this mini review, we aimed to evaluate the possible relationship between polycystic ovary syndrome and endometrial cancer.     

Recreational Physical Activity and Risk of Ovarian Cancer: a Meta-analysis

Our aim was to access the association between recreational physical activity (RPA) and risk of ovarian cancer (OC). The studies were retrieved from the PubMed and Embase databases up to February 20th, 2014. Risk ratios (OR) and 95% confidence intervals (CI) were used to estimate effect sizes. Random-effects or fixed-effects models were used to pool the data. The trim and fill method was applied for sensitivity analysis. Begg’s rank correlation test and Egger’s regression asymmetry test were employed to assess the publication bias. A total of 6 studies (435398 participants including 2983 OC patients) were included in this meta-analysis. The overall estimate indicated that there was weakly inverse association between RPA and OC risk (RR=0.90, 95%CI: 0.72-1.12, p=0.335). Meanwhile, for prospective cohort studies, a result consistent with the overall estimate was obtained (RR=1.12, 95% CI: 0.88-1.42, p=0.356). However, for case control studies, the pooled estimate of RR was 0.76 (95%CI: 0.64-0.90, p=0.002), indicating a clear significant association between RPA and OC risk. In addition,the sensitivity analysis indicated a significant link between RPA and risk of OC after removing Lahmann’s study (RR=0.80, 95% CI: 0.68-0.93, p=0.004). No significant publication bias was found (Begg’s test: p=1.00; Egger’s test: p=0.817). In conclusion, our meta-analysis indicated a weakly inverse relationship between RPA and the occurrence of OC.     

Evaluation of Ovarian Cysts in Breast Cancer Cases on Tamoxifen

Purpose: The anti- estrogen drug, tamoxifen, is one of the most important medications used in the treatmentof both advanced and localized breast cancer. However, such tamoxifen use may have some risks related to theendometrium and ovaries.We followed a group of women with breast cancer on tamoxifen for the developmentof ovarian cysts. Methods: Based on a cross sectional study, 35 pre and post menopausal patients with breastcancer on tamoxifen were followed by pelvic exam and vaginal ultrasonography for 3 cycles of 3 month intervals;occurrence and outcome of ovarian cysts were evaluated. Results: Of the 35 tmoxifen-treated patients enrolledin this study, 21 were postmenopausal and 14 were premenopausal .Their average age was 48.1±8.7 (range: 29-65 yrs) years. The mean duration of tamoxifen therapy was 30.5± 14 months (range: 12-60 months). Ovariancysts were diagnosed in 12 (34.3%) patients, with surgery required in 6; pathological examination revealedmalignancy in two cases. Conclusion: Development of ovarian cysts is a rather frequent event in women withbreast cancer on tamoxifen. The majority of cysts are simple, which may resolve spontaneously or withdiscontinuation of tamoxifen, but malignancy needs to be ruled out.