Abstract Progestin-resistance is a main obstacle to the success of conservative therapy in type I young endometrial cancer patients. We have established a progestin-resistant endometrial cancer cell line by long-term induction with gradual increasing of progestin concentration. Our previous study confirmed that progestin activated PI3K/Akt pathway through a non-genomic pathway independent of Progesterone receptor (PR). Blocking PI3K pathway up-regulated PR expression and restored the anti-proliferative effect of medoxyprogesterone acetate (MPA) in progestin-resistant cells. We propose that PI3K/Akt activation may not be the only mechanism of progestin-resistance. To further explore other molecular events leading to progestin-resistance and to search for any possible approaches to reverse this resistance in endometrial cancer, we have characterized functional proteomics by reverse phase protein array (RPPA) in progestin-sensitive and -resistant endometrial cancer cells, and the RPPA results were confirmed by Western blots. Our results demonstrated up-regulation of Insulin-like growth factor-1 receptor (IGF-1R), and down-regulation of IGF binding protein 2 (IGFBP2) and Ataxia Telangiectasia (ATM) [an upstream molecule of adenosine monophosphate-activated kinase (AMPK) pathway] in progestin-resistant cells, suggesting that IGF/AMPK metabolic pathways are involved in progestin-resistance of endometrial cancer therapy. We further identified the differential effects of insulin stimulation on metabolic changes in progestin-sensitive and -resistant cell lines. We found that acute stimulation with high concentration of insulin not only activated PI3K/Akt, but also reduced the expression of PR, EGFR and IGF-1R, and further mediated proliferation of primary endometrial cancer cells. Continually stimulation with insulin reduced MPA-mediated anti-proliferation effect in progestin-sensitive cells, but no effect in progestin-resistant cells, indicating the existing of altered insulin-responsiveness in progestin-resistant cells. Furthermore, Metformin, an insulin-independent AMPK activator and is commonly used as an insulin sensitizer, could restore progestin sensitivity in progestin-resistant endometrial cancer cells. The restoration was demonstrated directly related to the inhibition of PI3K/Akt pathway, activation of AMPK and upregulation of PR transcription. In summary, our study revealed that PR/AMPK-IGF/PI3K network plays an important role on progestin-resistance in endometrial cancer therapy. The combinatory treatment of progestin with PI3K inhibitor, or with AMPK activator-metformin might be an effective conservative approach for endometrial cancer patients who developed progestin-resistance in their therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5755. doi:1538-7445.AM2012-5755
<p>Semi-quantitative evaluation of the immunohistochemical staining of IL-17A, TET1, 5-hmC, and ERα expression in endometrial hyperplasia and cancer lesions</p>
Potential functional roles for the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPARβ/δ is expressed in liver, its function in this tissue is less clear. To determine the role of PPARβ/δ in chemically induced liver toxicity, wild-type and PPARβ/δ-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPARβ/δ-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl4) hepatoxicity was also observed in PPARβ/δ-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl4 were observed between wild-type or PPARβ/δ-null mice in response to CCl4. Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-κB) activity were noted in PPARβ/δ-null mice. Conclusion: Results from these studies show that PPARβ/δ is protective against liver toxicity induced by AOM and CCl4, suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (Hepatology 2007.)
About 10-66% of patients with atypical endometrial hyperplasia diagnosed before surgery (preoperative-AEH) are found to have concurrent endometrial cancer (EC) at definitive hysterectomy, leading to incomplete primary surgery and delayed adjuvant treatment. This study aims to investigate the potential risk factors of concurrent EC in preoperative-AEH patients in a clinical setting with a gynecological pathology review. All patients diagnosed with AEH by endometrial biopsy or curettage that then underwent definitive hysterectomy from January 2016 to December 2019 in a tertiary hospital were retrospectively analyzed. All diagnoses were reviewed by gynecological pathologists. A total of 624 preoperative-AEH patients were included, 30.4% of whom had concurrent EC. In multivariate analysis, postmenopausal status and CA125 ≥ 35 U/mL significantly correlated with concurrent EC (OR = 3.57; 95% CI = 1.80-7.06; OR = 2.15; 95% CI = 1.15-4.03). This risk was remarkably increased in patients with both postmenopausal status and CA125 ≥ 35 U/mL (OR = 16.20; 95% CI = 1.73-151.44). Notably, concurrent EC seemed to occur more frequently in women with postmenopausal time ≥ 5 years (OR = 4.04, 95% CI = 1.80-5.85). In addition, CA125 ≥ 35 U/mL seemed to be an independent risk factor (OR = 5.74; 95% CI = 1.80-18.27) for concurrent intermediate-high-risk EC. Intermediate-high-risk EC was also more commonly seen in preoperative-AEH women with postmenopausal time ≥ 5 years (OR = 5.52, 95% CI = 1.21-25.19, p = 0.027). In conclusion, preoperative-AEH patients with postmenopausal status or elevated level of CA125 might have a high risk of concurrent EC. Adequate pre-surgical evaluation might be suggested for such patients.
Ralstonia solanacearum is an important etiological agent that can cause serious bacterial wilt in a very wide range of potential host plants, including ginger. Here, we report the complete genome sequence of R. solanacearum SD54, a race 4 biovar 4 (R4B4) strain from a diseased ginger plant in China.
Abstract Background Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms. Methods The effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells. Results Our results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone. Conclusions The eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.
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