Endometrial Cancer Growth Research Articles

Progesterone inhibits endometrial cancer growth by inhibiting glutamine metabolism through ASCT2.

Endometrial carcinoma (EC) is a common malignancy that originates from the endometrium and grows in the female reproductive system. Surgeries, as current treatments for cancer, however, cannot meet the fertility needs of young women patients. Thus, progesterone (P4) therapy is indispensable due to its effective temporary preservation of female fertility. Many cancer cells are often accompanied by changes in metabolic phenotypes, and abnormally dependent on the amino acid glutamine. However, whether P4 exerts an effect on EC via glutamine metabolism is unknown. In the present study, we found that P4 could inhibit glutamine metabolism in EC cells and down-regulate the expression of the glutamine transporter ASCT2. This regulation of ASCT2 affects the uptake of glutamine. Furthermore, the in vivo xenograft studies showed that P4 inhibited tumor growth and the expression of key enzymes involved in glutamine metabolism. Our study demonstrated that the direct regulation of glutamine metabolism by P4 and its anticancer effect was mediated through the inhibition of ASCT2. These results provide a mechanism underlying the effects of P4 therapy on EC from the perspective of glutamine metabolism.

Abstract A014: Role of stromal CD10 expression in progression of endometrial and endometriosis-associated cancers

Abstract Endometriosis-associated carcinomas (EACs) and endometrial malignancies have many commonalities yet their pathophysiology, particularly those with high-risk histology such as clear cell, is understudied. EACs are histologically and clinically distinct from other gynecological cancers due to their unique origin within endometriosis. The endometriotic microenvironment is uniquely hypoxic with high levels of iron due to recurrent menstrual cycling, and this iron-rich microenvironment has been linked to promoting carcinogenesis through iron-induced oxidative stress. However, the mechanism by which the endometriotic microenvironment contributes to EAC tumorigenesis and how this compares with endometrial cancer is unknown. Most of our current knowledge of EACs is built on either epidemiologic analyses or correlative studies. Additionally, most studies of the endometriotic microenvironment primarily focus on the epithelial component while the role of the stroma has been largely unexplored. Mesenchymal stem cells (MSC) are a critical component of the stromal microenvironment. Recently, we identified a key role of endometriosis derived MSCs (enMSCs) in altering ovarian clear cell carcinoma iron regulation. Interestingly, enMSCs resemble the primary endometrium derived MSCs, which suggested their role in endometrial cancer. This stromal subset is characterized by the loss of surface CD10 expression. It is known that cancer cells, particularly clear cell carcinoma (CCC), have a unique requirement for high levels of iron. We hypothesize that CD10 negative enMSCs promote growth of EAC and endometrial cancer through iron regulation. MSCs were isolated from primary human benign endometriosis, benign endometrium, or endometrial cancer. Flow cytometry was used to measure surface CD10 expression. We investigated the role of CD10 negative enMSCs on CCC iron regulation. Our results showed that CD10 negative enMSCs promote CCC growth by exporting iron through the upregulation of Hephaestin (HEPH) and Ferroportin (FPO) which then led to increase labile iron pool (LIP) in CCC cells. However, increasing the LIP does not occur with iron supplementation alone, this indicates the critical role of CD10 negative enMSCs in regulating iron handling in CCC cells. Additionally, our data showed that CD10 negative enMSCs alter the balance of Ferritin L and Ferritin H- the main iron storage proteins- in CCC cells. Mechanistically, our preliminary data showed that CD10 negative enMSCs directly donate Ferritin L into CCC cells. Further, CD10 negative enMSCs enhance Ferritin H degradation through the upregulation of ferritinophagy in CCC cells. In conclusion, our results indicate there is a sub-population of enMSCs, marked by the loss of CD10 expression, that enhances EAC and endometrial cancer cell growth through iron regulation. This highlights the existence of a tumor-promoting stromal cell within both the endometrium and endometriosis which can be capitalized on as an “Achilles' heel” to uncover novel treatment targets for EAC and endometrial cancer. Citation Format: Huda I. Atiya, Lan G. Coffman. Role of stromal CD10 expression in progression of endometrial and endometriosis-associated cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A014.

IKBKE influences endometrial cancer growth and increases progestin resistance

IKBKE influences endometrial cancer growth and increases progestin resistance

Comprehensive analysis of HOX family genes in endometrial cancer.

Endometrial cancer (EC) is one of the most prevalent malignancies in the female population. Homeoboxes (HOXs) are a large family of transcription factors that have a variety of functions in biological processes (BPs), including developmental differentiation, and their dysregulated expression has been implicated in tumorigenesis. However, the involvement of HOXs in EC has received little attention. Thus, we aimed to identify the potential role of HOXs in EC from a multi-omics perspective through bioinformatics analysis. We obtained transcriptome, mutation, and methylation data and the corresponding clinical data for normal and tumor tissues from The Cancer Genome Atlas (TCGA) database. Abnormal expression of HOXs in EC was identified via differential analysis, and the diagnostic value of HOXs in EC was assessed with the receiver operating characteristic (ROC) method. Univariate and multivariate Cox regression models were employed to evaluate the predictive efficacy of HOXs in EC. Methylation and mutation analyses revealed epigenetic and genetic sequence alterations in HOXs. Single-sample gene set enrichment analysis (ssGSEA) was used to explore the altered immune microenvironment in EC. Moreover, the gene activity and pathway enrichment of downstream key HOX genes were revealed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis in EC. HOXs were found to be linked to the growth of EC and potentially playing a role in establishing the tumor immune microenvironment in patients with EC. HOXB9 was found to be a vital prognostic molecule in patients with EC and is expected to contribute to a novel treatment approach. We used bioinformatics techniques to clarify the potential role of HOXs from a multi-omics perspective, and our findings provide a foundation for future investigations into the molecular mechanisms of HOXs in EC.

A Multi-Omics Approach Revealed Common Dysregulated Pathways in Type One and Type Two Endometrial Cancers.

Endometrial cancer (EC) is the most frequent gynecologic cancer in postmenopausal women. Pathogenetic mechanisms that are related to the onset and progression of the disease are largely still unknown. A multi-omics strategy can help identify altered pathways that could be targeted for improving therapeutical approaches. In this study we used a multi-omics approach on four EC cell lines for the identification of common dysregulated pathways in type 1 and 2 ECs. We analyzed proteomics and metabolomics of AN3CA, HEC1A, KLE and ISHIKAWA cell lines by mass spectrometry. The bioinformatic analysis identified 22 common pathways that are in common with both types of EC. In addition, we identified five proteins and 13 metabolites common to both types of EC. Western blotting analysis on 10 patients with type 1 and type 2 EC and 10 endometria samples confirmed the altered abundance of NPEPPS. Our multi-omics analysis identified dysregulated proteins and metabolites involved in EC tumor growth. Further studies are needed to understand the role of these molecules in EC. Our data can shed light on common pathways to better understand the mechanisms involved in the development and growth of EC, especially for the development of new therapies.

Unraveling the relationship between the renin-angiotensin system and endometrial cancer: a comprehensive review.

Endometrial cancer (EC), the most common adenocarcinoma, represents 90% of uterine cancer in women with an increased incidence of occurrence attributed to age, obesity, hypertension, and hypoestrogenism. Being the most common gynecological malignancy in women, it shows a relation with the activation of different components of the renin-angiotensin system (RAS), which is predominantly involved in maintaining blood pressure, salt, water, and aldosterone secretion, thereby playing a significant role in the etiology of hypertension. The components of the RAS, i.e., ACE-I, ACE-II, AT1R, AT2R, and Pro(renin) receptor, are widely expressed in both glandular and stromal cells of the endometrium, with varying levels throughout the different phases of the menstrual cycle. This causes the endometrial RAS to implicate angiogenesis, neovascularization, and cell proliferation. Thus, dysfunctioning of the endometrial RAS could predispose the growth and spread of EC. Interestingly, the increased expression of AngII, AGTR1, and AGTR2 showed advancement in the stages and progression of EC via the prorenin/ATP6AP2 and AngII/AGTR1 pathway. Therefore, this review corresponds to unraveling the relationship between the progression and development of endometrial cancer with the dysfunction in the expression of various components associated with RAS in maintaining blood pressure.

Phospho-DIGE Identified Phosphoproteins Involved in Pathways Related to Tumour Growth in Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy of the endometrium. This study focuses on EC and normal endometrium phosphoproteome to identify differentially phosphorylated proteins involved in tumorigenic signalling pathways which induce cancer growth. We obtained tissue samples from 8 types I EC at tumour stage 1 and 8 normal endometria. We analyzed the phosphoproteome by two-dimensional differential gel electrophoresis (2D-DIGE), combined with immobilized metal affinity chromatography (IMAC) and mass spectrometry for protein and phosphopeptide identification. Quantities of 34 phosphoproteins enriched by the IMAC approach were significantly different in the EC compared to the endometrium. Validation using Western blotting analysis on 13 patients with type I EC at tumour stage 1 and 13 endometria samples confirmed the altered abundance of HBB, CKB, LDHB, and HSPB1. Three EC samples were used for in-depth identification of phosphoproteins by LC-MS/MS analysis. Bioinformatic analysis revealed several tumorigenic signalling pathways. Our study highlights the involvement of the phosphoproteome in EC tumour growth. Further studies are needed to understand the role of phosphorylation in EC. Our data shed light on mechanisms that still need to be ascertained but could open the path to a new class of drugs that could hinder EC growth.

Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/β-catenin signaling pathway

BackgroundMesenchymal 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.MethodsThe 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.ResultsOur 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.ConclusionsThe 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.

Abstract 937: Opposing roles of SPOP mutations in human prostate and endometrial cancers

Abstract Recurrent mutations in the gene encoding the Speckle Type POZ Protein, SPOP, the substrate-binding components of E3-ubiquitin ligase, have been identified as common alterations in prostate cancer (PCa) and endometrial cancer (EC). SPOP mutations are associated with PCa and EC growth and progression. Here, we characterized SPOP mutations in PCa and EC, and their association with molecular and immune signatures. 7,398 PCa and 19,188 EC samples were analyzed by next-generation sequencing (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Real world overall survival (rwOS) was extracted from insurance claims and depicted using Kaplan-Meier survival curves for molecularly defined cohorts from tissue collection to last contact. Statistical significance was determined using chi-square and Mann-Whitney U tests, with p-values adjusted for multiple comparisons (q<0.05). SPOP mutations were identified in 601 (8.1%) and 655 (3.4%) samples of PCa and EC, respectively. Mutations clustered in the SPOP MATH domain with hotspots at residues F133L (21.4%), F102C (11%), F133V (10.4%), F102V (7%) in PCa, and residues M117V (21.8%), R121Q (10.6 %), E47K (9%), E50K (8.5%) in EC. Importantly, no overlap of hotspot residues was noted in PCa and EC. SPOP-mutated PCa had higher frequency of APC (21.4% vs 5.8%) and BCOR (1.95% vs 0.2%) lesions, but SPOP-mutated EC had higher frequency of U2AF1 (4.28% vs 1.0%), POLE (5.24% vs 2.0%) and CASP8 (4.17% vs 1.79%) lesions (all q <0.05) compared to non-mutant SPOP. Analysis of epigenetic markers showed lower BRD2 (245.4 vs 312 TPM) transcripts in SPOP-mutated PCa, but higher BRD2 (227.0 vs 200.6) (all q <0.05) in SPOP-mutated EC, compared to non-mutant SPOP, the former diverging from earlier published data in PCa. Analysis of inferred immune cell infiltrates showed that in SPOP-mutated PCa, M1-MΦ (36.8% vs 48.1%), CD8 T cell (20.2% vs 30.4%) and DC (53.3% vs 79.4%) are decreased and M2-MΦ (100% vs 99.9%) are increased; while in SPOP-mutated EC, M1-MΦ (87.2% vs 83.3 %), CD8 T cells (56.8% vs 49.7%) and DC (94.9% vs 93.3%) are increased and M2-MΦ (98.8% vs 98.9%) are decreased (all q <0.05). In PCa, higher AR expression was found in SPOP-mutated vs non-mutated tumors (98.5% vs 97.3%, p=0.09), with improved OS outcomes after hormone targeting agents leuprolide (2125 vs 1803 days; HR: 0.71, 95% CI (0.51-0.99), p=0.04) and bicalutamide (2538 vs 1854 days; HR: 0.57, 95% CI (0.41-0.79), p<0.001). In EC, ER and PR expression was significantly lower in SPOP-mutated vs non-mutated tumors 50.8% vs 65.4% and 35.4 vs 49.5% (all q <0.05), respectively, although no difference in OS was noted in the overall EC population. These data indicate that SPOP-mutations drive different molecular and immune microenvironments in PCa and EC, with apparently opposing roles in these malignancies, and provide a rationale for tailored therapeutic approaches in SPOP-mutated PCa and EC. Citation Format: Ludimila Cavalcante, Sachin K. Desmukh, Benedito A. Carneiro, Kartik Angara, Tyler E. Mattox, Sharon Wu, Joanne Xiu, Philip Walker, Matthew Oberley, Chadi Nabhan, Emmanuel S. Antonarakis. Opposing roles of SPOP mutations in human prostate and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 937.

Vitexin suppresses the proliferation, angiogenesis and stemness of endometrial cancer through the PI3K/AKT pathway

Context Endometrial cancer is a common gynecologic malignancy. Vitexin is an active flavonoid compound with an antitumor function. Objective This study elucidated the role of vitexin in endometrial cancer development and clarified the potential mechanism. Materials and methods The toxicity of vitexin (0–80 μM) treatment for 24 h on HEC-1B and Ishikawa cells was tested utilizing the CCK-8 assay. Endometrial cancer cells were divided into vitexin 0, 5, 10, and 20 μM groups. Cell proliferation, angiogenesis and stemness in vitro after treatment with vitexin (0, 5, 10, 20 μM) for 24 h were evaluated using the EdU staining assay, tube formation assay and sphere formation assay, respectively. Twelve BALB/c mice were grouped into control and vitexin (80 mg/kg) groups to monitor tumour growth for 30 days. Results Vitexin suppressed cell viability of HEC-1B (IC50 = 9.89 μM) and Ishikawa (IC50 = 12.35 μM) cells. The proliferation (55.3% and 80% for HEC-1B; 44.7% and 75% for Ishikawa), angiogenesis (54.3% and 78.4% for HEC-1B; 47.1% and 68.2% for Ishikawa) and stemness capacity (57.2% and 87.3% for HEC-1B; 53.4% and 78.4% for Ishikawa) of endometrial cancer cells were inhibited by 10 and 20 μM vitexin. Furthermore, the inhibitory effects of vitexin on endometrial cancer were reversed by PI3K/AKT agonist 740Y-P (20 μM). Moreover, the xenograft tumour experiment lasting for 30 days proved that vitexin (80 mg/kg) blocked tumour growth of endometrial cancer in vivo. Discussion and conclusions Vitexin has therapeutic potential on endometrial cancer, which supports further clinical trials.

LncRNA SNHG4 Modulates EMT Signal and Antitumor Effects in Endometrial Cancer through Transcription Factor SP-1

Long non-coding RNAs (lncRNAs) are implicated in the initiation and progression of a variety of tumors, including endometrial cancer. However, the mechanisms of lncRNA in endometrial cancer formation and progression remain largely unknown. In this study, we confirmed that the lncRNA SNHG4 is upregulated in endometrial cancer and correlates with lower survival rates in endometrial cancer patients. Knock-down of SNHG4 significantly reduced cell proliferation, colonization, migration, and invasion in vitro, as well as modulating the cell cycle and reduced tumor growth of endometrial cancer in vivo. In addition, the effect of SNHG4 by the transcription factor SP-1 was confirmed in vitro. We found in this study that SNHG4/SP-1 plays an important role in endometrial cancer progression and may be used as a potential therapeutic and prognostic biomarker for endometrial cancer.

Stanniocalcin 2 is induced by estrogen and promotes growth in endometrial cancer via AMPK pathway.

Stanniocalcin 2 (STC2) is identified as a glycosylated peptide hormone and estrogen-responsive gene in cancer cells. STC2 participates in angiogenesis, cell development, cytoprotection, and calcium and phosphate regulation during the development of cancer. The role of STC2 in endometrial cancer (EC) remains unclear. The data from the bioinformatic and immunohistochemical analysis showed that STC2 was upregulated in the EC tissues. The EC cells were treated with 17β-estradiol (E2), and 0.1 μmol/L E2 increased the expression of STC2 in the EC cells. E2 also increased cell viability, promoted proliferation, and inhibited apoptosis of EC. However, the knockdown of STC2 decreased cell viability, reduced proliferation, and promoted apoptosis of E2-stimulated EC. Moreover, silencing of STC2 attenuated E2-induced downregulation of phosphorylated-AMP-activated protein kinase (AMPK) in the EC cells. The loss of STC2 reduced E2-stimulated tumor growth EC in vivo. In conclusion, STC2 deficiency suppressed E2-stimulated proliferation and tumor growth of EC through the activation of AMPK signaling.

CircSMAD2 accelerates endometrial cancer cell proliferation and metastasis by regulating the miR-1277-5p/MFGE8 axis.

Endometrial cancer (EC) is a common gynecological malignant tumor. CircRNAs play crucial roles in cancer progression and metastasis. However, the biological functions of circRNAs in EC remain largely unknown. CircSMAD2, miR-1277-5p, MFGE8 and relative maker protein expression in EC tissues or cell lines were analyzed by quantitative real-time polymerase chain reaction and Western blot. In vitro and in vivo functional assays, including EDU, CCK8, colony formation, transwell, tube formation and tumor xenograft assays, were conduct to explore the effects of circSMAD2 on EC. Mechanism assays were conducted to confirm the binding between miR-1277-5p and circSMAD2 or MFGE8 expression. Upregulation of circSMAD2 was uncovered in both EC tissues and cell lines. Functionally, silencing of circSMAD2 apparently inhibited the proliferation, migration, invasion and angiogenesis of EC cell lines in vitro. Mechanistically, circSMAD2 sponged miR-1277-5p to upregulate MFGE8 expression. The decrease of miR-1277-5p and increase of MFGE8 were observed both in EC tissues and cell lines. Then MFGE8 knockdown or miR-1277-5p upregulation suppressed EC cell oncogenic biological behavior. Rescue experiments showed that miR-1277-5p mimics countervailed the anticancer effects of circSMAD2 silencing on EC. Besides that, MFGE8 overexpression also attenuated the inhibitory action of miR-1277-5p mimic in EC. Moreover, knockdown of circSMAD2 inhibited EC growth in vivo. CircSMAD2 functions as an oncogene in promoting the progression of EC through miR-1277-5p/MFGE8 axis.

TBBPA rather than its main derivatives enhanced growth of endometrial cancer via p53 ubiquitination

Tetrabromobisphenol A (TBBPA) and its derivatives widely exist in various environments and biota. Although the available data indicate that TBBPA exposure is highly associated with the increased incidence of endometrial cancer (EC), the effects of TBBPA and its main derivatives on EC proliferation and the involved crucial mechanism remain unclear. The present study aimed to investigate the effects of TBBPA and its derivatives under environmental concentrations on the proliferation of EC, and the crucial mechanism on the progression of EC caused by bromine flame retardants exposure. In this research, TBBPA and two of the most common TBBPA derivatives including TBBPA bis (2-hydroxyethyl ether) (TBBPA-BHEE) and TBBPA bis (dibromopropyl ether) (TBBPA-BDBPE) were screened for their capacities in induced EC proliferation and explored the related mechanism by in vitro cell culture model and in vivo mice model. Under environmental concentrations, TBBPA promoted the proliferation of EC, the main derivatives of TBBPA (TBBPA-BHEE and TBBPA-BDBPE) did not present the similar facilitation effects. The ubiquitination degradation of p53 was crucial in TBBPA induced EC proliferation, which resulted in the increase of downstream cell cycle and decrease of apoptosis. The further molecular docking result suggested the high affinity between TBBPA and ubiquitinated proteasome. This finding revealed the effects of TBBPA and its derivatives on EC proliferation, thus providing novel insights into the underlying mechanisms of TBBPA-caused EC.

C/D box small nucleolar RNA SNORD104 promotes endometrial cancer by regulating the 2ʹ-O-methylation of PARP1

BackgroundSmall nucleolar RNAs (snoRNAs) are dysregulated in many cancers, although their exact role in tumor genesis and progression remains unclear.MethodsThe expression profiles of snoRNAs in endometrial cancer (EC) tissues were analyzed using data from The Cancer Genome Atlas, and SNORD104 was identified as an upregulated snoRNA in EC. The tumorigenic role of SNORD104 in EC was established in CCK8, colony formation, EdU, apoptosis, Transwell, and in vivo xenograft experiments. The molecular mechanisms of SNORD104 were analyzed by RNA immunoprecipitation (RIP), Nm-seq, RTL-P assay, RNA stability assay, qRT-PCR, and western blotting.ResultsAntisense oligonucleotide (ASO)-mediated knockdown of SNORD104 in Ishikawa cells significantly inhibited their proliferation, colony formation ability, migration, and invasion in vitro and increased apoptosis. On the other hand, overexpression of SNORD104 promoted EC growth in vivo and in vitro. RIP assay showed that SNORD104 binds to the 2ʹ-O-methyltransferase fibrillarin (FBL), and according to the results of Nm-seq and RTL-P assay, SNORD104 upregulated PARP1 (encoding poly (ADP-ribose) polymerase 1) 2ʹ-O-methylation. The binding of FBL to PARP1 mRNA was also verified by RIP assay. Furthermore, SNORD104 expression was positively correlated with PARP1 expression in EC tissues. In the presence of actinomycin D, SNORD104 increased the stability of PARP1 mRNA and promoted its nuclear localization. Finally, silencing FBL or PARP1 in the HEC1B cells overexpressing SNORD104 inhibited their proliferative and clonal capacities and increased apoptosis rates.ConclusionsSNORD104 enhances PARP1 mRNA stability and translation in the EC cells by upregulating 2ʹ-O-methylation and promotes tumor growth.

Bone morphogenetic protein signaling is a possible therapeutic target in gynecologic cancer.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling. Recently, BMP signaling has been found to have diverse effects on different types of tumors. In this review, we summarized the effects of BMP signaling on gynecologic cancer. BMP signaling has tumor-promoting effects on ovarian cancer (OC) and endometrial cancer (EC), whereas it has tumor-suppressing effects on uterine cervical cancer (UCC). Interestingly, EC has frequent gain-of-function mutations in ACVR1, encoding one of the type I BMP receptors, which are also observed in fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Little is known about the relationship between BMP signaling and other gynecologic cancers. Tumor-promoting effects of BMP signaling in OC and EC are dependent on the promotion of cancer stemness and epithelial-mesenchymal transition (EMT). In accordance, BMP receptor kinase inhibitors suppress the cell growth and migration of OC and EC. Since both cancer stemness and EMT are associated with chemoresistance, BMP signaling activation might also be an important mechanism by which OC and EC patients acquire chemoresistance. Therefore, BMP inhibitors are promising for OC and EC patients even if they become resistant to standard chemotherapy. In contrast, BMP signaling inhibits UCC growth in vitro. However, the in vivo effects of BMP signaling have not been elucidated in UCC. In conclusion, BMP signaling has a variety of functions, depending on the types of gynecologic cancer. Therefore, targeting BMP signaling should improve the treatment of patients with gynecologic cancer.

Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.For precancerous/endometrial cancer patients with fertility maintain desire, progestin resistance is the main obstacle of conservative therapy. The authors found that brusatol, as a natural compound, suppresses progestin metabolism through regulating the NRF2-TET1-AKR1C1 pathway to sensitize precancerous/endometrial cancers to progestin and relieve progestin resistance. This study indicates that progestin combined with brusatol may enhance the treatment effects and that AKR1C1 expression patterns may serve as an important biomarker of progestin resistance in endometrial cancer.

Tripartite Motif Containing 26 is a Positive Predictor for Endometrial Carcinoma Patients and Regulates Cell Survival in Endometrial Carcinoma.

Functioning as an E3 ubiquitin ligase, tripartite motif containing 26 (TRIM26) can regulate the tumor behavior and the relevant inflammatory immune response. Endometrial carcinoma is a major gynecological malignant tumor in the world, while no relevant research has been performed. KMplot, a web-based survival analysis tool, demonstrated that TRIM26 expression was positively correlated with the overall survival in gynecological tumors, such as ovarian, cervical, and endometrial cancer. The relatively low expression of TRIM26 was also found in endometrial cancer tissues and endometrial cancer cell lines. In the online Gene Expression Profiling Interactive Analysis (GEPIA) platform, TRIM26 was positively correlated with the pre-apoptosis genes of p53, BIM, BID, BAX, and BAK, and negatively correlated with the anti-apoptosis gene of BCLW. To further explore the function of TRIM26 in endometrial carcinoma, Ishikawa and KLE cells were infected with PLVX-TRIM26-derived lentivirus. TRIM26 overexpression suppressed the growth of endometrial cells, with downregulated p-AKT and upregulated BIM and BID expression. PLVX-TRIM26 overexpressed Ishikawa cells were injected subcutaneously into the side flanks of male BALB/C nude mice to construct a TRIM26-overexpression xenograft model. TRIM26 overexpression suppressed the growth of endometrial cancer as indicated by downregulated tumor volume and tumor weight with downregulated p-AKT expression. TRIM26 could regulate AKT pathway and apoptosis process to inhibit the growth of endometrial carcinoma, which can be utilized as a survival predictor.

Proteomic and functional characterization of intra-tumor heterogeneity in human endometrial cancer

SummaryEndometrial cancer is one of the most frequently diagnosed gynecological cancers worldwide, and its prevalence has increased by more than 50% over the last two decades. Despite the understanding of the major signaling pathways driving the growth and metastasis of endometrial cancer, clinical trials targeting these signals have reported poor outcomes. The heterogeneous nature of endometrial cancer is suspected to be one of the key reasons for the failure of targeted therapies. In this study, we perform a sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based comparative proteomic analysis of 63 tumor biopsies collected from 20 patients and define differences in protein signature in multiple regions of the same tumor. We develop organoids from multiple biopsies collected from the same tumor and show that organoids capture heterogeneity in endometrial cancer growth. Overall, using quantitative proteomics and patient-derived organoids, we define the heterogeneous nature of endometrial cancer within a patient’s tumor.

Overexpression of LPCAT1 enhances endometrial cancer stemness and metastasis by changing lipid components and activating the TGF/β-Smad2/3 signaling pathway.

The incidence of endometrial cancer (EC) increases annually and tends to occur in younger women. A particularly important relationship exists between EC and metabolic disorders. As one of the most important components of lipid metabolism, phospholipids play an indispensable role in metabolic balance. LPCAT1 is a key enzyme regulating phospholipid metabolism. In this study, we perform further investigations to seek mechanistic insight of LPCAT1 in EC. Our results demonstrate that silencing of LPCAT1 inhibits the growth of endometrial cancer, while overexpression of LPCAT1 results in enhanced stemness and metastasis in endometrial cancer cell lines. Meanwhile, the contents of various phospholipids including phosphatidylethanolamine (PE), phosphatidylcholine (PC), and triglyceride (TG) change significantly after overexpression of LPCAT1. In addition, through RNA-sequencing and western blot analysis, we observe that the TGF-β/Smad2/3 signaling pathway is of great importance in the tumor-promoting function of LPCAT1. LPCAT1 promotes the expressions of stem cell-related transcription factors and epithelial-mesenchymal transition (EMT) related proteins through the TGF-β/Smad2/3 signaling pathway. Moreover, we find that TSI-01, which can inhibit the activity of LPCAT1, is able to restrain the proliferation of EC cell lines and promote cell apoptosis. Collectively, we demonstrate that LPCAT1 enhances the stemness and metastasis of EC by activating the TGF-β/Smad2/3 signaling pathway and that TSI-01 may have potential use for the treatment of EC.