Search

Arachidonic acid metabolites are a family of bioactive lipids derived from membrane phospholipids. They are involved in cancer progression, but arachidonic acid metabolite profiles and their related biosynthetic pathways remain uncertain in colorectal cancer (CRC). To compare the arachidonic acid metabolite profiles between CRC patients and healthy controls, quantification was performed using a liquid chromatography-mass spectrometry-based analysis of serum and tissue samples. Metabolomics analysis delineated the distinct oxidized lipids in CRC patients and healthy controls. Prostaglandin (PGE2)-derived metabolites were increased, suggesting that the PGE2 biosynthetic pathway was upregulated in CRC. The qRT-PCR and immunohistochemistry analyses showed that the expression level of PGE2 synthases, the key protein of PGE2 biosynthesis, was upregulated in CRC and positively correlated with the CD68+ macrophage density and CRC development. Our study indicates that the PGE2 biosynthetic pathway is associated with macrophage infiltration and progression of CRC tumors. [ABSTRACT FROM AUTHOR]

Targeting programmed death 1(PD‐1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD‐L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP‐qPCR/PCR assays were used to determine the transcriptional regulation of PD‐L1 by PIK3CA‐E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA‐seq) and flow cytometry. The efficacy of PI3K inhibitor and anti‐PD‐1 therapy was assessed in cell‐derived xenografts (CDX) and patients‐derived xenografts (PDX). PD‐L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress‐free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD‐L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA‐E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD‐L1 by upregulating the transcription factor IRF1. PI3Kα‐specific inhibitor markedly activates immune microenvironment by regulating the PD‐1/L1‐related pathways and promoting CD8+ T cell differentiation and proliferation in Caski‐CDXs with PIK3CA‐E545K mutation. PI3Kα inhibitor significantly enhances the anti‐tumour efficacy of PD‐1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD‐1 blockade. The efficacy of PI3Kα inhibitors combined with PD‐1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations. [ABSTRACT FROM AUTHOR]

Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of NOTCH1-p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. NOTCH1-p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of NOTCH1 mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most serious and deadly cancers for female and currently no effective screening approaches have been achieved. Therefore it is usually diagnosed at an advanced stage and most patients have a poor prognosis. The development of ovarian cancer is a comprehensive process depending on the cross-talk between the various cells in the tumor microenvironment and the immune system. Thus, the immunotherapy may be revolutionized as an effective treatment of this disease. In this study, we firstly identified ASS1 as an immunomodulatory molecule. By RNA sequencing, antibody array and animal assys, we further provided new insights into understanding the crosstalk between ovarian cancer cells and their microenvironmental immune molecules , which may suggest a new potential therapeutic target for ovarian cancer. • ASS1 is highly expressed in high grade serous ovarian cancer. •ASS1 promotes ovarian cancer proliferation and metastasis. •ASS1 is associated with tumor microenvironment. •ASS1 activates IL-17 signaling and upregulates the expression of CXCL8. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most malignant gynecological cancers around the world. In spite of multiple treatment options, the five-year survival rate is still very low. Several metabolism alterations are described as a hallmark in cancers, but alterations of lipid metabolism in ovarian cancer have been paid less attention. To explore new markers/targets for accurate diagnosis, prognosis, and therapeutic treatments based on metabolic enzyme inhibitors, here, we reviewed available literature and summarized several key metabolic enzymes in lipid metabolism of ovarian cancer. In this review, the rate limiting enzymes associated with fatty acid synthesis (FASN, ACC, ACLY, SCD), the lipid degradation related enzymes (MAGL, CPT, 5-LO, COX2), and the receptors related to lipid uptake (FABP4, CD36, LDLR), which promote the development of ovarian cancer, were analyzed and evaluated. We also focused on the review of application of current metabolic enzyme inhibitors for the treatment of ovarian cancer through which the potential therapeutic agents may be developed for ovarian cancer therapy. [ABSTRACT FROM AUTHOR]

Gynaecologic and breast cancers share some similarities at the molecular level. The aims of our study are to highlight the similarities and differences about IDO1, an important immune‐related gene in female cancers. The NGS data from TCGA of cervical squamous cell carcinoma (CESC), ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS) and breast invasive carcinoma (BRCA) were analysed to identify molecular features, and clinically significant and potential therapeutic targets of IDO1. We found IDO1 was significantly up‐regulated in four gynaecologic cancers and breast cancer. According to breast cancer PAM50 classification scheme, IDO1 expression was higher in tumours of basal than other subtypes and showed better survival prognosis in BRCA and OV. Through immune infiltration analysis, we found a strong correlation between IDO1 and immune cell populations especially for dendritic cells and T cells. In addition, we investigated the association between IDO1 and tumour mutation burden (TMB) and found that IDO1 was significantly correlated with TMB in BRCA and CESC. GSVA revealed that hallmarks significantly correlated with IDO1 were involved in interferon gamma response, allograft rejection and inflammatory response. We also found PD‐L1 and LAG3 were highly positive related to IDO1 in gynaecologic cancers when comparing with their corresponding normal tissues. Our results indicated that IDO1 participated in anti‐tumour immune process and is correlated with mutation burden. These findings may expand our outlook of potential anti‐IDO1 treatments. [ABSTRACT FROM AUTHOR]

YB1 is a negative regulator in liver fibrosis. We wondered whether SJYB1, a homologous protein of YB1 from Schistosoma japonicum, has an effect on liver fibrosis in vitro. Recombinant SJYB1 (rSJYB1) protein was expressed in a bacterial system and purified by Ni‐NTA His·Bind Resin. A human hepatic stellate cell line, the LX‐2 cell line, was cultured and treated with rSJYB1. The role of rSJYB1 on LX‐2 cells was then analysed by Western blot and luciferase assay. We succeeded in expressing and purifying SJYB1 in a bacterial system and the purified rSJYB1 could be recognized by S japonicum‐infected rabbit sera. Western bolt analysis showed that rSJYB1 inhibited the expression of collagen type I, but had little effect on α‐smooth muscle actin (α‐SMA). Further analysis revealed that rSJYB1 inhibited the activity of collagen α1 (I) (COL1A1) promoter and functioned at −1592/−1176 region of COL1A1 promoter. Our data demonstrate that rSJYB1‐mediated anti‐fibrotic activity involves inhibiting the activity of COL1A1 promoter and subsequently suppressing the expression of collagen type I in hepatic stellate cells. [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research, targeting anoikis resistance remians a challenge. Here, we identify argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle, is markedly upregulated in OC cells in detached culture and is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by elevated ASS1 activates AMPK and its downstream factor, CPT1A. Then, ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses ASS1-induced FAO. Our study gives some new functional insights into OC metabolism and represents a shift from traditional views, expanding ASS1's relevance beyond nitrogen metabolism to fatty acid metabolism. It uncovers how ASS1-induced FAO disrupts the AMP/ATP balance, leading to AMPK activation. By identifying the ASS1/AMPK/CPT1A axis as crucial for OC anoikis resistance and metastasis, our study opens up new avenues for therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Arachidonic acid (AA) is a crucial polyunsaturated fatty acid in the human body, metabolized through the pathways of COX, LOX, and cytochrome P450 oxidase to generate various metabolites. Recent studies have indicated that AA and its metabolites play significant regulatory roles in the onset and progression of ovarian cancer. This article examines the recent research advancements on the correlation between AA metabolites and ovarian cancer, both domestically and internationally, suggesting their potential use as biological markers for early diagnosis, targeted therapy, and prognosis monitoring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xia, Gao, Yang, Xing and Ji.)

Objective: This study was aimed to profile hotspot exonuclease domain mutations (EDMs) of the DNA polymerase ϵ gene ( POLE ) in endometrial cancer (EC) and to investigate the effects of EDMs on tumor cell behavior and catalytic activities of Polϵ., Methods: POLE sequencing was performed in tumor tissue samples from patients with EC to identify hotspot EDMs. Bioinformatics tools were used to select the potential pathogenic EDMs. The association of EDMs with the clinical outcomes of patients was assessed. EC cells were transfected with wildtype POLE or POLE variants to examine the effects of the EDMs on EC cell behavior, including cell cycle, migration, and invasion. Co-immunoprecipitation was employed to obtain FLAG-tagged wildtype and mutant catalytic subunits of Polϵ, followed by the assessment of polymerase and exonuclease activities., Results: In addition to previously reported P286R and V411L, R375Q and P452L were identified as novel, and deleterious POLE hotspot EDMs of EC. Patients in EDM group had significantly better clinical outcomes than the rest of the cohort. Compared with wildtype POLE, overexpression of POLE variants promoted cisplatin resistance, G0/G1 cell cycle arrest, and cell migration and invasion in EC cells. Overexpression of POLE variants significantly increased the abundance of 3'-OH and upregulated the expression of DNA mismatch repair genes in HEK293T cells. Compared with wildtype Polϵ, Pol ϵ mutants exhibited undermined polymerase and exonuclease abilities in the presence of mismatched nucleotides in HEK293 cells., Conclusion: We characterized the of hotspot exonuclease domain mutations in the DNA polymerase ϵ gene and identified P286R, V411L, R375Q, and P452L as pathogenic POLE hotspot EDMs in endometrial cancer. These hotspot EDMs are associated with the malignant behavior of endometrial cancer cells in vitro and favorable prognosis in patients, suggesting that POLE affects a wide range of cellular processes beyond DNA replication and proofreading., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tian, Ji, Wang, Meng, Bi, Ren, Shan, Yang and Wang.)

As a significant component in ovarian cancer microenvironment, cancer-associated fibroblasts (CAFs) contribute to cancer progression through interaction with cancer cells. Recent studies demonstrate that interleukin-8 (IL-8) is overexpressed in multiple cancer types and is essential for tumor development. Nonetheless, the underlying mechanism that the CAF-derived IL-8 promotes ovarian tumorigenesis is unknown. Here, we show that IL-8 secreted from CAFs could activate normal ovarian fibroblasts (NFs) through multiple signaling and that IL-8 stimulated malignant growth of ovarian cancer cells in animals and increased the IC 50 of cisplatin (CDDP) in ovarian cancer cells. Further study showed that IL-8 induced cancer cell stemness via the activation of Notch3 and that the high level of IL-8 in ascites was positively correlated with the expression of Notch3 in ovarian cancer tissues. Collectively, IL-8 secreted from CAFs and cancer cells promotes stemness in human ovarian cancer via the activation of the Notch3-mediated signaling, which may provide a novel strategy for ovarian cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ji, Tian, Gao, Zang, Wang and Yang.)