Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-ß/SMADs signaling pathway.

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25-2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-ß/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-ß/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

PFDA promotes cancer metastasis through macrophage M2 polarization mediated by Wnt/ß-catenin signaling.

Perfluoroundecanoic acid (PFDA) is extensively utilized in the textile and food processing industries and may have a tumor-promoting effect by modulating the tumor microenvironment. Macrophages play crucial roles in tumor microenvironment as key regulators of tumor immunity. However, further investigation is needed to elucidate how PFDA interacts with macrophages and contributes to tumor progression. In this study, we treated the macrophage cell line RAW264.7 with various concentrations of PFDA and found that RAW264.7 transitioned into an M2 tumor-promoting phenotype. Through bioinformatic analysis and subsequent verification of molecular assays, we uncovered that PFDA could activate ß-catenin and enhance its nuclear translocation. Additionally, it was also observed that inhibiting ß-catenin nuclear translocation partly attenuated RAW264.7 M2 polarization induced by PFDA. The conditioned medium derived from PFDA-pretreated RAW264.7 cells significantly promoted the migration and invasion abilities of human ovarian cancer cells. Furthermore, in vivo studies corroborated that PFDA-pretreated RAW264.7 could promote tumor metastasis, which could be mitigated by pretreatment with the ß-catenin inhibitor ICG001. In conclusion, our study demonstrated that PFDA could promote cancer metastasis through regulating macrophage M2 polarization in a Wnt/ß-catenin-dependent manner.

Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells.

Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling.

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013-2016 data. We treated human ovarian cancer cells with 0-1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

Extracellular Vesicle-Packaged circATP2B4 Mediates M2 Macrophage Polarization via miR-532-3p/SREBF1 Axis to Promote Epithelial Ovarian Cancer Metastasis.

Ovarian cancer is one of the most common gynecologic malignancies with a highly immunosuppressive tumor microenvironment (TME) and poor prognosis. Circular RNA (circRNA) is a type of noncoding RNA with high stability, which has been shown to play an important role in biological processes and TME reprogramming in a variety of tumors. The biological function of a novel circRNA, circATP2B4, in epithelial ovarian cancer (EOC) was detected and evaluated. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of extracellular vesicles (EV)-packaged circATP2B4. Macrophage uptake of circATP2B4 was determined by EVs tracing. Dual luciferase reporter, FISH, Western blotting, and flow cytometry assays were used to investigate the interactions between circATP2B4 and miR-532-3p as well as sterol regulatory element-binding factor 1 (SREBF1) expression in macrophages. CircATP2B4 was upregulated in EOC tissues and positively correlated with ovarian cancer progression. Functionally, circATP2B4 promoted carcinogenic progression and metastasis of EOC both in vitro and in vivo. Mechanistically, EV-packaged circATP2B4 in EOC could be transmitted to infiltrated macrophages and acted as competing endogenous RNA of miR-532-3p to relieve the repressive effect of miR-532-3p on its target SREBF1. Furthermore, circATP2B4 induced macrophage M2 polarization by regulating the miR-532-3p/SREBF1/PI3Kα/AKT axis, thereby leading to immunosuppression and ovarian cancer metastasis. Collectively, these data indicate that circATP2B4-containing EVs generated by EOC cells promoted M2 macrophages polarization and malignant behaviors of EOC cells. Thus, targeting EVs-packaged circATP2B4 may provide a potential diagnosis and treatment strategy for ovarian cancer.