Ting-tao Chen

VNP20009-Abvec-Igκ-MIIP suppresses ovarian cancer progression by modulating Ras/MEK/ERK signaling pathway

Abstract Ovarian cancer poses a significant threat to women’s health, with conventional treatment methods encountering numerous limitations, and the emerging engineered bacterial anti-tumor strategies offer newfound hope for ovarian cancer treatment. In this study, we constructed the VNP20009-Abvec-Igκ-MIIP (VM) engineered strain and conducted initial assessments of its in vitro growth performance and the expression capability of migration/invasion inhibitory protein (MIIP). Subsequently, ID8 ovarian cancer cells and mouse cancer models were conducted to investigate the impact of VM on ovarian cancer. Our results revealed that the VM strain demonstrated superior growth performance, successfully invaded ID8 ovarian cancer cells, and expressed MIIP, consequently suppressing cell proliferation and migration. Moreover, VM specifically targeted tumor sites and expressed MIIP which further reduced the tumor volume of ovarian cancer mice (p < 0.01), via the downregulation of epidermal growth factor receptor (EGFR), Ras, p-MEK, and p-ERK. The downregulation of the PI3K/AKT signaling pathway and the decrease in Bcl-2/Bax levels also indicated VM’s apoptotic potency on ovarian cancer cells. In summary, our research demonstrated that VM exhibits promising anti-tumor effects both in vitro and in vivo, underscoring its potential for clinical treatment of ovarian cancer. Key points • This study has constructed an engineered strain of Salmonella typhimurium capable of expressing anticancer proteins • The engineered bacteria can target and colonize tumor sites in vivo • VM can inhibit the proliferation, migration, and invasion of ovarian cancer cells Graphical Abstract

Individuality and generality of intratumoral microbiome in the three most prevalent gynecological malignancies: an observational study

ABSTRACT Growing evidence have indicated the crucial role of intratumor microbiome in a variety of solid tumor. However, the intratumoral microbiome in gynecological malignancies is largely unknown. In the present study, a total of 90 Han patients, including 30 patients with cancer in cervix, ovary, and endometrium each were enrolled, the composition of intratumoral microbiome was assessed by 16S rDNA amplicon high throughput sequencing. We found that the diversity and metabolic potential of intratumoral microbiome in all three cancer types were very similar. Furthermore, all three cancer types shared a few taxa that collectively take up high relative abundance and positive rate, including Pseudomonas sp ., Comamonadaceae gen. sp ., Bradyrhizobium sp ., Saccharomonospora sp ., Cutibacterium acnes , Rubrobacter sp ., Dialister micraerophilus , and Escherichia coli . Additionally, Haemophilus parainfluenzae and Paracoccus sp . in cervical cancer, Pelomonas sp . in ovarian cancer, and Enterococcus faecalis in endometrial cancer were identified by LDA to be a representative bacterial strain. In addition, in cervical cancer patients, alpha-fetoprotein (AFP) (correlation coefficient = −0.3714) was negatively correlated ( r = 0.4, 95% CI: 0.03 to 0.7) with Rubrobacter sp . and CA199 (correlation coefficient = 0.3955) was positively associated ( r = 0.4, 95% CI: 0.03 to 0.7) with Saccharomonospora sp .. In ovarian cancer patients, CA125 (correlation coefficient = −0.4451) was negatively correlated ( r = −0.4, 95% CI: −0.7 to −0.09) with Porphyromonas sp. . In endometrial cancer patients, CEA (correlation coefficient = −0.3868) was negatively correlated ( r = −0.4, 95% CI: −0.7 to −0.02) with Cutibacterium acnes . This study promoted our understanding of the intratumoral microbiome in gynecological malignancies. IMPORTANCE In this study, we found the compositional spectrum of tumor microbes among gynecological malignancies were largely similar by sharing a few taxa and differentiated by substantial species owned uniquely. Certain species, mostly unreported, were identified to be associated with clinical characteristics. This study prompted our understanding of gynecological malignancies and offered evidence for tumor microbes affecting tumor biology among cancers in the female reproductive system.

Tripterygium glycosides reverse cisplatin resistance in epithelial ovarian cancer by activating ferroptosis via two different pathways

In our previous study, tripterygium glycosides (TG) demonstrated to combine with cisplatin (DDP) in reversing DDP resistance in A2780/DDP cells by exacerbating ferroptosis via downregulation of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (System Xc-) expression. However, the regulation of ferroptosis-related proteins alone is insufficient to explain the reversal of DDP resistance in epithelial ovarian cancer (EOC), suggesting the involvement of additional mechanisms. This study focused on the underlying mechanisms through which TG contributes to reversing DDP resistance in EOC. In this study, using DDP-resistant A2780/DDP cells and a nude mouse xenograft model, we comprehensively investigated the underlying mechanisms by which TG reverses DDP resistance via ferroptosis regulation through combined animal and cellular research. The results demonstrated that TG can induce ferroptosis in A2780/DDP cells. Mechanistic studies confirmed that TG induces ferroptosis through a dual-pathway mechanism involving both Keap1/Nrf2/ARE and HIF-1α/ACSL4 signaling. Furthermore, TG combined with DDP co-regulates the p53/Bax/Bcl-2 pathway to enhance apoptosis, thereby strengthening the inhibitory effect of DDP on drug-resistant EOC. Animal studies confirmed that the combination of TG and DDP significantly suppressed tumor growth compared to DDP monotherapy, with no observed increase in toxicity, indicating favorable treatment safety. In conclusion, our findings reveal for the first time that the TG combined with DDP reverses EOC drug resistance through the simultaneous induction of ferroptosis (HIF-1α/ACSL4 and Keap1/Nrf2/ARE) and apoptosis (p53/Bax/Bcl-2). These results provide experimental evidence supporting the clinical application of TG in overcoming DDP chemotherapy resistance in EOC.

Gut microbiota dysbiosis promotes the development of epithelial ovarian cancer via regulating Hedgehog signaling pathway

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, which remains a threat to female health at all ages. Hypotheses for EOC development include the continuous presence of inflammation, in which microbiota and inflammatory cytokines participate in cancer-related signaling pathway activation. Hedgehog (Hh) signaling is prominent for EOC progression, and interacts with inflammation response related to gut microbiota (GM). However, the precise roles of GM during this process are unknown. Here, we showed that the GM from patients with EOC differed from that of healthy women and had GM dysbiosis. We found that EOC modeling may lead to GM changes in mice, and it restored after the administration of GM from healthy controls, while GM from patients with EOC further exacerbated GM dysbiosis. Furthermore, we found that GM from EOC markedly promoted tumor progression and activated Hh signaling; meanwhile, it increased the extent of inflammation and activated NF-κB signaling, but GM from healthy controls improved them. Our results demonstrate how GM dysbiosis promoted EOC progression by activating Hh signaling mediated by TLR4/NF-κB signaling. We anticipate our assay to be a new thought for exploring the role of GM in EOC development. Furthermore, improving GM dysbiosis is a novel therapeutic approach for delaying EOC development.

Cysteine-Rich Intestinal Protein 1 Served as an Epithelial Ovarian Cancer Marker via Promoting Wnt/β-Catenin-Mediated EMT and Tumour Metastasis

Objective. To explore the expression, functions, and the possible mechanisms of cysteine-rich intestinal protein 1 (CRIP1) in epithelial ovarian cancer. Methods. Using open microarray datasets from The Cancer Genome Atlas (TCGA), we identified the tumorigenic genes in ovarian cancer. Then, we detected CRIP1 expression in 26 pairs of epithelial ovarian cancer tissue samples by immunohistochemistry (IHC) and performed a correlation analysis between CRIP1 and the clinicopathological features. In addition, epithelial ovarian cancer cell lines A2780 and OVCAR3 were used to examine CRIP1 expression by western blot and qRT-PCR. Various cell function experiments related to tumorigenesis were performed including the CCK8 assay, EdU, Annexin V-FITC/PI apoptosis assay, wound healing, and Transwell assay. In addition, the expression of epithelial-mesenchymal transition (EMT) markers was detected by western blot to illustrate the relationship between CRIP1 and EMT. Furthermore, KEGG pathway enrichment analysis and western blot were conducted to reveal the signaling pathways in which CRIP1 is involved in ovarian cancer pathogenesis. Results. CRIP1 was identified as an oncogene from the TCGA database. The IHC score demonstrated that the CRIP1 protein was expressed at a higher level in tumours than in tumour-adjacent tissues and was associated with a higher pathological stage, grade, and positive lymphatic metastasis. In cell models, CRIP1 was overexpressed in serous epithelial ovarian cancer. Cell function experiments showed that the knockdown of CRIP1 did not significantly affect cell proliferation or apoptosis but could exert an inhibitory effect on cell migration and invasion, and also induce changes in EMT markers. Furthermore, KEGG pathway enrichment analysis and western blot showed that CRIP1 could induce ovarian cancer cell metastasis through activation of the Wnt/β-catenin pathway. Conclusion. This study is the first to demonstrate that CRIP1 acts as an oncogene and may promote tumour metastasis by regulating the EMT-related Wnt/β-catenin signaling pathway, suggesting that CRIP1 may be an important biomarker for ovarian cancer metastasis and progression.