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Ovarian carcinoma inherently possesses a distinct metastatic organotropism for the adipose-rich omentum, contributing to disease progression. Although the premetastatic microenvironment (PMM) has been known to often play a prometastatic role during the process, incomplete mechanistic insight into PMM formation has prevented its therapeutic targeting. Omental fibroblasts can be activated by tumour cells to differentiate into myofibroblasts, termed the fibroblast-to-myofibroblast transition (FMT), which, in turn, enhances cancer aggressiveness. Here, we report crosstalk between cancer cells and omental fibroblasts through exosomal piR-25783, which fuels tumour metastasis. Tumour cell-secreted exosomal piR-25783 activates the TGF-β/SMAD2/SMAD3 pathway in fibroblasts and promotes the FMT in the omentum along with the secretion of various cytokines and elevation of proliferative, migratory, and invasive properties, contributing to the formation of PMMs. Furthermore, piR-25783-induced myofibroblasts promote tumour implantation and growth in the omentum. In addition, the overexpression of piR-25783 in ovarian carcinoma is associated with unfavourable clinicopathological characteristics and shorter survival. In this study, we provide molecular, functional, and translational evidence suggesting that exosomal piR-25783 plays an important role in the formation of PMMs and the development of metastatic diseases in vitro and in vivo and may serve as a potential therapeutic target for ovarian carcinoma with metastasis.

Bacterial AraC is a transcription factor family that initiates transcription by recruiting RNA polymerase to the promoter and directly regulating various bacterial phenotypes. It also directly regulates various bacterial phenotypes. However, how this transcription factor regulates bacterial virulence and affects host immunity is still largely unknown. In this study, deleting the orf02889 (AraC-like transcription factor) gene in virulent Aeromonas hydrophila LP-2 affected several important phenotypes, such as increasing biofilm formation and siderophore production abilities. Moreover, Δorf02889 also significantly decreased the virulence of A. hydrophila and has promising attenuated vaccine potential. To better understand the effects of orf02889 on biological functions, a data independent acquisition (DIA)-based quantitative proteomics method was performed to compare the differentially expressed proteins between Δorf02889 and the wild-type strain in extracellular fractions. The following bioinformatics analysis suggested that ORF02889 may regulate various metabolic pathways, such as quorum sensing and ATP binding cassette (ABC) transporter metabolism. Moreover, 10 selected genes from the top 10 decreasing abundances in proteomics data were deleted, and their virulence to zebrafish was evaluated, respectively. The results showed that ΔcorC, Δorf00906, and Δorf04042 significantly reduced bacterial virulence. Finally, the following chromatin immunoprecipitation and polymerase chain reaction (ChIP-PCR) assay validated that the promoter of corC was directly regulated by ORF02889. Overall, these results provide insight into the biological function of ORF02889 and demonstrate its inherent regulatory mechanism for the virulence of A. hydrophila.

Supplementary Table S1 shows the association between PARP1 expression and the clinicopathological features in ovarian cancer patients.

Supplementary Figure S1 shows the expression of IGF1R and p-Akt in let-7e-inhibited xenograft tumors.

Supplementary Figure S2 shows the cellular viability of A2780, SKOV3 and Caov3 cell lines treated with cisplatin and/or olaparib for indicated duration.

Supplementary Table S2 shows the association between different parameters and the PFS, OS and chemotherapy response in ovarian cancer patients.

microRNAs (miRNAs) and N6-methyladenosine (mTo screen mA total of 126 miRNAs were identified as mmiR-30c-5p inhibits OvCa progression and reduces the m

Lanqing Gong,1,* Liqiong Cai,1,* Guodong Li,2 Jing Cai,1 Xiaoqing Yi1 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China; 2Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoqing YiDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, People’s Republic of ChinaTel/Fax: +86 27 85351649Email yxq1987724@126.comBackground: Growth arrest and DNA-damage-inducible 45 beta (GADD45B) is overexpressed and is associated with poor clinical outcomes in many human cancers, but the clinical implication of GADD45B in epithelial ovarian cancer (EOC) remains unclear.Methods: Bioinformatics analysis of The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) cohorts was used to illustrate the relationship between GADD45B expression and metastasis, as well as the survival time of EOC. GADD45B was downregulated by siRNAs in EOC cells, and migration ability was determined by a transwell assay and wound-healing assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) were conducted to discover the downstream pathway of GADD45B. The regulation of epithelial–mesenchymal transition (EMT) by GADD45B was verified by Western blotting and qRT-PCR. Finally, the correlation of GADD45B expression with EOC metastasis was investigated in EOC tissues by immunohistochemistry.Results: Overexpression of GADD45B indicates shorter overall survival time and progression-free survival time, and it is an independent risk factor for poor survival in EOC patients. Elevated GADD45B is related to venous invasion, lymphatic invasion and peritoneal carcinomatosis. Downregulation of GADD45B decreases the migration of ES2 and SKOV3 cells. Further KEGG enrichment analysis and GSEA revealed that EMT may be the downstream pathway of GADD45B. In addition, reduced GADD45B increases the expression of E-cadherin and decreases that of N-cadherin and vimentin. Finally, immunohistochemical analysis of GADD45B expression revealed that the expression of GADD45B in omental metastatic tissues was higher than that in matched primary ovarian cancer tissues. These results suggest that elevated GADD45B promotes the motility of ovarian cancer cells through EMT and is associated with EOC metastasis.Conclusion: GADD45B can promote the motility of ovarian cancer cells through EMT, is associated with EOC metastasis, and may be a new biomarker of metastasis and prognosis.Keywords: epithelial ovarian cancer, GADD45B, metastasis, epithelial–mesenchymal transition

Background Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2)-expressing monocytes (TEMs) are a highly proangiogenic subset of myeloid cells, which are characterized by expressing the angiopoietin receptor Tie2 with pro-tumor activity. Purpose The present study aimed to determine the clinical value of circulating TEMs (cTEMs) for cervical cancer. Patients and methods Peripheral blood mononuclear cells (PBMCs) were obtained from 7 healthy volunteers, 17 uterine fibroid patients, 24 cervical intraepithelial neoplasia (CIN) II patients, 31 CIN III patients and 99 patients with cervical cancer. The cTEMs were evaluated by the ratio of Tie2+ CD14+ cells to all CD14+ monocytes in the PBMCs through flow cytometry. The diagnostic value of cTEM was assessed by receiver operating characteristic (ROC) curves and the correlation between cTEM and clinicopathological characters in cervical cancer patients was analyzed. Results The proportion of cTEMs was gradually increasing from healthy volunteers to patients with non-invasive lesions, then to cervical cancer patients. The area under the ROC curve was 0.913 when the level of cTEMs was used to distinguish cervical cancer from all the other women ranging from healthy volunteers to CIN III patients. In cervical cancer, an increased cTEM fraction was significantly correlated with advanced tumor stage, larger tumor size, lymph node metastasis (LNM), deep stromal infiltration, parametrial involvement and lymph-vascular space invasion and was an independent risk factor for LNM. Conclusion The cTEM proportion might be a promising biomarker for the malignant transformation of cervical lesions and the progression of cervical cancer.

Increased DNA damage repair is one of the mechanisms implicated in cisplatin resistance. Our previous study indicated that the deregulation of let-7e promoted cisplatin resistance and that let-7e could suppress DNA double-strand break repair in ovarian cancer. In this study, we further characterized the role of let-7e in DNA damage repair and cisplatin resistance in ovarian cancer, and investigated the underlying mechanisms. The alkaline and neutral comet assay indicated that let-7e impeded both DNA single- and double-strand break repairs through downregulating its target gene PARP1. In vitro and in vivo experiments provided evidence that the let-7e–PARP1–DNA repair axis was involved in the modulation of cisplatin sensitivity in ovarian cancer. Contrary to let-7e, PARP1 was overexpressed in cisplatin-resistant ovarian cancer tissues, and patients with high PARP1 expression exhibited poor progression-free survival (PFS) and overall survival (OS). Multivariate logistic and Cox regression analyses showed that let-7e and FIGO stage were independent prognostic factors for PFS and OS, whereas let-7e and PARP1 were able to independently predict chemotherapy response. Taken together, our results indicated that low expression of let-7e promoted DNA single- and double-strand break repairs and subsequently contributed to cisplatin resistance by relieving the suppression on PARP1 in ovarian cancer. Implications: Targeting the let-7e–PARP1–DNA repair axis might be an effective strategy for the treatment of chemoresistant ovarian cancer.

Ascitic multicellular aggregates (MCAs) promote peritoneal metastasis of ovarian cancer. The aim of the present study was to elucidate the role of cancer-associated fibroblasts (CAFs) in MCA formation and metastasis in patients with high-grade serous ovarian cancer (HGSOC). Immunohistochemistry was used to identify the cell phenotypes and the presence of CAFs in ascitic MCAs. The role of CAFs in tumor-cell MCA formation was assessed by co-culture in suspension. Primary ascitic tumor cells and omental CAFs were used to generate ex vivo MCAs in hanging drops, and the invasiveness of MCAs was evaluated by mesothelial clearance and adhesion assays in vitro and in vivo. MCAs containing CAFs and tumor cells were identified in the ascitic fluid. CAFs facilitated tumor cell aggregation and compaction to form MCAs, and enhanced the mesothelial clearance and adhesion abilities of tumor-cell MCAs. These findings suggest that ascitic CAFs promote peritoneal metastasis by forming heterotypic aggregates with tumor cells, and that they may serve as potential targets for the treatment of HGSOC.