Ascites-derived CDCP1+ extracellular vesicles subcluster as a novel biomarker and therapeutic target for ovarian cancer.

Introduction: Ovarian cancer (OVCA) is one of the most prevalent malignant tumors of the female reproductive system, and its diagnosis is typically accompanied by the production of ascites. Although liquid biopsy has been widely implemented recently, the diagnosis or prognosis of OVCA based on liquid biopsy remains the primary emphasis. Methods: In this study, using proximity barcoding assay, a technique for analyzing the surface proteins on single extracellular vesicles (EVs). For validation, serum and ascites samples from patients with epithelial ovarian cancer (EOC) were collected, and their levels of CDCP1 was determined by enzyme-linked immunosorbent assay. Tissue chips were prepared to analyze the relationship between different expression levels of CDCP1 and the prognosis of ovarian cancer patients. Results: We discovered that the CUB domain-containing protein 1+ (CDCP1+) EVs subcluster was higher in the ascites of OVCA patients compared to benign ascites. At the same time, the level of CDCP1 was considerably elevated in the ascites of OVCA patients. The overall survival and disease-free survival of the group with high CDCP1 expression in EOC were significantly lower than those of the group with low expression. In addition, the receiver operating characteristic curve demonstrates that EVs-derived CDCP1 was a biomarker of early response in OVCA ascites. Discussion: Our findings identified a CDCP1+ EVs subcluster in the ascites of OVCA patients as a possible biomarker for EOC prevention.

T-Box Transcription Factor 2 Enhances Chemoresistance of Endometrial Cancer by Mediating NRF2 Expression.

BACKGROUND: The roles of T-Box transcription factor (TBX2) in endometrial cancer are still not clear. This study was designed to explore the roles of TBX2 in endometrial cancer and the underlying mechanisms. METHODS: The knockdown and overexpression of TBX2 in endometrial cancer cell lines were constructed by using lentivirus transduction. The xenograft animal model was established by using stable endometrial cancer cell lines. Cell viability was determined by the CCK-8 assay. The mRNA and protein levels of target genes were determined by using qPCR and Western blotting, respectively. ChIP assay was used to determine the interactions between TBX2 and nuclear factor erythroid 2-related factor 2 (NRF2). RESULTS: The upregulation of TBX2 was observed in endometrial cancer tissues from patients with Cisplatin- resistance and Cisplatin-resistant cells. Interestingly, TBX2 regulated cell viability and Cisplatin resistance of endometrial cancer cells. In addition, the regulatory effects of TBX2 on chemo-resistance of endometrial cancer cells were associated with the NRF2 signaling pathways. Consistently, the endometrial cancer xenograft animal model revealed that TBX2 regulated tumor growth and Cisplatin resistance, and its regulatory effects were in part by the regulation of NRF2 signaling pathways. CONCLUSION: TBX 2 enhanced Cisplatin resistance of endometrial cancer by regulating the NRF2 signaling pathways.

Hypoxia-induced HIF1α dependent COX2 promotes ovarian cancer progress.

Hypoxia can promote the progression and metastasis of ovarian cancer, while the underlying mechanisms are still unclear. Hypoxia culture or CoCl2 induced-oxygen deprivation condition could promote SKOV3 cells to express cyclooxygenase-2 (COX2). Luciferase assay indicates that hypoxia-inducible factor 1α (HIF1α) could bind directly with the promoter region of COX2 to promote the transcription. COX2 over-expressed SKOV3 cells show up-regulated stemness-related markers expression, proinflammatory gene expression, and increased tumor sphere formation. The inflammatory molecules (interleukin-6, C-X-C motif chemokine ligand 12, interleukin-1B, interleukin-10, and C-C motif chemokine ligand 2) and COX2 expression show positive correlations in the Cancer Genome Atlas data. COX2 over-expression could promote SKOV3 cell proliferation in the subcutaneous tumor model and metastasis in the transfer model. In conclusion, hypoxia-induced HIF-1α mediated COX2 expression could promote the proliferation, inflammation, and metastasis of ovarian cancer.

High mobility group box 3 promotes cervical cancer proliferation by regulating Wnt/ß-catenin pathway.

OBJECTIVE: High mobility group box 3 (HMGB3) plays an important role in the development of various cancer. This study aims to explore whether HMGB3 regulates cervical cancer (CC) progression and elucidate the underlying mechanism. METHODS: HMGB3 expression in clinical patients' tumor samples were determined by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. HMGB3 overexpression/knockdown were used to investigate its function. Cell apoptosis and cycle were detected by Annexin V/PI staining and flow cytometry. In vivo tumor model was made by subcutaneous injection of HeLa cells transfected with shRNAs targeting HMGB3 (sh-HMGB31) into the flank area of nude mice. Western blot was used to detect the levels of ß-catenin, c-Myc, and matrix metalloproteinase-7 (MMP-7) in Hela and CaSki cells transfected with sh-HMGB3 or shRNAs targeting ß-catenin. RESULTS: Both messenger RNA and protein levels of HMGB3 were upregulated in CC tissues from patients. High expression level of HMGB3 had positive correlation with serosal invasion, lymph metastasis, and tumor sizes in CC patient. Functional experiments showed that HMGB3 could promote CC cell proliferation both in vitro and in vivo. The expression levels of c-Myc and MMP-7 were increased, resulting in regulating cell apoptosis, cell cycle, and activating Wnt/ß-catenin pathway. CONCLUSIONS: Our data indicated that HMGB3 may serve as an oncoprotein. It could be used as a potential prognostic marker and represent a promising therapeutic strategy for CC treatment.

LINC01410/miR-23c/CHD7 functions as a ceRNA network to affect the prognosis of patients with endometrial cancer and strengthen the malignant properties of endometrial cancer cells.

In previous studies, long non-coding RNA LINC01410 (LINC01410) has been found to promote cells proliferation and invasion in colon and gastric cancers. However, the function of LINC01410 in endometrial cancer (EC) is still elusive. The expression patterns of LINC01410/miR-23c/Chromodomain Helicase DNA-Binding Protein 7 (CHD7) in EC tissues and the prognosis of patients with different expression of LINC01410/miR-23c/CHD7 were determined by consulting TCGA database. EC patients with complete clinical data were applied for clinicopathological correlation analysis. The biological characteristics of EC cells were analyzed with the support of CCK-8 and transwell assays. CHD7 expression was assessed by qRT-PCR and western blot assays. Targeted associations between LINC01410 and miR-23c, as well as miR-23c and CHD7 were speculated by prediction website and verified by dual-luciferase assay. Rescue assays were performed to explore the interrelation among LINC01410, miR-23c and CHD7. Our data illustrated that LINC01410 high expression was presented in EC tissues and was positively related to the poor prognosis of patients in EC, as well as the malignant behaviors of EC cells. Through bioinformatics analysis, we surmised that LINC01410/miR-23c/CHD7 may play a role through the formation of competing endogenous RNA (ceRNA) mechanism. CHD7 expression was positively regulated by LINC01410, and inversely controlled by miR-23c. Furthermore, the promoting effects of miR-23c inhibitor or CHD7 upregulation on EC cell growth and aggressiveness were attenuated by LINC01410 silencing. Our results indicated that high expression of LINC01410 promoted EC cell progression through modulating miR-23c/CHD7 axis, providing a new direction for revealing the molecular mechanism of EC.