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Cancer‐associated fibroblasts (CAFs), as important components of the tumor microenvironment, can regulate intercellular communication and tumor development by secreting extracellular vesicles (EVs). However, the role of CAF‐derived EVs in ovarian cancer has not been fully elucidated. Here, using an EV‐microRNA sequencing analysis, we reveal specific overexpression of microRNA (miR)‐296‐3p in activated CAF‐derived EVs, which can be transferred to tumor cells to regulate the malignant phenotypes of ovarian cancer cells. Moreover, overexpression of miR‐296‐3p significantly promotes the proliferation, migration, invasion, and drug resistance of ovarian cancer cells in vitro, as well as tumor growth in vivo, while its inhibition has the opposite effects. Further mechanistic studies reveal that miR‐296‐3p promotes ovarian cancer progression by directly targeting PTEN and SOCS6 and activating AKT and STAT3 signaling pathways. Importantly, increased expression of miR‐296‐3p encapsulated in plasma EVs is closely correlated with tumorigenesis and chemoresistance in patients with ovarian cancer. Our results highlight the cancer‐promoting role of CAF‐derived EVs carrying miR‐296‐3p in ovarian cancer progression for the first time, and suggest that miR‐296‐3p encapsulated in CAF‐derived EVs could be a diagnostic biomarker and therapeutic target for ovarian cancer.

Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up‐regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human‐like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR‐296‐3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR‐296‐3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.

Diabetic nephropathy is a leading cause of end‐stage renal disease globally. The vital role of circular RNAs (circRNAs) has been reported in diabetic nephropathy progression, but the molecular mechanism linking diabetic nephropathy to circRNAs remains elusive. In this study, we investigated the significant function of circ‐AKT3/miR‐296‐3p/E‐cadherin regulatory network on the extracellular matrix accumulation in mesangial cells in diabetic nephropathy. The expression of circ‐AKT3 and fibrosis‐associated proteins, including fibronectin, collagen type I and collagen type IV, was assessed via RT‐PCR and Western blot analysis in diabetic nephropathy animal model and mouse mesangial SV40‐MES13 cells. Luciferase reporter assays were used to investigate interactions among E‐cadherin, circ‐AKT3 and miR‐296‐3p in mouse mesangial SV40‐MES13 cells. Cell apoptosis was evaluated via flow cytometry. The level of circ‐AKT3 was significantly lower in diabetic nephropathy mice model group and mouse mesangial SV40‐MES13 cells treated with high‐concentration (25 mmol/L) glucose. In addition, circ‐AKT3 overexpression inhibited the level of fibrosis‐associated protein, such as fibronectin, collagen type I and collagen type IV. Circ‐AKT3 overexpression also inhibited the apoptosis of mouse mesangial SV40‐MES13 cells treated with high glucose. Luciferase reporter assay and bioinformatics tools identified that circ‐AKT3 could act as a sponge of miR‐296‐3p and E‐cadherin was the miR‐296‐3p direct target. Moreover, circ‐AKT3/miR‐296‐3p/E‐cadherin modulated the extracellular matrix of mouse mesangial cells in high‐concentration (25 mmol/L) glucose, inhibiting the synthesis of related extracellular matrix protein. In conclusion, circ‐AKT3 inhibited the extracellular matrix accumulation in diabetic nephropathy mesangial cells through modulating miR‐296‐3p/E‐cadherin signals, which might offer novel potential opportunities for clinical diagnosis targets and therapeutic biomarkers for diabetic nephropathy.

Background Lung cancer is the most commonly diagnosed cancer and leading cause of cancer death, with 80%–85% of non‐small cell lung cancer (NSCLC). Circular RNAs (circRNAs) have been shown to be promising early diagnostic and therapeutic molecular biomarkers for NSCLC. However, biological role and regulatory mechanism of circRNA WHSC1 (circWHSC1) in NSCLC are unknown. Therefore, we aim to explore the function and mechanism of circWHSC1 in NSCLC oncogenesis and progression. Methods qRT‐PCR was used for circWHSC1 level evaluation; Kaplan‐Meier was used for survival analysis; bioinformatics, dual‐luciferase activity, and RNA pull‐down were used for evaluating competing endogenous RNA (ceRNA) network; cell viability, colony formation, apoptosis, migration, and invasion were used for cell function analysis; function gain and loss with rescue experiments were used for exploring mechanism of circWHSC1 in NSCLC development. Results Significantly up‐regulated circWHSC1 and down‐regulated microRNA‐296‐3p (miR‐296‐3p) were identified in NSCLC tissues and cells. Up‐regulated circWHSC1 was associated with poor prognosis in NSCLC patients. MiR‐296‐3p was sponged by circWHSC1, and AKT serine/threonine kinase 3 (AKT3) was target of miR‐296‐3p; meanwhile, miR‐296‐3p over‐expression significantly down‐regulated AKT3 expression, and co‐transfecting anti‐miR‐296‐3p rescued circWHSC1 silence caused AKT3 down‐regulation. CircWHSC1 silence significantly inhibited colony formation, viability, invasion, and migration, while increased NSCLC cell apoptosis, which were partially rescued by anti‐miR‐296‐3p. Conclusion CircWHSC1 is an independent indicator of poor prognosis in NSCLC patients, and functions as a ceRNA of miR‐296‐3p to up‐regulate AKT3, consequently promotes NSCLC cell growth and metastasis. Targeting circWHSC1 might be a prospective strategy for diagnosis, therapeutics, and prognosis of NSCLC. However, miR‐296‐3p over‐expression significantly down‐regulated AKT3 expression, and co‐transfecting anti‐miR‐296‐3p rescued circWHSC1 silence caused down‐regulation of AKT3. Therefore, circWHSC1 is an independent indicator of poor prognosis in NSCLC patients, and functions as a competing endogenous RNA (ceRNA) of miR‐296‐3p to up‐regulate AKT3, consequently promotes NSCLC cell growth and metastasis.

MicroRNAs (miRNAs) have been demonstrated to play critical roles in the tumorigenesis of triple-negative breast cancer (TNBC). In this work, we addressed the sepecific role of miR-296-3p in TNBC. The levels of miR-296-3p and SOX4 were determined using RT-qPCR. The function of miR-296-3p overexpression on TNBC cell proliferation, migration, invasion, cancer stem cell (CSC)-like proterties, and Wnt pathway activation was investigated by MTT, EdU, wound healing, Transwell, sphere formation assays and western blot. Mechanistic investigations, including luciferase reporter, RNA pull-down, and RIP assays, were conducted to explore the regulatory mechanisms of miR-296-3p. We found that miR-296-3p was downregulated in TNBC tissues and cells. Overexpression of miR-296-3p suppressed TNBC cell proliferation, migration, invasion, and CSC-like proterties. Furthermore, miR-296-3p could bind to SOX4 and negatively modulate SOX4 expression. In addition, miR-296-3p was verified to inhibit Wnt/β-catenin pathway by downregulating SOX4. Moreover, overexpression of SOX4 or activation of Wnt pathway rescued the miR-296-3p upregulation-mediated suppressive effect on cellular processes in TNBC. In conclusion, miR‑296‑3p inhibits Wnt/β-catenin pathway by targeting SOX4 and exerts anti-tumor effects in TNBC.