Exosomes carrying microRNAs (miRNAs) have been demonstrated to play critical roles in the regulation of development, growth and metastasis of cancer. Bioinformatic predictions identified differentially expressed SRY-box 9 (SOX9) in OC, and the regulatory miRNA miR-139-5p. Here, we aim to evaluate the function of exosomal miR-139-5p in the sensitivity of ovarian cancer (OC) cells to cis-diamminedichloroplatinum(II) (DDP). Expression pattern of miR-139-5p and SOX9 in ovarian cancer cells (SKOV3) and DDP-resistant cells (SKOV3/DDP) was identified using reverse transcription quantitative polymerase chain reaction and western blot analysis. The relationship between miR-139-5p and SOX9 was validated using a dual-luciferase reporter assay. SKOV3/DDP cell line was developed and introduced with miR-30a-5p mimic to analyse the effects of miR-30a-5p on resistance to DDP. The in vitro and in vivo effects of exosomal miR-30a-5p on resistance of SKOV3 cells to DDP were assessed in a co-culture system of exosomes and OC cells as well as in tumour-bearing nude mice. High expression of SOX9 and low expression of miR-30-5p were witnessed in OC. Furthermore, miR-30-5p, a downregulated miRNA in SKOV3/DDP cells, increased the rate of cell apoptosis and enhanced the sensitivity of SKOV3/DDP cells to DDP by targeting SOX9. Moreover, exosomes carrying miR-30a-5p were identified to sensitize SKOV3/DDP cells to DDP both in vitro and in vivo . These data together supported an important conclusion that DDP-resistant OC cell-derived exosomal miR-30a-5p enhanced cellular sensitivity to DDP, highlighting a potential strategy to overcome drug resistance.
Pre‐eclampsia (PE) is a major cause of maternal and perinatal death. Previous research has indicated the role of histone deacetylase 2 (HDAC2) in the pathogenesis of PE but the relevant molecular mechanisms are unknown. However, there is hitherto little information concerning the molecular mechanism behind HDAC2 in PE. Herein, we hypothesized that HDAC2 promotes trophoblast cell proliferation and this requires the involvement of microRNA‐183 (miR‐183), forkhead box protein A1 (FOXA1), and interleukin 8 (IL‐8). We collected placental specimens from 30 PE affected and 30 normal pregnant women. HDAC2 and FOXA1 were poorly expressed while miR‐183 and IL‐8 were highly expressed in placental tissues in PE. In vitro, HDAC2 overexpression enhanced the proliferation, migration, and invasion of human trophoblast cells HTR‐8/SVNEO. HDAC2 inhibited the expression of miR‐183 by diminishing H4 acetylation in the miR‐183 promoter region. miR‐183 inhibition by its specific inhibitor increased the expression of FOXA1 and thus enhanced HTR‐8/SVNEO cell proliferation, migration, and invasion. FOXA1, a transcriptional factor, enhanced HTR‐8/SVNEO cell proliferation, migration, and invasion by inhibiting the transcription of IL‐8. We also observed HDAC2 knockdown was lost upon FOXA1 overexpression, suggesting that HDAC2 could promote HTR‐8/SVNEO proliferation, migration, and invasion through the miR‐183/FOXA1/IL‐8 pathway. In summary, the results highlighted the role of the HDAC2/miR‐183/FOXA1/IL‐8 pathway in PE pathogenesis and thus suggest a novel molecular target for PE.
Ovarian cancer is one of the five most malignant types of cancer in females, and the only currently effective therapy is surgical resection combined with chemotherapy. Wnt family member 10A (Wnt10a) has previously been identified to serve an oncogenic function in several tumor types, and was revealed to have clinical significance in renal cell carcinoma; however, there is still only limited information regarding the function of Wnt10a in the carcinogenesis of ovarian cancer. The present study identified increased expression levels of Wnt10a in two cell lines, SKOV3 and A2780, using reverse transcription-polymerase chain reaction. Functional analysis indicated that the viability rate and migratory ability of SKOV3 cells was significantly inhibited following Wnt10a knockdown using short interfering RNA (siRNA) technology. The viability rate of SKOV3 cells decreased by ~60% compared with the control and the migratory ability was only ~30% of that in the control. Furthermore, the expression levels of β-catenin, transcription factor 4, lymphoid enhancer binding factor 1 and cyclin D1 were significantly downregulated in SKOV3 cells treated with Wnt10a-siRNA3 or LGK-974, a specific inhibitor of the canonical Wnt signaling pathway. However, there were no synergistic effects observed between Wnt10a siRNA3 and LGK-974, which indicated that Wnt10a activated the Wnt/β-catenin signaling pathway in SKOV3 cells. In addition, using quantitative PCR, Wnt10a was overexpressed in the tumor tissue samples obtained from 86 patients with ovarian cancer when compared with matching paratumoral tissues. Clinicopathological association analysis revealed that Wnt10a was significantly associated with high-grade (grade III, P=0.031) and late-stage (T4, P=0.008) ovarian cancer. Furthermore, the estimated 5-year survival rate was 18.4% for patients with low Wnt10a expression levels (n=38), whereas for patients with high Wnt10a expression (n=48) the rate was 6.3%. The results of the present study suggested that Wnt10a serves an oncogenic role during the carcinogenesis and progression of ovarian cancer via the Wnt/β-catenin signaling pathway.
Ethnopharmacological relevanceOestrogen deficiency, high incidences of hyperlipidaemia (HLP) and accelerated bone loss frequently occur in postmenopausal women. There is an urgent need to develop functional foods or specific drugs to protect against bone loss induced by oestrogen deficiency with HLP.Aim of the studyIn this study, we investigated the potential inhibitory effects of Sargassum integerrimum (SI) on bone loss in an ovariectomized rat model with HLP.Materials and methodsThe rats were treated for 12 weeks, and then, bone mineral density, bone biomechanical, bone microstructure, bone morphology, biomarkers of HLP oxidative stress and side effects were determined. Immunohistochemical staining and Western blot were performed to evaluate related protein expression.ResultsThe femur bone mineral density increased (P < 0.05), and the microscopic structures (ratio of bone volume to total volume [BV/TV], connectivity density [Conn.D], trabecular number [Tb.N] and trabecular thickness [Tb.Th]) of the bone trabecula and mechanical properties (maximum and breaking load [ML and BL, respectively]) improved after SI treatment (P < 0.05). Furthermore, the levels of HLP biomarkers (total cholesterol, triglyceride and low-density lipoprotein) were significantly decreased (P < 0.05), whereas the levels of antioxidant markers (superoxide dismutase and total antioxidant capacity) were increased (P < 0.05). Similar results were obtained with immunohistochemical staining, whereas the Western blot assay showed that SI stimulated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in bone.ConclusionOur data indicate that rats exposed to SI treatment for 12 weeks did not exhibit noticeable side effects. In conclusion, SI suppressed bone loss induced by ovariectomized and the associated HLP in rats by activating Nrf2, which could be a promising treatment option for osteoporosis induced by oestrogen deficiency and HLP in postmenopausal women.Translational scope statementOur study verified that SI prevented bone loss in rats with oestrogen deficiency with HLP by upregulating nuclear factor (erythroid-derived 2)-like 2. Furthermore, no side effect was observed after the long-term administration of SI. Those results suggested SI could be developed as a functional food or drug for postmenopausal osteoporosis induced by oestrogen deficiency with HLP.
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