摘要: Objectives In diabetic nephropathy (DN), hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF-1 alpha, such as haem oxygenase-1 (HO-1), but the exact mechanisms are incompletely understood. Materials and methods Mice with proximal tubule-specific knockout of HIF-1 alpha (PT-HIF-1 alpha(-/-)mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl2) was applied to HK-2 cells. Results Our study first verified that conditional knockout of HIF-1 alpha worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT-HIF-1 alpha(-/-)mice. In vitro study showed that compared to control group, HK-2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF-1 alpha or treatment with a HO-1 agonist. Importantly, cotreatment with a HIF-1 alpha inhibitor and a HO-1 agonist rescued the HK-2 cells from the negative impacts of the HIF-1 alpha inhibitor. Conclusions These data revealed that HIF-1 alpha exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO-1 upregulation.

摘要: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with negativity for oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). Non-coding RNAs (ncRNAs) make up most of the transcriptome and are widely present in eukaryotic cells. In recent years, emerging evidence suggests that ncRNAs, mainly microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs), play prominent roles in the tumorigenesis and development of TNBC, but the functions of most ncRNAs have not been fully described. In this review, we systematically elucidate the general characteristics and biogenesis of miRNAs, lncRNAs and circRNAs, discuss the emerging functions of these ncRNAs in TNBC and present future perspectives in clinical practice.

摘要: Objectives Downregulation of miR-502-5p has emerged as a critical factor in tumour progression in several cancers. Herein, we elucidated the role of miR-502-5p in bladder cancer. Materials and methods RT-qPCR was performed to examine the expression of miR-502-5p in bladder cancer. And DNA methylation analysis showed that epigenetic mechanisms may contribute to the downregulation of miR-502-5p. Then, wound-healing assay, transwell assay, colony formation assay, CCK8 assay and flow cytometry analysis were applied to evaluate the function of miR-502-5p in bladder cancer cell lines. Western blot was conducted to measure the protein levels of related genes. Furthermore, dual-luciferase reporter assay, in vivo tumorigenesis assay and immunohistochemical staining were also conducted as needed. Results MiR-502-5p is frequently downregulated in BCa. Meanwhile, hypermethylation of CpG islands contributes to the downregulation of miR-502-5p. Functionally, overexpression of miR-502-5p inhibited cell proliferation and migration in vitro and repressed tumour growth in vivo. CCND1, DNMT3B and NOP14 were identified as direct targets of miR-502-5p. Interestingly, DNMT3B and miR-502-5p established a positive feedback loop in the regulation of bladder cancer. In addition, rescue experiments further validated the direct molecular interaction between miR-502-5p and its targets. Conclusions Our study proposed and demonstrated that the miR-502-5p-mediated regulatory network is critical in bladder cancer; this network may be useful in the development of more effective therapies against bladder cancer.

摘要: Objectives Tanshinone I (Tan-I) is one of the vital fatsoluble monomer components, which extracted from Chinese medicinal herb Salvia miltiorrhiza Bunge. It has been shown that Tan-I exhibited anti-tumour activities on different types of cancers. However, the underlying mechanisms by which Tan-ROMAN NUMERAL ONE regulates apoptosis and autophagy in ovarian cancer remain unclear. Thus, this study aimed to access the therapy effect of Tan-ROMAN NUMERAL ONE and the underlying mechanisms. Methods Ovarian cancer cells A2780 and ID-8 were treated with different concentrations of Tan-ROMAN NUMERAL ONE (0, 1.2, 2.4, 4.8 and 9.6 mu g/mL) for 24 hours. The cell proliferation was analysed by CCK8 assay, EdU staining and clone formation assay. Apoptosis was assessed by the TUNEL assay and flow cytometry. The protein levels of apoptosis protein (Caspase-3), autophagy protein (Beclin1, ATG7, p62 and LC3II/LC3I) and PI3K/AKT/mTOR pathway were determined by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy. Anti-tumour activity of Tan-ROMAN NUMERAL ONE was accessed by subcutaneous xeno-transplanted tumour model of human ovarian cancer in nude mice. The Ki67, Caspase-3 level and apoptosis level were analysed by immunohistochemistry and TUNEL staining. Results Tan-ROMAN NUMERAL ONE inhibited the proliferation of ovarian cancer cells A2780 and ID-8 in a dose-dependent manner, based on CCK8 assay, EdU staining and clone formation assay. In additional, Tan-ROMAN NUMERAL ONE induced cancer cell apoptosis and autophagy in a dose-dependent manner in ovarian cancer cells by TUNEL assay, flow cytometry and Western blot. Tan-ROMAN NUMERAL ONE significantly inhibited tumour growth by inducing cell apoptosis and autophagy. Mechanistically, Tan-ROMAN NUMERAL ONE activated apoptosis-associated protein Caspase-3 cleavage to promote cell apoptosis and inhibited PI3K/AKT/mTOR pathway to induce autophagy. Conclusions This is the first evidence that Tan-ROMAN NUMERAL ONE induced apoptosis and promoted autophagy via the inactivation of PI3K/AKT/mTOR pathway on ovarian cancer and further inhibited tumour growth, which might be considered as effective strategy.

摘要: Objectives Integrin beta-like 1 (ITGBL1) is involved in the migration and invasion of several cancers; however, its roles in the development and progression of hepatocellular carcinoma (HCC) remain largely unknown. Materials and methods Immunohistochemistry staining was used to investigate the expression pattern of ITGBL1 and its prognostic values in HCC patients. The transwell, wound-healing assays, xenograft and orthotopic mouse models were employed to determine the effects of ITGBL1 on HCC cell migration and invasion in vitro and in vivo. The biological mechanisms involved in cell migration and invasion caused by ITGBL1 were determined with Western blotting and RT-PCR methods. Results ITGBL1 expression was significantly increased in HCC tissues compared to adjacent normal tissues. Patients with higher ITGBL1 expression were associated with more reduced overall survival. ITGBL1 overexpression promoted migration and invasion in SMMC-7721 and HepG2 cells in vitro and in vivo, whereas knockdown or knockout ITGBL1 in CSQT-2 cells significantly reduced cell migration and invasion abilities. In SMMC-7721 cells, ITGBL1 overexpression stimulated TGF-beta/Smads signalling pathway, along with the KRT17 and genes involved in the epithelial-mesenchymal transition (EMT). In contrast, ITGBL1 knockout inhibited the TGF-beta/Smads signalling pathway in CSQT-2 cells. Conclusions These findings suggested that ITGBL1 promoted migration and invasion in HCC cells by stimulating the TGF-beta/Smads signalling pathway. ITGBL1 could be a promising prognostic biomarker, as well as a potential therapeutic target in HCC.