SLC12A5 interacts and enhances SOX18 activity to promote bladder urothelial carcinoma progression via upregulating MMP7

Solute carrier family 12 member 5 (SLC12A5) has an oncogenic role in bladder urothelial carcinoma. The present study aimed to characterize the molecular mechanisms of SLC12A5 in bladder urothelial carcinoma pathogenesis. Functional assays identified that in bladder urothelial carcinoma SLC12A5 interacts with and stabilizes SOX18, and then upregulates matrix metalloproteinase 7 (MMP7). In vivo and in vitro assays were performed to confirm the effect of SLC12A5’s interaction with SOX18 on MMP7‐mediated bladder urothelial carcinoma progression. SLC12A5 was upregulated in human bladder tumors, and correlated with the poor survival of patients with bladder urothelial carcinoma tumor invasion and metastasis, promoted by SLC12A5 overexpression. We demonstrated that SLC12A5 interacted with SOX18, and then upregulated MMP7, thus enhancing tumor progression. Importantly, SLC12A5 expression correlated positively with SOX18 and MMP7 expression in bladder urothelial carcinoma. Furthermore, SLC12A5 expression was suppressed by miR‐133a‐3p. Ectopic expression of SLC12A5 partly abolished miR‐133a‐3p‐mediated suppression of cell migration. SLC12A5‐SOX18 complex‐mediated upregulation on MMP7 was important in bladder urothelial carcinoma progression. The miR‐133a‐3p/SLC12A5/SOX18/MMP7 signaling axis was critical for progression, and provided an effective therapeutic approach against bladder urothelial carcinoma.     

miR-149与肿瘤关系的研究进展

miRNAs是一类长度约为20~25个核苷酸，参与基因调控表达的内源性非编码RNA。miR-149作为miRNAs的重要成员，在多种肿瘤中表达异常，其表达水平与肿瘤细胞增殖、转移、凋亡、耐药、患者的早期诊断及预后密切相关。因此，miR-149有望成为新一类抗肿瘤治疗的靶点。     

Multiple functions of miR‐8‐3p in the development and metamorphosis of the red flour beetle,Tribolium castaneum

The microRNA miR‐8‐3p is conserved among insects and closely involved in development and immunity, but its functions in vivo are unexplored in the red flour beetle, Tribolium castaneum. Here, we show that miR‐8‐3p was highly expressed in late larva and early adult stages, as determined by quantitative real‐time PCR. It was enriched in the fat body and cuticle in late larval tissues and abundant in the head and cuticle in early adult tissues, indicating this microRNA plays important roles during T. castaneum development. Specific inhibition of miR‐8‐3p in late larvae led to metamorphosis defects in the development of wings, eyes, legs and embryo. Moreover, a series of genes related to organism development were identified as miR‐8‐3p targets by computational prediction and microRNA–messenger RNA interaction validation, including Wingless, Eyg, Fpps and Sema‐1a. These genes were critical for the regulation of the larva‐to‐adult transition. Eyg, as a functional target of miR‐8‐3p, participates in eye development, which was further confirmed by luciferase assay and loss‐of‐function analyses. In brief, miR‐8‐3p is broadly involved in the development of wings, eyes and legs through its target genes and has extensive regulatory roles during T. castaneum development.     

miR‐210‐3p mediates metabolic adaptation and sustains DNA damage repair of resistant colon cancer cells to treatment with 5‐fluorouracil

Chemoresistance is the primary cause of chemotherapy failure. Compelling evidence shows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward a resistant phenotype. We investigate the role of miRNAs in the response to acute treatment with 5‐FU in colon cancer‐resistant cells. We performed a global gene expression profile for the entire miRNA genome and found a change in the expression of four miRNAs following acute treatment with 5‐FU. Among them, we focused on miR‐210‐3p, previously described as a key regulator of DNA damage repair mechanisms and mitochondrial metabolism. We show that miR‐210‐3p downregulation enables resistant cells to counteract the toxic effect of the drug increasing the expression of RAD‐52 protein, responsible for DNA damage repair. Moreover, miR‐210‐3p downregulation enhances oxidative phosphorylation (OXPHOS), increasing the expression levels of succinate dehydrogenase subunits D, decreasing intracellular succinate levels and inhibiting HIF‐1α expression. Altogether, these adaptations lead to increased cells survival following drug exposure. These evidence suggest that miR‐210‐3p downregulation following 5‐FU sustains DNA damage repair and metabolic adaptation to counteract drug treatment.     

Interaction of transforming growth factor‐β‐Smads/microRNA‐362‐3p/CD82 mediated by M2 macrophages promotes the process of epithelial‐mesenchymal transition in hepatocellular carcinoma cells

Abnormal tumor microenvironment and the epithelial‐mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor‐associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)‐362‐3p. In this study, we found that by releasing TGF‐β, M2 macrophages mediate binding of Smad2/3 to miR‐362‐3p promoter, leading to overexpression of miR‐362‐3p. MicroRNA‐362‐3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR‐362‐3p can serve as a core factor mediating cross‐talk between the TGF‐β pathway in tumor‐associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.