The role of LIN28B in tumor progression and metastasis in solid tumor entities

LIN28B is an RNA-binding protein that targets a broad range of microRNAs and modulates their maturation and activity. Under normal conditions, LIN28B is exclusively expressed in embryogenic stem cells, blocking differentiation and promoting proliferation. In addition, it can play a role in epithelial-to-mesenchymal transition by repressing the biogenesis of let-7 microRNAs. In malignancies, LIN28B is frequently overexpressed, which is associated with increased tumor aggressiveness and metastatic properties. In this review, we discuss the molecular mechanisms of LIN28B in promoting tumor progression and metastasis in solid tumor entities and its potential use as a clinical therapeutic target and biomarker.     

Effects of miR-200a and FH535 combined with taxol on proliferation and invasion of gastric cancer

Gastric cancer is one of the most common cancers in the world; taxol displayed modest efficacy as first-line chemotherapy for gastric cancer, conversely, it has limitations used alone. β-catenin is a multifunctional oncogenic protein and the elevation in expression and activity of β-catenin has been implicated in many cancers. Therefore, we assume that the inhibition of β-catenin can enhanced the efficacy of taxol. The purpose of this study was to investigate the inhibitory effect of miR-200a mimics, FH535 combined with taxol on proliferation and invasion of human gastric cancer cell lines SGC-7901 and BGC-823. In the current study, we identified that the combination of FH535 and miR-200a with taxol had potent growth-inhibitory and pro-apoptotic effects. Further, similar results were also observed in vivo, intratumoral injection of FH535, taxol and miR-200a mimics which also delayed tumor growth in nude mice harboring subcutaneous SGC-7901 xenografts. Collectively, miR-200a and FH535 can enhance the inhibitory effect of taxol on cell proliferation and moderate the invasion of human gastric cancer.     

MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2

Malignant glioma is the most common and deadly primary brain tumor in adults. However, the mechanisms underlying the malignancy of glioma remain unclear. In the present study, we found that Fos-related antigen-2 (Fra-2) was overexpressed in most glioma cells, and knockdown of Fra-2 prevented cell proliferation, migration, and invasion. Mechanistically, Fra-2 silencing led to a significant reduction in cell-cycle drivers (Cyclin D1 and Cyclin E1), one invasion-associated gene (MMP9), the mesenchymal marker (Vimentin), and induction of the epithelial marker (E-cadherin). Further study confirmed that miR-124-3p decreased the expression of Fra-2 via directly targeting the 3′-UTR, and transfection with miR-124-3p in glioma cells inhibited expression of the above cell-cycle and EMT promoters. Phenotypic experiments also showed that overexpression of Fra-2 weakened the inhibitory effects of miR-124-3p on the proliferation, migration, and invasion of glioma cells. In addition, Fra-2 knockdown impaired the malignant phenotypes enhanced by miR-124-3p inhibition, which suggested a crucial role for the miR-124-3p/Fra-2 pathway in glioma development. Consistently, high expression of Fra-2 was closely associated with low miR-124-3p level and indicated a poor prognosis in patients with glioma. In conclusion, this study indicates the existence of an aberrant miR-124-3p/Fra-2 pathway that results in glioma aggressiveness, which suggests novel therapeutic opportunities for this fatal disease.     

Non-coding RNAs: Regulators of glioma cell epithelial-mesenchymal transformation

GBM (glioblastoma multiforme) is the most malignant form of glioma and is the most commonly occurring primary malignant brain tumour. GBM is difficult to completely excise, resulting in an extremely high recurrence rate. The occurrence of an aggressive glioma phenotype depends on EMT (epithelial-mesenchymal transformation), in which epithelial cells transform into mesenchymal cells by losing their cell-cell adhesion and polarity. NcRNAs (non-coding RNAs) play a significant role in the cellular progression from a normal phenotype to a cancerous phenotype. Recently, many studies have shown that there are two essential regulatory ncRNAs, miRNAs (microRNAs) and lncRNAs, which are closely related to EMT. In this review, we conducted a comprehensive investigation of the dysregulated lncRNAs and miRNAs in gliomas with particular attention to the function and regulatory mechanisms of several important lncRNAs and miRNAs, and we discussed their roles as glioma diagnostic and prognostic biomarkers and their potential clinical applications as therapeutic targets.     

IL4 and IL-17A provide a Th2/Th17-polarized inflammatory milieu in favor of TGF-β1 to induce bronchial epithelial-mesenchymal transition (EMT)

Severe asthma is a chronic airway disease characterized by the Th2/Th17-polarized inflammation along with permanent airway remodeling. Despite past extensive studies, the exact role for Th2 and Th17 cytokines in asthmatic pathoetiology, particularly in the pathogenesis of bronchial epithelial-mesenchymal transition (EMT), is yet to be fully addressed. We herein conducted studies in 16-HBE cells and demonstrated that Th2-derived IL-4 and Th17-derived IL-17A provide a chronic inflammatory milieu that favors TGF-β₁ to induce bronchial EMT. A synergic action was noted between TGF-β₁, IL-4 and IL-17A in terms of induction of EMT. IL-4 and IL-17A synergized with TGF-β₁ to induce epithelial cells re-entering cell cycle, and to promote epithelial to mesenchymal morphological transistion, and by which they enhanced the capacity of TGF-β₁ to suppress E-cadherin expression, and to induce a-SMA expression in epithelial cells. Mechanistic studies revealed that this synergic action is coordinated by the regulation of ERK1/2 activity. Our results not only provide a novel insight into the understanding of the mechanisms underlying airway remodeling in asthmatic condition, but also have the potential for developing more effective therapeutic strategies against severe asthmatics in clinical settings.     

The effects of miR-429 on cell migration and invasion by targeting Slug in esophageal squamous cell carcinoma

Increasing evidence indicates that microRNAs may play important roles in tumor development and may take part in different processes in different cancers. miR-429 is known as a cancer suppressor or oncogene that is dysregulated in different malignancies, including esophageal squamous cell carcinoma (ESCC). However, the effect of miR-429 in ESCC has not been fully explored. The purpose of this study was to investigate the functions of miR-429 in ESCC. qRT-PCR assays were performed to detect miR-429 expression in ESCC tissues and cell lines. To assess the effects of miR-429 on ESCC cells, wound healing and transwell assays were used. Luciferase reporter and western blot assays were employed to determine whether Slug is a major target of miR-429.Our results showed that the expression levels of miR-429 in ESCC tissues and cells were lower than in normal esophageal epithelial tissues and cells. Furthermore, overexpression of endogenous miR-429 inhibited the migration and invasion of ESCC cell lines. In addition, Luciferase reporter and western blot assays provided evidence that miR-429 can bind to the 3′ untranslated regions of Slug to regulate its expression and that of downstream epithelial-to-mesenchymal transition (EMT) markers. We found that Slug serves as a major target of miR-429. miR-429 plays a vital role in ESCC progression and represents a new therapeutic target for ESCC.     

神经型钙黏附蛋白与恶性肿瘤的关系

神经型钙黏附蛋白（N-cadherin）在上皮恶性肿瘤中表达上调,且与上皮-间质转换关系密切,N-cadherin高表达提示肿瘤的能动性和转移能力增强,在肿瘤的发生、浸润、转移、血管生成中起了重要作用。ADH-1作为N-cadherin抗体的一个全身性抗癌药,诱导靶细胞的凋亡,破坏肿瘤组织中的血管,通过破坏胞外N-cadherin间的黏附,改变N-cadherin和成纤维细胞生长因子受体（FGFR-1）间的关系,破坏FGFR-1,导致FGFR-1表达缺失,从而破坏肿瘤血管,抑制肿瘤的生长,为临床肿瘤的治疗提供了理论基础。     

The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT)

Congenital heart disease is the most common birth defect, affecting 1.35 million newborns every year. Heart failure is a primary cause of late morbidity and mortality after myocardial infarction. Heart development is involved in several rounds of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET). Errors in these processes contribute to congenital heart disease, and exert deleterious effects on the heart and circulation after myocardial infarction. The identification of factors that are involved in heart development and disease, and the development of new approaches for the treatment of these disorders are of great interest. G protein coupled receptors (GPCRs) comprise 40% of clinically used drug targets, and their signaling are vital components of the heart during development, cardiac repair and in cardiac disease pathogenesis. This review focuses on the importance of EMT program in the heart, and outlines the newly identified GPCRs as potential therapeutic targets of reprogramming EMT to support cardiac cell fate during heart development and after myocardial infarction. More specifically we discuss prokineticin, serotonin, sphingosine-1-phosphate and apelin receptors in heart development and diseases. Further understanding of the regulation of EMT/MET by GPCRs during development and in the adult hearts can provide the following clinical exploitation of these pathways.