BackgroundMicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. Low level expression of miR-26b has been found in glioma cells. However, its underlying mechanism of action has not been determined.Methodology/Principal FindingsReal-time PCR was employed to measure the expression level of miR-26b in glioma patients and cells. The level of miR-26b was inversely correlated with the grade of glioma. Ectopic expression of miR-26b inhibited the proliferation, migration and invasion of human glioma cells. A binding site for miR-26b was identified in the 3′UTR of EphA2. Over-expression of miR-26b in glioma cells repressed the endogenous level of EphA2 protein. Vasculogenic mimicry (VM) experiments were performed to further confirm the effects of miR-26b on the regulation of EphA2, and the results showed that miR-26b inhibited the VM processes which regulated by EphA2.SignificanceThis study demonstrated that miR-26b may act as a tumor suppressor in glioma and it directly regulates EphA2 expression. EphA2 is a direct target of miR-26b, and the down-regulation of EphA2 mediated by miR-26b is dependent on the binding of miR-26b to a specific response element of microRNA in the 3′UTR region of EphA2 mRNA.

Hepatocellular carcinoma (HCC) is one of the most dominant causes of neoplasm-related deaths worldwide. In this study, we identify and characterize HCCL5, a novel cytoplasmic long noncoding RNA (lncRNA), as a crucial oncogene in HCC. HCCL5 promoted cell growth, G 1-S transition, invasion, and metastasis while inhibiting apoptosis of HCC cells both in vitro and in vivo. Moreover, HCCL5 was upregulated in TGF-b1-induced classical epithelial-to-mesenchymal transition (EMT) models, and this lncRNA in turn accelerated the EMT phenotype by upregulating the expression of transcription factors Snail, Slug, ZEB1, and Twist1. HCCL5 was tran-scriptionally driven by ZEB1 via a super-enhancer and was significantly and frequently overexpressed in human HCC tissues, correlating with worse overall survival of patients with HCC. Together, this study characterizes HCCL5 as a superenhancer-driven lncRNA promoting HCC cell viability, migration, and EMT. Our data also suggest that HCCL5 may serve as a novel prognostic biomarker and therapeutic target in HCC. Significance: These findings identify the lncRNA HCCL5 as a super-enhancer-driven oncogenic factor that promotes the malignancy of hepatocellular carcinoma.

Since anoctamin 1 ANO1 (TMEM16A) was found to be a molecular component of Ca2+-activated Cl− channels, its role in tumorigenesis has gained attention at a fast pace. ANO1 overexpression frequently occurs in the cancer tissues along with 11q13 chromosome amplification. Poor prognosis of many types of cancers has been closely correlated with ANO1 gene amplification and protein overexpression. ANO1 is now considered an excellent biomarker for certain cancers. Recent research suggests that it is the channel function of ANO1 that is involved in the tumorigenesis. However, how the overexpression of the functional ANO1 causes malignant transformation of tissues via signaling pathways, for example, MAPK remains to be investigated. Clarification of the reasons in future will avail to make ANO1 as a target for cancer treatment.

Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway is essential for migration and invasion of malignant glioma. It is efficient to inhibit migration and invasion of glioma cells by targeting this pathway. Oleanolic acid (OA) has been well demonstrated to suppress survival, growth and angiogenesis of glioma cells. However, it is still unknown if OA affects the migration and invasion of glioma cells. We utilized U-87 MG glioma cell lines and primary glioma cells from patients to study the effect of OA on migration and invasion of glioma cells with multidisciplinary approaches. In this study, we found that OA significantly decreased the ability of glioma cells to migrate and invade. Epithelial-mesenchymal transition (EMT) of glioma cells was also suppressed by OA treatment. Furthermore, MAPK/ERK pathway was greatly inhibited in glioma cells under OA treatment. MAPK/ERK reactivation induced by a recombinant lentiviral vector, Lv-MEK, was able to rescue the inhibitory effect of OA on migration and invasion of glioma cells. Taken together, we provided evidences that OA was a MAPK/ERK pathway-targeting anti-tumor agent. Although the concentrations we used exceeded its physiological level, OA may be used to prevent migration and invasion of glioma cells by developing its derivatives with enhanced bioactivity.

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Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

Glioblastoma multiforme (GBM), the most common brain tumor in adults, is neurologically destructive and has a dismal response to virtually all therapeutic modalities. One phenomenon that can contribute to this complexity is the presence of a relatively small subset of glioma stem cells (GSCs) within the tumor and the activation of pathways that control cellular differentiation. The Notch signaling pathway, which is responsible for maintaining a balance between cell proliferation and apoptosis, is believed to be deregulated in cancer stem cells (CSCs), leading to tumor growth through the generation or expansion of CSCs. In this study, Notch-1 small interfering RNA (siRNA) was used to silence Notch-1 gene expression in GSCs. An MTT assay demonstrated inhibitory effects on the proliferation of GSCs in vitro. Real-time PCR showed that Notch-1 expression levels were markedly decreased in GSCs transfected with Notch-1 siRNA in vitro. Notch-1 silenced GSCs engrafted on Balb/c nude mice showed a significantly greater reduction in oncogenicity than the control group (P < 0.05). Furthermore, direct intratumoral injections of Notch-1-siRNA/PEI significantly delayed the growth of pre-established tumors in nude mice (P < 0.05). These results suggest that siRNA-mediated silencing of the Notch-1 gene may represent a novel target for gene therapy of GBM.

Background Similarities in the symptoms of chronic fatigue syndrome (CFS) and inflammatory bowel disease (IBD) have been observed as follows: severe disease activity in IBD correlates with severe fatigue, major psychiatric signs, the common use of medication, and bacterial translocation. One of several hypotheses for explaining the mechanisms underlying CFS suggests a similarity to the impaired intestinal mucosa of IBD. “This study investigated the risk of incident CFS among patients with IBD”. Methods We conducted a population-based retrospective cohort study by using Taiwan’s National Health Insurance Research Database to evaluate the subsequent risk of CFS in patients with IBD, according to demographic characteristics and comorbidities. The exposure cohort comprised 2163 patients with new diagnoses of IBD. Each patient was randomly selected and frequency matching according to gender and age with four participants from the general population who had no history of CFS at the index date (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between IBD and the subsequent risk of CFS. Results The exposure cohort had a significantly higher overall risk of subsequent CFS than that of the control group [adjusted hazard ratio (Christophi in Inflamm Bowel Dis 18(12):2342–2356, 2012 ) = 2.25, 95%, confidence interval (Aaron and Buchwald in Ann Intern Med 134(9 Pt 2):868–881, 2001 ; Farraye et al. in Am J Gastroenterol 112:241, 2017 ) 1.70–2.99]. Further analysis indicated a significantly higher risk of CFS in patients who were male (HR = 3.23, 95% CI 2.12–4.91), were older than 35 years, and had IBD but without comorbidity status, e.g. Cancers, diabetes, obesity, depression, anxiety, sleep disorder, renal disease (HR = 2.50, 95% CI 1.63–3.84) after adjustment. Conclusion The findings from this population-based retrospective cohort study suggest that IBD, especially Crohn’s disease, is associated with an increased risk of subsequent CFS. Electronic supplementary material The online version of this article (10.1186/s12967-019-1797-3) contains supplementary material, which is available to authorized users.