GNA13 has been found overexpressed in various types of cancer, which is related to tumor metastasis and progression. However, the biological functions of GNA13 in colorectal cancer (CRC) progression remain unclear. This study aimed to explore the role of GNA13 in CRC and investigate the mechanism of how GNA13 promotes tumor growth. Interestingly, our findings showed that GNA13 is commonly upregulated in CRC, where these events are associated with a worse histologic grade and poor survival. Increased expression levels of GNA13 promoted cell growth, migration, invasion, and epithelial‐mesenchymal transition, whereas GNA13 silencing abrogated these malignant phenotypes. In addition, overexpressing GNA13 in cancer cells increased the levels of the chemokines CXCL1, CXCL2, and CXCL4, which contributed to CRC proliferation and colony formation. Moreover, our mechanistic investigations suggest that the NF‐κB/p65 signaling pathway was activated by the increase in GNA13 levels. Inhibiting the NF‐κB/p65 pathway with an inhibitor decreased GNA13‐induced migration, invasion and CXCL chemokine level increases, indicating the critical role of NF‐κB/p65 signaling in mediating the effects of GNA13 in CRC. Together, these results demonstrate a key role of GNA13 overexpression in CRC that contributes to malignant behavior in cancer cells, at least in part through stimulating angiogenesis and increasing the levels of the NF‐κB‐dependent chemokines CXCL1, CXCL2, and CXCL4.

HCC (hepatocellular carcinoma) is a major health threat for the Chinese population and has poor prognosis because of strong resistance to chemotherapy in patients. For instance, a considerable challenge for the treatment of HCC is sorafenib resistance. The aberrant glucose metabolism in cancer cells aerobic glycolysis is associated with resistance to chemotherapeutic agents. Drug-resistance cells and tumors were exposed to sorafenib to establish sorafenib-resistance cell lines and tumors. Western blotting and real-time PCR or IHC staining were used to analyze the level of CLCF1 in the sorafenib resistance cell lines or tumors. The aerobic glycolysis was analyzed by ECAR assay. The mechanism mediating the high expression of CLCF1 in sorafenib-resistant cells and its relationships with miR-130-5p was determined by bioinformatic analysis, dual luciferase reporter assays, real-time PCR, and western blotting. The in vivo effect was evaluated by xenografted with nude mice. The relation of CLCF1 and miR-30a-5p was determined in patients’ samples. In this study, we report the relationship between sorafenib resistance and increased glycolysis in HCC cells. We also show the vital role of CLCF1 in promoting glycolysis by activating PI3K/AKT signaling and its downstream genes, thus participating in glycolysis in sorafenib-resistant HCC cells. Furthermore, we also show that miR-30a-5p directly targets CLCF1 and that sorafenib-mediated suppression of miR-30a-5p results in the upregulation of CLCF1 in HCC cells resistant to sorafenib. We also found that when a cholesterol modified agomiR-30a-5p was delivered systemically to mice harboring sorafenib-resistant HCC tumors, tumor growth decreased significantly. There is an uncharacterized mechanism of biochemical resistance to hormone therapies orchestrated by the miR-30a-5p/CLCF1 axis to mediate sorafenib resistance and aerobic glycolysis in HCC. Therefore, this study indicates that targeting the miR-30a-5p/CLCF1 axis may hold promise for therapeutic intervention in HCC sorafenib resistance patients.

An increasing number of studies have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may serve an important role in tumor progression. Previous studies have reported that the lncRNA, colon cancer associated transcript 2 (CCAT2), was highly expressed in various tumors. However, the function of CCAT2 in hepatocellular carcinoma (HCC) has not yet been elucidated. The aim of the present study was to identify novel oncogene lncRNAs and investigate their physiological function and mechanism in HCC. Using reverse transcription-quantitative polymerase chain reaction, it was observed that CCAT2 was upregulated in HCC tissues and human HCC cell lines. Furthermore, the impacts of CCAT2 on cell proliferation, migration and apoptosis were analyzed using cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assay analysis respectively. The overexpression of CCAT2 using a synthesized vector significantly promoted cell migration and proliferation, and inhibited apoptosis of HCC cells in vitro. The suppression of CCAT2 expression resulted in opposing effects. To the best of our knowledge, the present study is the first to demonstrate that CCAT2 functions as a oncogene in HCC. Further investigation is required to clarify the molecular mechanisms of this lncRNA in HCC development.

Neuronal apoptosis is one of the major causes of poststroke neurological deficits. Inflammation during the acute phase of stroke results in nuclear translocation of NFB in affected cells in the infarct area. Macrophage migration inhibitory factor (MIF) promotes cardiomyocyte survival in mice following heart ischemia. However, the role of MIF during stroke remains limited. In this study, we showed that MIF expression is down-regulated by 0.75 ؎ 0.10-fold of the control in the infarct area in the mouse brains. Two functional cis-acing NFB response elements were identified in the human MIF promoter. Dual activation of hypoxia and NFB signaling resulted in significant reduction of MIF promoter activity to 0.86 ؎ 0.01-fold of the control. Furthermore, MIF reduced caspase-3 activation and protected neurons from oxidative stressand in vitro ischemia/reperfusion-induced apoptosis. Key Words: macrophage migration inhibitory factor ⅐ caspase-3 ⅐ nuclear factor B Ischemic stroke that results from disturbance of blood supply to the brain accounts for 80% of stroke cases and significantly causes poststroke neurological deficits and death (1). Among a number of mechanisms involved in stroke pathogenesis, activation of the inflammatory response and the apoptotic pathways have been shown to play pivotal roles in stroke progression (2-4).Ischemic stroke differentially affects brain regions and results in an ischemic core and penumbra. Neurons in the ischemic core are rarely salvageable due to their immediate necrosis. In contrast, neurons in the penumbra experience a relatively milder ischemic insult and undergo delayed cell death and are the targets for therapeutic intervention (4). In the penumbra, neurons can undergo both necrosis and apoptosis. Necrosis induced by glutamate diffusion from the necrotic core can be diminished by blocking a specific subtype of NMDA receptors (5). Most of the neurons in 1 These authors contributed equally to this work 2 Correspondence: Department of Psychiatry, The University of British Columbia, 2255 Westbrook Mall, Vancouver, BC V6T 1Z3, Canada. E-mail: weihong@mail.ubc.ca doi: 10.1096/fj.14-253625 This article includes supplemental data. Please visit http:// www.fasebj.org to obtain this information.Abbreviations: ChIP, chromatin immunoprecipitation; CRE, cyclic-AMP response element; E, embryonic day; EMSA, electrophoretic mobility shift assay; GSA, gel shift assay; HIF-1␣, hypoxia-inducible factor 1␣; HEK293, human embryonic kidney 293; HRE, hypoxia responsive element; IP, immunoprecipitation; MCA, middle cerebral artery; MCAl, middle cerebral artery ligation; MCAo, middle cerebral artery occlusion; MIF, macrophage migration inhibitory factor; mu-NFB, mutant nuclear factor B; NFB, nuclear factor B; OGD, oxygen-glucose deprivation; PFA, paraformaldehyde; rCCA, right common carotid artery; RLU, relative luciferase unit; rMCA, right middle cerebral artery; ROS, reactive oxygen species; tMCAl, transient distal middle cerebral artery ligation; TTC, 2,3,5-triphenyl-tetrazolium chloride; TU...