The role of alternative splicing in lung cancer.

Aberrant alternative splicing (AS) events are frequently observed in lung cancer, which can be attributed to aberrant gene AS, alterations in splicing regulatory factors, or changes in splicing regulatory mechanisms. Consequently, the dysregulation of alternative RNA splicing is the fundamental cause of lung cancer. In this review, we have summarized the pivotal role of AS in the development, progression, invasion, metastasis, angiogenesis, and drug resistance of lung cancer. Ultimately, this review emphasizes the potential of AS as biomarkers in lung cancer prognosis and diagnosis, and introduces some applications of AS isoform in the treatment of lung cancer. The comprehension of the AS may provide a glimmer of hope for the eradication of lung cancer.

Hydroxysafflor Yellow A Alleviates Ischemic Stroke in Rats via HIF-1[Formula: see text], BNIP3, and Notch1-Mediated Inhibition of Autophagy.

Stroke has become a major cause of death and disability worldwide. The cellular recycling pathway autophagy has been implicated in ischemia-induced neuronal changes, but whether autophagy plays a beneficial or detrimental role is controversial. Hydroxysafflor Yellow A (HSYA), a popular herbal medicine, is an extract of Carthamus tinctorius and is used to treat ischemic stroke (IS) in China. HSYA has been shown to prevent cardiovascular and cerebral ischemia/reperfusion injury in animal models. However, the specific active ingredients and molecular mechanisms of HSYA in IS remain unclear. Here, we investigated the effect of HSYA treatment on autophagy in a rat model of IS. IS was induced in rats by middle cerebral artery occlusion. Rats were treated once daily for 3 days with saline, HYSA, or the neuroprotective agent Edaravone. Neurobehavioral testing was performed on days 1, 2, and 3 post-surgery. Brains were removed on day 3 post-surgery for histological evaluation of infarct area, morphology, and for qRT-PCR and western blot analysis of the expression of the autophagy factor LC3 and the signaling molecules HIF-1[Formula: see text], BNIP3, and Notch1. Molecular docking studies were performed in silico to predict potential interactions between HSYA and LC3, HIF-1[Formula: see text], BNIP3, and Notch1 proteins. The result showed that HSYA treatment markedly alleviated IS-induced neurobehavioral deficits and reduced brain infarct area and tissue damage. HSYA also significantly reduced hippocampal expression levels of LC3, HIF-1[Formula: see text], BNIP3, and Notch1. The beneficial effect of HSYA was generally superior to that of Edaravone. Molecular modeling suggested that HSYA may bind strongly to HIF-1[Formula: see text], BNIP3, and Notch1 but weakly to LC3. In conclusion, HSYA inhibits post-IS autophagy induction in the brain, possibly by suppressing HIF-1[Formula: see text], BNIP3 and Notch1. HSYA may have utility as a post-IS neuroprotective agent.

Elevated expression of the rhythm gene NFIL3 promotes the progression of TNBC by activating NF-κB signaling through suppression of NFKBIA transcription.

BACKGROUND: Epidemiological studies have confirmed that abnormal circadian rhythms are associated with tumorigenesis in breast cancer. However, few studies have investigated the pathological roles of rhythm genes in breast cancer progression. In this study, we aimed to evaluate the aberrant expression of 32 rhythm genes in breast cancer and detect the pathological roles and molecular mechanisms of the altered rhythm gene in regulating the progression of triple negative breast cancer (TNBC). METHODS: The aberrant expression of rhythm genes in breast cancer was screened by searching the GEPIA database and validated by using qRT-PCR and immunohistochemistry staining. Bioinformatics analysis combined with luciferase reporter experiment and chromatinimmunopercitation (ChIP) were used to investigate the molecular mechanism about aberrant expression of identified rhythm gene in breast cancer. The pathological roles of identified rhythm gene in TNBC progression was evaluated by colony formation assay, wound healing experiment, transwell assay, subcutaneous tumor formation and the mouse tail vein injection model through gain-of-function and loss-of-function strategies respectively. mRNA array, bioinformatics analysis, luciferase reporter experiment, ChIP and immunoflurescence assay were employed to investigate the key molecules and signaling pathways by which the identified rhythm gene regulating TNBC progression. RESULTS: We identified that nuclear factor interleukin 3 regulated (NFIL3) expression is significantly altered in TNBC compared with both normal breast tissues and other subtypes of breast cancer. We found that NFIL3 inhibits its own transcription, and thus, downregulated NFIL3 mRNA indicates high expression of NFIL3 protein in breast cancer. We demonstrated that NFIL3 promotes the proliferation and metastasis of TNBC cells in vitro and in vivo, and higher expression of NFIL3 is associated with poor prognosis of patients with TNBC. We further demonstrated that NFIL3 enhances the activity of NF-κB signaling. Mechanistically, we revealed that NFIL3 directly suppresses the transcription of NFKBIA, which blocks the activation of NF-κB and inhibits the progression of TNBC cells in vitro and in vivo. Moreover, we showed that enhancing NF-κB activity by repressing NFKBIA largely mimics the oncogenic effect of NFIL3 in TNBC, and anti-inflammatory strategies targeting NF-κB activity block the oncogenic roles of NFIL3 in TNBC. CONCLUSION: NFIL3 promotes the progression of TNBC by suppressing NFKBIA transcription and then enhancing NF-κB signaling-mediated cancer-associated inflammation. This study may provide a new target for TNBC prevention and therapy.

The RNA-Binding Motif Protein Family in Cancer: Friend or Foe?

The RNA-binding motif (RBM) proteins are a class of RNA-binding proteins named, containing RNA-recognition motifs (RRMs), RNA-binding domains, and ribonucleoprotein motifs. RBM proteins are involved in RNA metabolism, including splicing, transport, translation, and stability. Many studies have found that aberrant expression and dysregulated function of RBM proteins family members are closely related to the occurrence and development of cancers. This review summarizes the role of RBM proteins family genes in cancers, including their roles in cancer occurrence and cell proliferation, migration, and apoptosis. It is essential to understand the mechanisms of these proteins in tumorigenesis and development, and to identify new therapeutic targets and prognostic markers.