Probes for LONG

Long non-coding RNA RAD51 antisense RNA 1 (RAD51-AS1, also known as TODRA) has been shown to be down-regulated by E2F1, a key cell cycle and apoptosis regulator, in breast cancer. Little is known regarding the role of RAD51-AS1 in disease. Here, we investigate the role of RAD51-AS1 in epithelial ovarian cancer (EOC). Using luciferase reporter and chromatin immunoprecipitation experiments, we verified RAD51-AS1 as a target of E2F1 under negative regulation in EOC. We then examined RAD51-AS1 expression in EOC samples using in situ hybridization (ISH). RAD51-AS1 was localized to the nucleus and found to be a critical marker for clinical features that significantly correlated with poor survival in EOC patients. RAD51-AS1 was also an independent prognostic factor for EOC. Overexpression of RAD51-AS1promoted EOC cell proliferation, while silencing of RAD51-AS1 inhibited EOC cell proliferation, delayed cell cycle progression and promoted apoptosis in vitro and in vivo. RAD51-AS1 may participate in carcinogenesis via regulation of p53 and p53-related genes. Our study highlights the role of RAD51-AS1 as a prognostic marker of EOC. Based on its regulation of the tumor suppressor p53, RAD51-AS1-based therapy may represent a viable therapeutic option for EOC in the near future.

Corylin, a biologically active agent extracted from Psoralea corylifolia L. (Fabaceae), promotes bone differentiation and inhibits inflammation. Currently, few reports have addressed the biological functions that are regulated by corylin, and to date, no studies have investigated its antitumor activity. In this study, we used cell functional assays to analyze the antitumor activity of corylin in hepatocellular carcinoma (HCC). Furthermore, whole-transcriptome assays were performed to identify the downstream genes that were regulated by corylin, and gain-of-function and loss-of-function experiments were conducted to examine the regulatory roles of the above genes. We found that corylinsignificantly inhibited the proliferation, migration, and invasion of HCC cells and increased the toxic effects of chemotherapeutic agents against HCC cells. These properties were due to the induction of a long noncoding RNA, RAD51-AS1, which bound to RAD51 mRNA, thereby inhibiting RAD51 protein expression, thus inhibiting the DNA damage repair ability of HCC cells. Animal experiments also showed that a combination treatment with corylin significantly increased the inhibitory effects of the chemotherapeutic agent etoposide (VP16) on tumor growth. These findings indicate that corylin has strong potential as an adjuvant drug in HCC treatment and that corylin can strengthen the therapeutic efficacy of chemotherapy and radiotherapy.

Abstract

RATIONALE:

Given the paucity of effective treatments for Idiopathic Pulmonary Fibrosis (IPF), new insights into the deleterious mechanisms controlling lung fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Transforming growth factor β (TGF-β) is the main pro-fibrotic factor, but its inhibition is associated with severe side effects due to its pleiotropic role.

OBJECTIVES:

We hypothesized that downstream non-coding effectors of TGF-β in fibroblasts may represent new effective therapeutic targets whose modulation may be well-tolerated.

METHODS:

We investigated the whole non-coding fraction of TGF-β-stimulated lung fibroblast transcriptome to identify new genomic determinants of lung fibroblast differentiation into myofibroblast. Differential expression of the long non-coding RNA DNM3OS and its associated miRNAs was validated in a murine model of pulmonary fibrosis and in IPF tissue samples. Distinct and complementary antisense oligonucleotide-based strategies aiming at interfering with DNM3OS were used to elucidate the role of DNM3OS and its associated miRNAs in IPF pathogenesis.

MEASUREMENTS AND MAIN RESULTS:

We identified DNM3OS as a fibroblast-specific critical downstream effector of TGF-β-induced lung myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to three distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way. In vivo, we showed that interfering with DNM3OS function not only prevents lung fibrosis but also improves established pulmonary fibrosis.

CONCLUSION:

Pharmacological approaches aiming at interfering with DNM3OS may represent new effective therapeutic strategies in IPF.