Search

e14711 Background: Mitochondria-nuclear crosstalk is a bidirectional pathway of communication between mitochondria and nucleus that influences many cellular and organismal activities. This crosstalk can regulate several oncogenic pathways involved in tumorigenesis. MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), a nucleus-encoded lncRNA, dysregulated in multiple human malignancies is recently found to drive mitochondria dysfunction in Mitochondria-nuclear crosstalk. Methods: RNA sequencing, “RNA reverse transcription-associated trap sequencing” (RAT-seq), RNA immunoprecipitation(RIP), fluorescence in situ hybridization (FISH), were performed to detect the position of the MALAT1, and its interaction protein and DNAs in HepG2 cell line. After silencing MALAT1 by shRNAs, Seahorse, ATP production, lysotracker staining, Western blot, and electronic microscope were used to measure metabolism, ROS amount, mitophagy, apoptosis and mitochondrial morphology of the silencing cell lines. Results: By combining mitochondrial RNA-Seq with FISH, it is surprised to discover that MALAT1 was enriched in the mitochondria of HepG2 cells. Using RAT-seq approach, MALAT1 was found to utilized it 3’-fragment to interact with multiple loci of mitochondrial DNA( D-loop, COX2, ND3, and CYTB ). The RIP and affinity RNA pulldown assays suggested that the RNA-binding protein HuR mediated the transportation of MALAT1 to the mitochondria. Also, mitochondria transmembrane protein mitochondrial carrier 2(MTCH2) is found to interacted MALAT1, suggesting that MALAT1 may through the MTCH2 to get into the inside of the mitochondria. Knockdown of MALAT1 induced multiple abnormalities in mitochondrial functions, including low OXPHOS, low ATP production, reduced mitophagy, declined mtDNA copy number, and activation of the mitochondrial apoptosis pathway. Conclusions: Together, this study greatly expands our knowledge of the nucleus-encoded lncRNA MALAT1 driving the mitochondria dysfunction. Our study establishes MALAT1 as a regulator through interacting with MT-DNA, HuR, MTCH2 protein, revealing a new regulatory mechanism of mitochondria. Many novel nucleus-encoded RNAs existing in mitochondria were identified at the first time, suggesting novel biological functions of lncRNAs, laying the foundation for further clarifying their roles.

e20573Background: Small cell lung cancer (SCLC) is ranked as the most devastative type of human lung malignancies. We have found Friend leukemia virus integration 1 (FLI1) circular RNA (cFLI1) is a...

e20015 Background: Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies, mostly due to their rapid and disseminated growth pattern. However, the molecular factors that drive rapid progression of SCLC remain unclear. Friend leukemia virus integration 1( FLI1),an Ets transcription factor family member, was identified as a proto-oncogene in some tumors via regulation of different target genes. In this study, we explored the potential role of FLI1 in SCLC. Methods: FLI1 protein expression was evaluated by immunohistochemistry in 67 primary SCLC, 20 non-small cell lung cancer (NSCLC) and 20 normal lung specimens. Correlation between FLI1 expression and clinical characteristics was evaluated with the logistic regression. Cell proliferation, cell cycle, apoptosis, colony formation assays in vitro and tumorigenesis assay in vivo were used to explore the function of FLI1 in SCLC cells. Use the miR-17-92 promoter/luciferase reporter assay to identify the regulation of FLI1 on miR-17-92 cluster promoter. Results: Immunohistochemical staining data showed that FLI1 was significantly upregulated in SCLC tissues compared to that in NSCLC and normal lung tissues ( p< 0.01). The expression score of FLI1 oncoprotein was associated with the extensive stage of SCLC and the overexpressed Ki67. Knockdown of FLI1 promoted apoptosis and induced repression of cell proliferation, tumor colony formation and in vivo tumorigenicity in highly aggressive SCLC cell lines. Importantly, we discovered that FLI1 promoted tumorigenesis by activating the miR-17-92 cluster family transcritption. Conclusions: This study uncovers that FLI1 is an important driving factor that promotes tumor growth in SCLC through the miR-17-92 pathway, and may serve as an attractive target for therapeutic intervention of SCLC.

e15272 Background: Interferon alpha (IFNa) has been used to treat a variety of tumors, but its efficacy in the treatment of solid tumors has been significantly hindered by relatively low antitumor ...

7018 Background: RUNX1, a master regulator of hematopoiesis, is the most commonly perturbed target of chromosomal abnormalities in hematopoietic malignancies. About 30%–40% of acute myeloid leukemi...