LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C.
Ducoli Luca,Agrawal Saumya,Sibler Eliane,Kouno Tsukasa,Tacconi Carlotta,Hon Chung-Chao,Berger Simone D,Müllhaupt Daniela,He Yuliang,Kim Jihye,D'Addio Marco,Dieterich Lothar C,Carninci Piero,de Hoon Michiel J L,Shin Jay W,Detmar Michael
Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.
m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression.
Cell death & disease
Gefitinib has been widely applied for the treatment of lung adenocarcinoma (LUAD). However, the long-term application of gefitinib usually leads to acquired drug resistance in tumour patients, resulting in clinical treatment failure. Small nucleolar host gene 17 (SNHG17) has been shown to play a regulatory role in LUAD progression. Nevertheless, the role of SNHG17 in LUAD gefitinib resistance remains elusive. The expression pattern of SNHG17 was examined in tissues and cell lines of gefitinib-sensitive and gefitinib-resistant LUAD, respectively. Gain- and loss-of-function experiments were employed to assess the biological functions of SNHG17 in cell proliferation and apoptosis, as well as aggressive phenotypes of LUAD cells. MeRIP-qPCR and colorimetric quantificational analysis were performed to detect m6A modifications and contents. Fluorescence in situ hybridisation (FISH) and subcellular fractionation analysis were used to reveal the distribution of SNHG17. RIP and ChIP assays were performed to further validate the SNHG17/EZH2/LATS2 regulatory axis. A xenograft tumour growth assay was conducted to evaluate the role of SNHG17 in LUAD gefitinib resistance in vivo. SNHG17 was upregulated in gefitinib-resistant LUAD tissues and cell lines. Functional assays showed that SNHG17 aggravated the malignant phenotypes of gefitinib-resistant LUAD cells. In addition, METTL3-mediated N-methyladenosine modification could induce the upregulation of SNHG17by stabilising its RNA transcript. Mechanistically, SNHG17 epigenetically repressed the expression of LATS2 by recruiting EZH2 to the promoter region of LATS2. The regulatory role of the SNHG17/EZH2/LATS2 axis in LUAD gefitinib resistance was further supported in vivo. Collectively, our findings suggested that SNHG17 induced by METTL3 could promote LUAD gefitinib resistance by epigenetically repressing LATS2 expression.
Cancer-associated fibroblasts-derived extracellular vesicles carrying lncRNA SNHG3 facilitate colorectal cancer cell proliferation via the miR-34b-5p/HuR/HOXC6 axis.
Cell death discovery
Cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) can mediate tumorigenesis. Long noncoding RNA (LncRNA) SNHG3 is implicated in colorectal cancer (CRC) progression. The current study sought to clarify the role of CAFs-EVs carrying SNHG3 in CRC cell proliferation. Firstly, CAFs and normal fibroblasts (NFs) were cultured and identified, followed by isolation and characterization of CAFs-EVs and NFs-EVs. CRC cells were cultured with CAFs-EVs or CAFs-EVs overexpressing SNHG3. The effects of SNHG3 on CRC cell proliferation was evaluated using CCK-8, colony formation, and EdU staining assays. The binding relationships among SNHG3, miR-34b-5p, and HuR were validated, in addition to analyzing the binding between HuR and HOXC6. Lastly, xenograft tumor model was established to verify the role of CAFs-EVs carrying SNHG3 in vivo. SNHG3 was highly expressed in CRC cells and CAFs-EVs, whereas CAFs-EVs facilitated CRC cell proliferation. Mechanically, CAFs-EVs carried SNHG3 into CRC cells to upregulate HuR expression by competitively binding to miR-34b-5p, promote the binding of HuR and HOXC6, and enhance HOXC6 transcription. miR-34b-5p over-expression or HOXC6 silencing annulled the effect of CAFs-EVs. SNHG3 carried by CAFs-EVs facilitated CRC proliferation via the miR-34b-5p/HuR/HOXC6 axis in vivo. Collectively, our findings indicated that CAFs-EVs carried SNHG3 into CRC cells to upregulate HuR expression by sponging miR-34b-5p and finally enhance HOXC6 transcription, thereby facilitating CRC cell proliferation.
Exosome-Transported circRNA_0000253 Competitively Adsorbs MicroRNA-141-5p and Increases IDD.
Song Jian,Chen Zhen-Hao,Zheng Chao-Jun,Song Ke-Han,Xu Guang-Yu,Xu Shun,Zou Fei,Ma Xiao-Sheng,Wang Hong-Li,Jiang Jian-Yuan
Molecular therapy. Nucleic acids
The pathogenesis of intervertebral disc degeneration (IDD) is complex, and a better understanding of IDD pathogenesis may provide a better method for the treatment of IDD. Exosomes are 40-100 nm nanosized vesicles that are released from many cell types into the extracellular space. We speculated that exosome-transported circular RNAs (circRNAs) could regulate IDD. Exosomes from different degenerative grades were isolated and added to nucleus pulposus cells (NPCs), and indicators of proliferation and apoptosis were detected. Based on the previous circRNA microarray results, the top 10 circRNAs were selected. PCR was performed to determine the circRNA with the maximum upregulation. Competing endogenous RNA (ceRNA) analysis was carried out, and the sponged microRNA (miRNA) was identified. Further functional verification of the selected circRNA was carried out in vivo and in vitro. NPCs of different degenerative grades secreted exosomes, which could regulate IDD. circRNA_0000253 was selected as having the maximum upregulation in degenerative NPC exosomes. ceRNA analysis showed that circRNA_0000253 could adsorb miRNA-141-5p to downregulate SIRT1. circRNA_0000253 was confirmed to increase IDD by adsorbing miRNA-141-5p and downregulating SIRT1 in vivo and in vitro. Exosomal circRNA_0000253 owns the maximum upregulation in degenerative NPC exosomes and could promote IDD by adsorbing miRNA-141-5p and downregulating SIRT1.
Exosome-transmitted miRNA-335-5p promotes colorectal cancer invasion and metastasis by facilitating EMT via targeting RASA1.
Sun Xuecheng,Lin Feiyan,Sun Wenjing,Zhu Weijian,Fang Daoquan,Luo Lifang,Li Shuhan,Zhang Wenqi,Jiang Lei
Molecular therapy. Nucleic acids
Exosomal microRNA (miRNA) secretion has been characterized as a vital factor in intercellular communication among cancer cells. However, little is known about cancer-secreted miRNAs specifically involved in metastasis of colorectal cancer (CRC). Here, we found that exosomes derived from metastatic CRC cell line SW620 promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells. The profiling of exosome miRNAs revealed that microRNA (miR)-335-5p was highly expressed in exosomes from metastatic SW620 cells compared to those derived from primary SW480 cells. miR-335-5p was transmitted from metastatic SW620 cells to CRC cells via exosomes and promoted migration, invasion, and EMT of CRC cells. Moreover, exosome-transmitted miRNA-335-5p promotes CRC cell invasion and metastasis by facilitating EMT via targeting RAS p21 protein activator 1 (). Overexpression of abolished the promotive effects of exosomal miR-335-5p on CRC cell migration, invasion, and EMT. Collectively, our data revealed that exosomal miR-335-5p derived from metastatic CRC cells promotes CRC cell invasion and metastasis by facilitating EMT via targeting , which may serve as a potential therapeutic target for CRC metastasis.
Promotion of tumor progression by exosome transmission of circular RNA circSKA3.
Du William W,Li Xiangmin,Ma Jian,Fang Ling,Wu Nan,Li Feiya,Dhaliwal Preet,Yang Weining,Yee Albert J,Yang Burton B
Molecular therapy. Nucleic acids
We performed and experiments to investigate the role of the circular RNA circSKA3 in tumor development. We examined the effects of circSKA3 on mediating breast cancer metastasis. , we found that the circular RNA circSKA3 was transferred between breast cancer cells, which were decreased by inhibiting exosome secretion. , circSKA3-containing exosomes potentiated tumor development and invasion that were inhibited by blocking exosome transmission. The ascites isolated from tumor-bearing mice or breast cancer patients showed high levels of circSKA3 and integrin β1. Single-cell culture and single-cell PCR showed that circSKA3 was heterogeneously expressed, the cells expressing higher levels of circSKA3 had a higher potential to form large colonies. This property was similar to c-myc, but circSKA3 expression had no correlation with c-myc levels. The effects of circSKA3 on cell migration and invasion appeared to predominate c-myc functions. By releasing circSKA3-containing exosomes to cancer cells expressing lower levels of circSKA3, the large colonies could regulate the activities of small colonies, enhancing the tumor-forming capacity of the entire population. Thus, we provide evidence that the transmission of circular RNAs in tumor-derived exosomes may allow for the maintenance of advantageous invasive sub-clones in breast cancer.
Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA.
Qu Le,Ding Jin,Chen Cheng,Wu Zhen-Jie,Liu Bing,Gao Yi,Chen Wei,Liu Feng,Sun Wen,Li Xiao-Feng,Wang Xue,Wang Yue,Xu Zhen-Yu,Gao Li,Yang Qing,Xu Bin,Li Yao-Ming,Fang Zi-Yu,Xu Zhi-Peng,Bao Yi,Wu Deng-Shuang,Miao Xiong,Sun Hai-Yang,Sun Ying-Hao,Wang Hong-Yang,Wang Lin-Hui
Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.