Integrated lncRNA function upon genomic and epigenomic regulation. Molecular cell Although some long noncoding (lnc)RNAs are known since the 1950s, the past 25 years have uncovered myriad lncRNAs with diverse sequences, structures, and functions. The advent of high-throughput and sensitive technologies has further uncovered the vast heterogeneity of lncRNA-interacting molecules and patterns of expressed lncRNAs. We propose a unifying functional theme for the expansive family of lncRNAs. At an elementary level, the genomic program of gene expression is elicited via canonical transcription and post-transcriptional mRNA assembly, turnover, and translation. Building upon this regulation, an epigenomic program refines the basic genomic control by modifying chromatin architecture as well as DNA and RNA chemistry. Superimposed over the genomic and epigenomic programs, lncRNAs create an additional regulatory dimension: by interacting with the proteins and nucleic acids that regulate gene expression in the nucleus and cytoplasm, lncRNAs help establish robust, nimble, and specific transcriptional and post-transcriptional control. We describe our present understanding of lncRNA-coordinated control of protein programs and cell fate and discuss challenges and opportunities as we embark on the next 25 years of lncRNA discovery. 10.1016/j.molcel.2022.05.027

Review: RNA-based diagnostic markers discovery and therapeutic targets development in cancer. Pharmacology & therapeutics The present review aimed to outline different types of RNAs in cancer diagnostics and treatment, and to provide novel insights into their clinical applications. RNAs, including mRNA, long non-coding (lnc)RNA, circular (circ)RNA and micro (mi)RNA, are now increasingly utilized in the diagnosis and treatment of various cancers. Each aforementioned type of RNA possess their own unique characteristics and could be aberrantly expressed as diagnostic markers or therapeutic targets in different cancers. In addition to mRNAs, which have become a promising alternative in cancer diagnostics and therapy, the uses of lncRNA, circRNA and miRNA in predictive tumor diagnostics and therapy has rapidly increased in recent years. In the present review, the mechanisms of mRNA, lncRNA, circRNA and miRNA in regulating and participating in the development of different cancers were determined, and their potential capacity in cancer diagnostics and therapy were investigated. In addition, the present review analyzed the assoaciations between different RNAs and their subsequent potential in cancer prediction and treatment. 10.1016/j.pharmthera.2022.108123

Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer. Journal of experimental & clinical cancer research : CR BACKGROUND:Lung cancer is the most common and deadliest cancer worldwide, and approximately 90% of all lung cancer deaths are caused by tumor metastasis. Tumor-derived exosomes could potentially promote tumor metastasis through the delivery of metastasis-related molecules. However, the function and underlying mechanism of exosomal long noncoding RNA (lncRNA) in lung cancer metastasis remain largely unclear. METHODS:Cell exosomes were purified from conditioned media by differential ultracentrifugation and observed using transmission electron microscopy, and the size distributions were determined by nanoparticle tracking analysis. Exosomal lncRNA sequencing (lncRNA-seq) was used to identify long noncoding RNAs. Cell migration and invasion were determined by wound-healing assays, two-chamber transwell invasion assays and cell mobility tracking. Mice orthotopically and subcutaneously xenografted with human cancer cells were used to evaluate tumor metastasis in vivo. Western blot, qRT‒PCR, RNA-seq, and dual-luciferase reporter assays were performed to investigate the potential mechanism. The level of exosomal lncRNA in plasma was examined by qRT‒PCR. MS2-tagged RNA affinity purification (MS2-TRAP) assays were performed to verify lncRNA-bound miRNAs. RESULTS:Exosomes derived from highly metastatic lung cancer cells promoted the migration and invasion of lung cancer cells with low metastatic potential. Using lncRNA-seq, we found that a novel lncRNA, lnc-MLETA1, was upregulated in highly metastatic cells and their secreted exosomes. Overexpression of lnc-MLETA1 augmented cell migration and invasion of lung cancer. Conversely, knockdown of lnc-MLETA1 attenuated the motility and metastasis of lung cancer cells. Interestingly, exosome-transmitted lnc-MLETA1 promoted cell motility and metastasis of lung cancer. Reciprocally, targeting lnc-MLETA1 with an LNA suppressed exosome-induced lung cancer cell motility. Mechanistically, lnc-MLETA1 regulated the expression of EGFR and IGF1R by sponging miR-186-5p and miR-497-5p to facilitate cell motility. The clinical datasets revealed that lnc-MLETA1 is upregulated in tumor tissues and predicts survival in lung cancer patients. Importantly, the levels of exosomal lnc-MLETA1 in plasma were positively correlated with metastasis in lung cancer patients. CONCLUSIONS:This study identifies lnc-MLETA1 as a critical exosomal lncRNA that mediates crosstalk in lung cancer cells to promote cancer metastasis and may serve as a prognostic biomarker and potential therapeutic target for lung cancer diagnosis and treatment. 10.1186/s13046-023-02859-y

lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5. Molecular therapy : the journal of the American Society of Gene Therapy Cisplatin resistance is a major therapeutic challenge in advanced head and neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the key signaling pathway for cisplatin resistance in HNSCC cells. Vomeronasal type-1 receptor 5 (VN1R5) was identified as a cisplatin resistance-related protein and was highly expressed in cisplatin-resistant HNSCC cells and tissues. The long noncoding RNA (lncRNA) lnc-POP1-1 was confirmed to be a downstream target induced by VN1R5. VN1R5 transcriptionally regulated lnc-POP1-1 expression by activating the specificity protein 1 (Sp1) transcription factor via the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. VN1R5 promoted cisplatin resistance in HNSCC cells in a lnc-POP1-1-dependent manner. Mechanistically, lnc-POP1-1 bound to the minichromosome maintenance deficient 5 (MCM5) protein directly and decelerated MCM5 degradation by inhibiting ubiquitination of the MCM5 protein, which facilitated the repair of DNA damage caused by cisplatin. In summary, we identified the cisplatin resistance-related protein VN1R5 and its downstream target lnc-POP1-1. Upon upregulation by VN1R5, lnc-POP1-1 promotes DNA repair in HNSCC cells through interaction with MCM5 and deceleration of its degradation. 10.1016/j.ymthe.2021.06.006