Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.

A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response

The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

https://www.mdpi.com/2073-4409/8/9/1015/pdf

Long Non-Coding RNA in the Pathogenesis of Cancers.

Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.

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The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

The development and application of whole genome sequencing technology has greatly broadened our horizons on the capabilities of long non-coding RNAs (lncRNAs). LncRNAs are more than 200 nucleotides in length and lack protein-coding potential. Increasing evidence indicates that lncRNAs exert an irreplaceable role in tumor initiation, progression, as well as metastasis, and are novel molecular biomarkers for diagnosis and prognosis of cancer patients. Furthermore, lncRNAs and the pathways they influence might represent promising therapeutic targets for a number of tumors. Here, we discuss the recent advances in understanding of the specific regulatory mechanisms of lncRNAs. We focused on the signal, decoy, guide, and scaffold functions of lncRNAs at the epigenetic, transcription, and post-transcription levels in cancer cells. Additionally, we summarize the research strategies used to investigate the roles of lncRNAs in tumors, including lncRNAs screening, lncRNAs characteristic analyses, functional studies, and molecular mechanisms of lncRNAs. This review will provide a short but comprehensive description of the lncRNA functions in tumor development and progression, thus accelerating the clinical implementation of lncRNAs as tumor biomarkers and therapeutic targets.

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Long Non-Coding RNAs: The Regulatory Mechanisms, Research Strategies, and Future Directions in Cancers.

The pathogenesis and biomarkers of ovarian cancer (OC) remain not well-known in diagnosis, effective therapy, and prognostic assessment in OC personalized medicine. The novel identified lncRNA and mRNA biomarkers from gene co-expression modules associated with clinical traits provide new insight for effective treatment of ovarian cancer. Long non-coding RNAs (lncRNAs) are relevant to tumorigenesis via multiple mechanisms. This study aimed to investigate cancer-specific lncRNAs and mRNAs, and their related networks in OCs. This study comprehensively analyzed lncRNAs and mRNAs with associated competing endogenous RNA (ceRNA) network and lncRNA–RNA binding protein–mRNA network in the OC tissues in the Cancer Genome Atlas, including 2562 cancer-specific lncRNAs (n = 352 OC tissues) and 5000 mRNAs (n = 359 OC tissues). The weighted gene co-expression network analysis (WGCNA) was used to construct the co-expression gene modules and their relationship with clinical traits. The statistically significant difference of identified lncRNAs and mRNAs was confirmed with qRT-PCR in OC cells. An lncRNA-based co-expression module was significantly correlated with patient age at initial pathologic diagnosis, lymphatic invasion, tissues source site, and vascular invasion, and identified 16 lncRNAs (ACTA2-AS1, CARD8-AS1, HCP5, HHIP-AS1, HOTAIRM1, ITGB2-AS1, LINC00324, LINC00605, LINC01503, LINC01547, MIR31HG, MIR155HG, OTUD6B-AS1, PSMG3-AS1, SH3PXD2A-AS1, and ZBED5-AS1) that were significantly related to overall survival in OC patients. An mRNA-based co-expression module was significantly correlated with patient age at initial pathologic diagnosis, lymphatic invasion, tumor residual disease, and vascular invasion; and identified 21 hub-mRNA molecules and 11 mRNAs (FBN3, TCF7L1, SBK1, TRO, TUBB2B, PLCG1, KIAA1549, PHC1, DNMT3A, LAMA1, and C10orf82) that were closely linked with OC patients’ overall survival. Moreover, the prognostic model of five-gene signature (OTUD6B-AS1, PSMG3-AS1, ZBED5-AS1, SBK1, and PLCG1) was constructed to predict risk score in OC patients. Furthermore, starBase bioinformatics constructed the lncRNA–miRNA–mRNA and lncRNA–RNA binding protein-mRNA networks in OCs. These new findings showed that lncRNA-related networks in OCs are a useful resource for identification of biomarkers in OCs.

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Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can play a pivotal role in regulation of diverse cellular processes. In particular, lncRNAs can serve as master gene regulators at transcriptional and posttranscriptional levels, leading to tumorigenesis. In this review, we discuss latest developments in lncRNA-meditated gene expression at the post-transcriptional level, including gene splicing, mRNA stability, protein stability and nuclear trafficking.

Di-Xian Luo

Papers

Emerging roles of lncRNAs in the post-transcriptional regulation in cancer.