مقالات پذیرفته شده در سومین کنگره بین المللی زیست پزشکی
Regulatory roles of lncRNAs in cancers
Regulatory roles of lncRNAs in cancers
Maedeh Arabpour,1,*Sepideh Mehrpour Layeghi,2
1. Department of Medical Genetics, school of medicine, Tehran university of medical sciences, Tehran, Iran 2. Department of Medical Genetics, school of medicine, Tehran university of medical sciences, Tehran, Iran
Introduction: The human genome contains about 16000 lncRNA genes. lncRNAs have more than 200 bp length and constitute one class of non-coding RNAs. Most of the lncRNAs are located in the nucleus and some of them are located in the cytoplasm or in both cytoplasm and nucleus. They have distinct features from other regulatory ncRNAs, and also they have diverse regulatory roles in different cancers.
Transcriptional regulation:
I) RNA polymerase II and TFs recruitment:
lncRNAs may directly act on transcriptional complexes or alter chromatin structure or act as scaffold to recruit RNA polymerase II to bind to the promoter of specific genes.
lncRNAs can guide TFs to specific sites in the genome. Some lncRNA locuses overlap with the promoter of another gene, so (as a result) transcription of these lncRNAs can lead to the suppression of promoter of that gene.
II) Remodeling of chromatin structure:
lncRNAs can control the remodeling of chromatin structure. They can interact with RNA binding proteins (RBPs) to form ribonucleoprotein (RNP) complexes. EZH2 and PRC2 are chromatin remodeling enzymes that act as RNA binding proteins. They also regulate gene expression epigenetically by binding to lncRNAs. For example, ANRIL lncRNA recruit PRC1 and PRC2 into the INK4a/ARF locus and induce trimethylation of the histon and reduce transcription of the INK4a/ARF locus.
Post-transcriptional and translational regulation:
I) mRNA stability:
Various types of RBPs determine mRNA stability and mRNA level through interaction with lncRNAs. For example, LIN28 as an RBP interact with lncRNA MACC1-AS1 and stabilize MACC1 mRNA.
II) miRNA interaction:
Some lncRNAs bind to specific miRNAs and prevent miRNPs from binding to the target mRNAs. These lncRNAs that compete with miRNAs are called competing endogenous RNAs (ceRNAs).
III) Alternative splicing and RNA processing:
Some antisense lncRNAs can bind to the homologous mRNA at the splice site and block spliceosome assembly. on the other hand, some lncRNAs are required for proper localization of splicing factors. Some of them regulate alternative splicing of downstream genes by absorbing alternative splicing factors.
IV) Protein translation:
lncRNAs can also have an impact on translation. They can interact with rRNAs, ribosomes or eIFs (eukaryotic initiation factors) to regulate protein translation. For example, lncRNA-p21 recruit translational repressors and repress translation of Jun-B and β-catenin mRNAs.
Post-translational regulation:
I) Protein stability:
Proteins undergo some post-translational modifications such as acetylation, phosphorylation, ubiquitination that change their activity, stability and subcellular localization. lncRNAs can regulate protein stability through protein modifications. Also, some lncRNAs regulate protein stability via modulating protein localization. In addition, lncRNAs enhance or attenuate protein stability by binding to them.
Cancer invasion and metastasis:
lncRNAs are divided into two categories: EMT promoters (pro-EMT) and the EMT-suppressors (anti-EMT). One study demonstrated that 1853 lncRNAs have aberrant expression in the metastatic breast cancers. About ¼ of them are natural antisense transcripts (NATs). Also, some lncRNAs regulate expressions of invasion and metastasis related factors including cell adhesion molecules, extracellular matrix, and matrix metallo-proteinases. lncRNAs can decrease the strength of cancer cellular adhesion and increase cellular motility by downregulating E-cadherin. Also, lncRNAs can regulate tumor invasion and metastasis by changing the expressions of MMPs.
Upregulation of some lncRNAs is associated with cancer development processes such as proliferation, invasion and metastasis. Studies indicated that high expression of HOTAIR increased invasion of breast cancers.
Cancer immunity regulator:
lncRNAs paly different roles in innate and adaptive immunity regulation. Studies indicated that lncRNAs contribute in some phases of cancer immunity including infiltration into cancer tissues, antigen presentation, antigen release, immune activation, immune cell migration and destroying of cancer cells.
Methods: We studied and reviewed 21 articles about regulation of gene expression and invasion and metastasis by lncRNAs in different cancers and collected key points about the roles of lncRNAs in regulation of gene expression.
Results: As a result, study of 21 articles indicated that lncRNAs involved in many different cellular and molecular processes. Also, they have been known to play important roles in each stage of gene regulation including transcription, post-transcription, translation and post-translation (epigenetically or non-epigenetically).
Conclusion: A number of studies revealed that lncRNAs participate in many processes of cancer cells and act in many levels of gene expression and cancer progression.