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LncRNAs in Translation: Comparison
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Please note this is a comparison between Version 1 by Didem Karakas and Version 2 by Vicky Zhou.

Long non-coding RNAs (lncRNAs), a group of non-protein coding RNAs with lengths of more than 200 nucleotides, exert their effects by binding to DNA, mRNA, microRNA, and proteins and regulate gene expression at the transcriptional, post-transcriptional, translational, and post-translational levels. Depending on cellular location, lncRNAs are involved in a wide range of cellular functions, including chromatin modification, transcriptional activation, transcriptional interference, scaffolding and regulation of translational machinery.

  • non-coding RNAs
  • long non-coding RNAs
  • ncRNAs
  • translation
  • cancer

1. Introduction

The majority of the mammalian genome consists of non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), and small ncRNAs such as microRNAs (miRNAs), small nuclear RNAs (snRNA) and circular RNAs (circRNAs), while only a small portion (~1.5%) of it is comprised of protein-coding mRNAs [1].

lncRNA transcripts, which are a group of ncRNAs longer than 200 nucleotides, account for the majority (98%) of the ncRNAs. Currently, about 30,000 different lncRNA transcripts are belived to exist in the human genome [2]. Since most lncRNAs are transcribed by RNA polymerase II (RNAP II), they share some similarities with mRNAs, such as poly-adenylation and the presence of 5′-cap structure. Just like mRNAs, lncRNAs form secondary structures, undergo post-transcriptional processing (i.e., 5’-cap structure, polyadenylation) and splicing [3], present in the nucleus, cytosol, and mitochondria [4], and can have tissue-specific expression patterns.

lncRNAs have been shown to play a pivotal role in a wide range of cellular processes such as gene expression, translation regulation, splicing, chromosomal organization and X chromosome silencing [5][6][7]. Besides, specific lncRNAs are known to be dysregulated in various diseases, such as cancer, neurological diseases, and diabetes [8]. Considering their extensive roles in both health and disease, a better understanding of the functions of lncRNAs in the regulation of cellular events is needed.

2. LncRNAs Involved in Signaling Pathways Regulating Protein Translation

The PI3K/AKT/mTOR is one of the major signaling pathways known to regulate vital cellular processes including cell proliferation, growth, survival, metabolism and protein translation. The role of PI3K/AKT/mTOR and MAPK pathways in the regulation of translational machinery are well documented and they are frequently overactivated in most types of cancer [9]. Both pathways involve the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery in homeostasis, their dysregulation results in aberrant translation which is often detected in diabetes, neurological disorders, and cancer [10][11][12][13]. The MAPK family consists of a serine/threonine kinases, that includes ERKs, JNKs and p38/SAPKs [14]. Especially the MAPK/ERK signaling pathway is amongst the most well-studied, signaling and dysregulating one-third of all human cancers [15].

PI3K/AKT/mTOR pathway regulates cell growth and proliferation by phosphorylating two downstream targets which are 4E-BP1 and ribosomal protein S6 kinase (S6Ks). mTOR complex I (mTORC1) controls translational activation by phosphorylating eIF4E inhibitor, 4E-BP1, which releases eIF4E to interact with initiation complex (eIF4F) [16]. S6K protein requires sequential phosphorylations at multiple serine/threonine sites and mTORC1 regulates its activation by phosphorylation. Once S6K is activated, it phosphorylates and activates eIF4B, which increases the recruitment of eIF4B to eEF4A and enhances translation [17]. Besides, S6K and mTORC1 signaling pathways can phosphorylate EF2-Kinase (EF2K) and decrease its sensitivity to Ca/Calmoduline for its activation [18]. Similarly, eEF2K activity is negatively regulated by MAPKs and their downstream effectors, reducing phosphorylation of eEF2, leading to increased translation by promoting peptide elongation phase of protein systhesis [19][20]. Considering the significant regulatory roles of PI3K/AKT/mTOR and MAPK signaling pathways in protein translation, regulation of their activity by lncRNAs indicate that the lncRNAs are involved in controlling protein translation through regulation of these key signaling pathways. For instance, lncRNA UASR1 promotes cell growth and migration of breast cancer cells by regulating AKT/mTOR pathway [21]. In these cells, active mediators of this pathway such as p-AKT, p-TSC2, p-4EBP1 and p-p70S6K are increased by overexpression of UASR1. Thus, UASR1 plays an oncogenic role in breast cancer cells through activation of the AKT/mTOR signaling pathway. Another lncRNA H19 is overexpressed in colorectal cancer tissues and it promotes the activity of PI3K/AKT pathway by acting as a ceRNA and regulating some components of this pathway. H19 regulates various cancer-related mRNAs (such as (AKT3, CSF1, MET, COL1A1) by competitively sponging various miRNAs. Knockdown of H19 reduced protein level of MET, ZEB1, and COL1A1 in vitro [22]. The other study showed that H19 inhibits mTORC1-mediated 4E-BP1 phosphorylation, but it does not affect the activation of S6K1 [23]. lncRNA CASC9 has been shown to suppress apoptosis and promote aggressiveness of oral squamous cell carcinoma cells by activating the AKT/mTOR pathway [24].

In contrast, some lncRNAs might negatively regulate the abovementioned pathways. For instance, lncRNA FER1L4 suppresses cell proliferation and metastasis through downregulating the expressions of PI3K and AKT in lung cancer cells [25]. Overall, lncRNAs can regulate signaling pathways involved in translational control that is an integral part of these survival adaptive pathways in normal and cancer cells. Some of these regulatory lncRNAs and their functions on signaling pathways are summarized in Table 1Table 2.

Table 12. lncRNAs in the regulation of signaling pathways and their roles in various cancers [26][27][28][29][30][31][32][33][34][35].

LncRNA Target Function Reference
MALAT1 mTOR signaling Improves glucose metabolism to contribute aggressiveness in hepatocellular carcinoma cells [26]
HOXB-AS3 PI3K/AKT signaling Increases proliferation, migration, and invasion of lung cancer cells [27]
AK023391 PI3K/AKT signaling Promotes tumorigenesis and invasion of gastric cancer [28]
LOC101928316 PI3K/AKT/mTOR signaling Inhibits cell proliferation, invasion and tumorigenesis of gastric cancer cells [29]
UCA1 PI3K/AKT signaling Promotes cell proliferation and inhibits apoptosis in retinoblastoma cells [30]
OECC PI3K/AKT/mTOR signaling Increases proliferation, migration and invasion of lung cancer cells [31]
GAS5 PTEN/PI3K/AKT signaling Suppresses proliferation and invasion of osteosarcoma cells and promotes PTEN expression by sponging miR-23a-3p [32]
LINC01503 MAPK/ERK signaling Increases proliferation and tumor forming-ability of hepatocellular carcinoma cells [33]
ST8SIA6-AS1 p38 MAPK signaling Promotes proliferation, migration and invasion of breast cancer cells [34]
FENDRR p38 MAPK signaling Inhibits cell proliferation and induces apoptosis in hepatocellular carcinoma cells [35]

3. Conclusions

Advances in high throughput technologies resulted in the identification of a large number of lncRNAs. Although thousands of lncRNAs have been identified in the genomes of higher eukaryotes, our understanding of the mechanisms by which lncRNAs exert their precise function for most of them remains unknown. Elucidating the function of these lncRNAs is expected to provide deeper insight into the molecular mechanisms regarding their function in human diseases, including cancer and the interaction of lncRNAs with other molecules may help to design novel strategies. Accumulating evidence indicates that lncRNAs display pivotal roles in the regulation of almost every cellular process by binding to the target proteins, mRNAs, miRNA, and/or DNAs, indicating the complicated roles of lncRNAs. Recent findings revealed that lncRNAs can play important roles in the pathogenesis of human cancers, contributing to tumor growth and progression. Thefore, a better understanding of the role of lncRNAs is needed to elucidate the missing links in the molecular mechanims involved in human diseases, including cancer.

References

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