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Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer

View Article: PubMed Central - PubMed

ABSTRACT

Epithelial cancers comprise 80-90% of human cancers. During the process of cancer progression, cells lose their epithelial characteristics and acquire stem-like mesenchymal features that are resistant to chemotherapy. This process, termed the epithelial-mesenchymal transition (EMT), plays a critical role in the development of metastases. Because of the unique migratory and invasive properties of cells undergoing the EMT, therapeutic control of the EMT offers great hope and new opportunities for treating cancer. In recent years, a plethora of genes and noncoding RNAs, including miRNAs, have been linked to the EMT and the acquisition of stem cell-like properties. Despite these advances, questions remain unanswered about the molecular processes underlying such a cellular transition. In this article, we discuss how expression of the normally repressed LINE-1 (or L1) retrotransposons activates the process of EMT and the development of metastases. L1 is rarely expressed in differentiated stem cells or adult somatic tissues. However, its expression is widespread in almost all epithelial cancers and in stem cells in their undifferentiated state, suggesting a link between L1 activity and the proliferative and metastatic behaviour of cancer cells. We present an overview of L1 activity in cancer cells including how genes involved in proliferation, invasive and metastasis are modulated by L1 expression. The role of L1 in the differential expression of the let-7 family of miRNAs (that regulate genes involved in the EMT and metastasis) is also discussed. We also summarize recent novel insights into the role of the L1-encoded reverse transcriptase enzyme in epithelial cell plasticity that suggest it might be a potential therapeutic target that could reverse the EMT and the metastasis-associated stem cell-like properties of cancer cells.

No MeSH data available.


Related in: MedlinePlus

A schematic picture of L1 retrotransposition. (A) Structure of a functional L1 showing the 5’-UTR promoter, ORF1- and ORF2-protein encoding genes, and the poly-A tail. ENase endonuclease, RTase reverse transcriptase enzyme. L1 expression/activation is mostly undetectable in normal cells due to the presence of DNA hypermethylation. In contrast, the majority of epithelial cancers exhibit high levels of L1 activation. Red and green closed circles on sticks denote hypermethylated and hypomethylated L1 promoters, respectively. Blue arrows indicate bidirectional transcripts from sense and antisense promoters within L1 promoter regions. (B) Characteristics of typical L1 activation in cancer cells. 1) A newly retrotransposed L1 DNA copy (blue coloured box) is commonly inserted into tumor-suppressor genes (e.g., ST18, SLC21, PHGDH), resulting in altered expression of the genes or disruption of gene function. 2) The presence of a retrotransposon in the upstream region of an oncogene can activate its expression and induce tumorigenesis. 3) The presence of a retrotransposon in the upstream of some tumor-suppressor genes (e.g., TFP1-2) may lead to the expression of L1 chimeric sequences (LCT), which suppress gene expression through antisense RNA interference. 4) A retrotransposon carries sense and antisense promoters that can initiate both upstream and downstream (e.g., c-MET) expression, thereby activating normally repressed genes, which can itself eventually lead to metastasis. 5) L1 retrotransposition often activates the expression of long noncoding RNA-like transcript (lncRNA) by read-through transcription of nearby promoters, which often confer tumor-promoting properties through activation of the ß-catenin/Wnt-signaling pathway. Moreover, changes in the expression of certain types of genes alone may be sufficient to activate the process of EMT and metastasis in multiple ways. (Color images available online).
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Figure 1: A schematic picture of L1 retrotransposition. (A) Structure of a functional L1 showing the 5’-UTR promoter, ORF1- and ORF2-protein encoding genes, and the poly-A tail. ENase endonuclease, RTase reverse transcriptase enzyme. L1 expression/activation is mostly undetectable in normal cells due to the presence of DNA hypermethylation. In contrast, the majority of epithelial cancers exhibit high levels of L1 activation. Red and green closed circles on sticks denote hypermethylated and hypomethylated L1 promoters, respectively. Blue arrows indicate bidirectional transcripts from sense and antisense promoters within L1 promoter regions. (B) Characteristics of typical L1 activation in cancer cells. 1) A newly retrotransposed L1 DNA copy (blue coloured box) is commonly inserted into tumor-suppressor genes (e.g., ST18, SLC21, PHGDH), resulting in altered expression of the genes or disruption of gene function. 2) The presence of a retrotransposon in the upstream region of an oncogene can activate its expression and induce tumorigenesis. 3) The presence of a retrotransposon in the upstream of some tumor-suppressor genes (e.g., TFP1-2) may lead to the expression of L1 chimeric sequences (LCT), which suppress gene expression through antisense RNA interference. 4) A retrotransposon carries sense and antisense promoters that can initiate both upstream and downstream (e.g., c-MET) expression, thereby activating normally repressed genes, which can itself eventually lead to metastasis. 5) L1 retrotransposition often activates the expression of long noncoding RNA-like transcript (lncRNA) by read-through transcription of nearby promoters, which often confer tumor-promoting properties through activation of the ß-catenin/Wnt-signaling pathway. Moreover, changes in the expression of certain types of genes alone may be sufficient to activate the process of EMT and metastasis in multiple ways. (Color images available online).

Mentions: L1 is capable of generating genetic mutations by inserting copies of itself into genes and affecting gene function (Fig. 1). While most L1 are defective due to truncations or mutations, L1 belonging to the human-specific Ta1 subfamily are intact, full-length retrotransposons and are potentially active in human cells. At present, at least 100 copies of L1 have been identified as functional elements [14], retaining their ability to move about the genome i.e. they are retrotransposition-competent. An active L1 comprises an internal promoter, two open reading frames and a 3’ poly-A tail. The open reading frames encode two proteins: ORF1p with RNA-binding activity and ORF2p containing a reverse transcriptase (RT) and an endonuclease. ORF2p cleaves genomic DNA to form a 3'-end primer from which L1 mRNA is reverse-transcribed into a DNA copy, which is then integrated into a new genomic site, resulting in a newly retrotransposed L1 copy. These L1 insertions are capable of altering the transcriptome by disrupting gene function, altering gene splicing, increasing the frequency of recombination [12], and negatively affecting the stability and integrity of the genome because of their ability to create breaks in genomic DNA during the process of mobilization [15, 16]. In addition, L1 facilitates the mobilization of the Alu family of short interspersed nuclear elements (SINE), certain cellular RNAs, and noncoding RNAs to new sites in the genome [17], thereby reshaping cellular function in multiple ways.


Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer
A schematic picture of L1 retrotransposition. (A) Structure of a functional L1 showing the 5’-UTR promoter, ORF1- and ORF2-protein encoding genes, and the poly-A tail. ENase endonuclease, RTase reverse transcriptase enzyme. L1 expression/activation is mostly undetectable in normal cells due to the presence of DNA hypermethylation. In contrast, the majority of epithelial cancers exhibit high levels of L1 activation. Red and green closed circles on sticks denote hypermethylated and hypomethylated L1 promoters, respectively. Blue arrows indicate bidirectional transcripts from sense and antisense promoters within L1 promoter regions. (B) Characteristics of typical L1 activation in cancer cells. 1) A newly retrotransposed L1 DNA copy (blue coloured box) is commonly inserted into tumor-suppressor genes (e.g., ST18, SLC21, PHGDH), resulting in altered expression of the genes or disruption of gene function. 2) The presence of a retrotransposon in the upstream region of an oncogene can activate its expression and induce tumorigenesis. 3) The presence of a retrotransposon in the upstream of some tumor-suppressor genes (e.g., TFP1-2) may lead to the expression of L1 chimeric sequences (LCT), which suppress gene expression through antisense RNA interference. 4) A retrotransposon carries sense and antisense promoters that can initiate both upstream and downstream (e.g., c-MET) expression, thereby activating normally repressed genes, which can itself eventually lead to metastasis. 5) L1 retrotransposition often activates the expression of long noncoding RNA-like transcript (lncRNA) by read-through transcription of nearby promoters, which often confer tumor-promoting properties through activation of the ß-catenin/Wnt-signaling pathway. Moreover, changes in the expression of certain types of genes alone may be sufficient to activate the process of EMT and metastasis in multiple ways. (Color images available online).
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Related In: Results  -  Collection

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Figure 1: A schematic picture of L1 retrotransposition. (A) Structure of a functional L1 showing the 5’-UTR promoter, ORF1- and ORF2-protein encoding genes, and the poly-A tail. ENase endonuclease, RTase reverse transcriptase enzyme. L1 expression/activation is mostly undetectable in normal cells due to the presence of DNA hypermethylation. In contrast, the majority of epithelial cancers exhibit high levels of L1 activation. Red and green closed circles on sticks denote hypermethylated and hypomethylated L1 promoters, respectively. Blue arrows indicate bidirectional transcripts from sense and antisense promoters within L1 promoter regions. (B) Characteristics of typical L1 activation in cancer cells. 1) A newly retrotransposed L1 DNA copy (blue coloured box) is commonly inserted into tumor-suppressor genes (e.g., ST18, SLC21, PHGDH), resulting in altered expression of the genes or disruption of gene function. 2) The presence of a retrotransposon in the upstream region of an oncogene can activate its expression and induce tumorigenesis. 3) The presence of a retrotransposon in the upstream of some tumor-suppressor genes (e.g., TFP1-2) may lead to the expression of L1 chimeric sequences (LCT), which suppress gene expression through antisense RNA interference. 4) A retrotransposon carries sense and antisense promoters that can initiate both upstream and downstream (e.g., c-MET) expression, thereby activating normally repressed genes, which can itself eventually lead to metastasis. 5) L1 retrotransposition often activates the expression of long noncoding RNA-like transcript (lncRNA) by read-through transcription of nearby promoters, which often confer tumor-promoting properties through activation of the ß-catenin/Wnt-signaling pathway. Moreover, changes in the expression of certain types of genes alone may be sufficient to activate the process of EMT and metastasis in multiple ways. (Color images available online).
Mentions: L1 is capable of generating genetic mutations by inserting copies of itself into genes and affecting gene function (Fig. 1). While most L1 are defective due to truncations or mutations, L1 belonging to the human-specific Ta1 subfamily are intact, full-length retrotransposons and are potentially active in human cells. At present, at least 100 copies of L1 have been identified as functional elements [14], retaining their ability to move about the genome i.e. they are retrotransposition-competent. An active L1 comprises an internal promoter, two open reading frames and a 3’ poly-A tail. The open reading frames encode two proteins: ORF1p with RNA-binding activity and ORF2p containing a reverse transcriptase (RT) and an endonuclease. ORF2p cleaves genomic DNA to form a 3'-end primer from which L1 mRNA is reverse-transcribed into a DNA copy, which is then integrated into a new genomic site, resulting in a newly retrotransposed L1 copy. These L1 insertions are capable of altering the transcriptome by disrupting gene function, altering gene splicing, increasing the frequency of recombination [12], and negatively affecting the stability and integrity of the genome because of their ability to create breaks in genomic DNA during the process of mobilization [15, 16]. In addition, L1 facilitates the mobilization of the Alu family of short interspersed nuclear elements (SINE), certain cellular RNAs, and noncoding RNAs to new sites in the genome [17], thereby reshaping cellular function in multiple ways.

View Article: PubMed Central - PubMed

ABSTRACT

Epithelial cancers comprise 80-90% of human cancers. During the process of cancer progression, cells lose their epithelial characteristics and acquire stem-like mesenchymal features that are resistant to chemotherapy. This process, termed the epithelial-mesenchymal transition (EMT), plays a critical role in the development of metastases. Because of the unique migratory and invasive properties of cells undergoing the EMT, therapeutic control of the EMT offers great hope and new opportunities for treating cancer. In recent years, a plethora of genes and noncoding RNAs, including miRNAs, have been linked to the EMT and the acquisition of stem cell-like properties. Despite these advances, questions remain unanswered about the molecular processes underlying such a cellular transition. In this article, we discuss how expression of the normally repressed LINE-1 (or L1) retrotransposons activates the process of EMT and the development of metastases. L1 is rarely expressed in differentiated stem cells or adult somatic tissues. However, its expression is widespread in almost all epithelial cancers and in stem cells in their undifferentiated state, suggesting a link between L1 activity and the proliferative and metastatic behaviour of cancer cells. We present an overview of L1 activity in cancer cells including how genes involved in proliferation, invasive and metastasis are modulated by L1 expression. The role of L1 in the differential expression of the let-7 family of miRNAs (that regulate genes involved in the EMT and metastasis) is also discussed. We also summarize recent novel insights into the role of the L1-encoded reverse transcriptase enzyme in epithelial cell plasticity that suggest it might be a potential therapeutic target that could reverse the EMT and the metastasis-associated stem cell-like properties of cancer cells.

No MeSH data available.


Related in: MedlinePlus