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

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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

Expression of L1 occurs at an early stage of cancer formation and is seen all grades and stages of cancer including metastatic cancers. L1 may result in upregulation (green arrow) or downregulation (red arrow) of a number of genes involved in cellular dedifferentiation and cancer progression. Some of the most commonly altered genes and their functions in the process of EMT and metastasis are shown. L1-encoded RT enzyme may be a potential target for anticancer therapy. Inhibition of RT in the early stages of cancer by antiretroviral (ARV) drugs such as efavirenz, nevirapine or combination of RT inhibitors can modulate the expression of genes involved in cell proliferation and migration, thereby promoting cellular differentiation and reducing morbidity and mortality from epithelial cancers. (Color images available online).
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Figure 2: Expression of L1 occurs at an early stage of cancer formation and is seen all grades and stages of cancer including metastatic cancers. L1 may result in upregulation (green arrow) or downregulation (red arrow) of a number of genes involved in cellular dedifferentiation and cancer progression. Some of the most commonly altered genes and their functions in the process of EMT and metastasis are shown. L1-encoded RT enzyme may be a potential target for anticancer therapy. Inhibition of RT in the early stages of cancer by antiretroviral (ARV) drugs such as efavirenz, nevirapine or combination of RT inhibitors can modulate the expression of genes involved in cell proliferation and migration, thereby promoting cellular differentiation and reducing morbidity and mortality from epithelial cancers. (Color images available online).

Mentions: Viruses that use reverse transcription in their life cycles, such as HIV or hepatitis B virus, are a major healthcare problem, and enormous efforts have been focused on developing drugs for these infections. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTIs) that is widely used to treat HIV infections. It is a broad-spectrum inhibitor, which acts allosterically by binding to a hydrophobic region of the HIV RT enzyme, inducing a conformational change in the enzyme and inhibiting its activity [51]. Recently, efavirenz has also been reported to inhibit the activity of the L1-encoded RT enzyme in a manner similar to that of L1-specific siRNA in A-375 melanoma and PC3 prostate cancer cells [41]. Several in vivo mouse studies have validated the cytotoxic effect of efavirenz at inhibiting L1 in H69 lung carcinoma and HT29 colon carcinoma [39]. In addition, we have shown that L1 expression decreases markedly in T47D and MCF7 breast cancer cells after treatment with efavirenz [42]. These cancer cells normally grow in multilayer clumps with indistinct cell borders and shapes due to loss of their cell-cell adhesions and an increased tendency to form aggregates, features that are characteristic of the EMT process. When cancer cells are treated with efavirenz, the cells show significant changes in morphology [39, 42] and regaining epithelial features in a manner that is reminiscent of the reverse process of EMT, i.e. the MET (Fig. 2).


Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer
Expression of L1 occurs at an early stage of cancer formation and is seen all grades and stages of cancer including metastatic cancers. L1 may result in upregulation (green arrow) or downregulation (red arrow) of a number of genes involved in cellular dedifferentiation and cancer progression. Some of the most commonly altered genes and their functions in the process of EMT and metastasis are shown. L1-encoded RT enzyme may be a potential target for anticancer therapy. Inhibition of RT in the early stages of cancer by antiretroviral (ARV) drugs such as efavirenz, nevirapine or combination of RT inhibitors can modulate the expression of genes involved in cell proliferation and migration, thereby promoting cellular differentiation and reducing morbidity and mortality from epithelial cancers. (Color images available online).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 2: Expression of L1 occurs at an early stage of cancer formation and is seen all grades and stages of cancer including metastatic cancers. L1 may result in upregulation (green arrow) or downregulation (red arrow) of a number of genes involved in cellular dedifferentiation and cancer progression. Some of the most commonly altered genes and their functions in the process of EMT and metastasis are shown. L1-encoded RT enzyme may be a potential target for anticancer therapy. Inhibition of RT in the early stages of cancer by antiretroviral (ARV) drugs such as efavirenz, nevirapine or combination of RT inhibitors can modulate the expression of genes involved in cell proliferation and migration, thereby promoting cellular differentiation and reducing morbidity and mortality from epithelial cancers. (Color images available online).
Mentions: Viruses that use reverse transcription in their life cycles, such as HIV or hepatitis B virus, are a major healthcare problem, and enormous efforts have been focused on developing drugs for these infections. Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTIs) that is widely used to treat HIV infections. It is a broad-spectrum inhibitor, which acts allosterically by binding to a hydrophobic region of the HIV RT enzyme, inducing a conformational change in the enzyme and inhibiting its activity [51]. Recently, efavirenz has also been reported to inhibit the activity of the L1-encoded RT enzyme in a manner similar to that of L1-specific siRNA in A-375 melanoma and PC3 prostate cancer cells [41]. Several in vivo mouse studies have validated the cytotoxic effect of efavirenz at inhibiting L1 in H69 lung carcinoma and HT29 colon carcinoma [39]. In addition, we have shown that L1 expression decreases markedly in T47D and MCF7 breast cancer cells after treatment with efavirenz [42]. These cancer cells normally grow in multilayer clumps with indistinct cell borders and shapes due to loss of their cell-cell adhesions and an increased tendency to form aggregates, features that are characteristic of the EMT process. When cancer cells are treated with efavirenz, the cells show significant changes in morphology [39, 42] and regaining epithelial features in a manner that is reminiscent of the reverse process of EMT, i.e. the MET (Fig. 2).

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