LINE-1-encoded Reverse Transcriptase in the genesis and therapy of cancer

Abstract

Long Interspersed Nuclear Elements (LINE-1) make up a large family of autonomous retrotransposons, accounting for about 17% of the human genome. They constitute the major source of non telomeric Reverse Transcriptase (RT), an essential component of the retrotransposition machinery. Expression of RT-encoding LINE-1 sequences is low in differentiated, non-pathological cells and highly active in early embryos, germ cells and in a broad spectrum of cancers. Growing evidence functionally implicate RT in control of cell growth and differentiation and suggest causative roles in cancer onset. Indeed, inhibition of RT activity reduces proliferation, promotes differentiation and antagonizes cancer progression in animal models. More recently, RT inhibition proved effective in a phase II clinical trial with metastatic prostate cancer patients. Furthermore, the LINE-1-encoded ORF2p product, ecompassing the RT-encoding sequence, was found to be already esxpressed in precancerous lesions, increasing in progressive stages, while being undetectable in normal tissues. RT emerges therefore as a promising therapeutic target and a potential marker for early cancer detection. At the molecular level, the inhibition of LINE-1-encoded RT yields a global reprogramming of the gene expression profile in cancer cells, involving all RNA classes: coding mRNAs, long and small non-coding transcripts, including miRNAs - some of which are themselevs key players in cancer progression, invasion, and metastasis. In summary, the LINE-1-encoded RT emerges as a key component of a genome-wide regulatory mechanism that is active in embryogenesis, repressed during cell differentiation, and aberrantly reactivated in cancer cells.