ABSTRACT
Long interspersed nuclear element 1 (LINE-1) is a dominant autonomous retrotransposon in human genomes which plays a role in affecting the structure and function of somatic genomes, resulting in human disorders including genetic disease and cancer. LINE-1 encoded ORF1p protein which possesses RNA-binding and nucleic acid chaperone activity, and interacts with LINE-1 RNA to form a ribonucleoprotein particle (RNP). ORF1p can be detected in many kinds of tumors and its overexpression has been regarded as a hallmark of histologically aggressive cancers. In this study, we developed an In-Cell Western (ICW) assay in T47D cells to screen the compounds which can decrease the expression of ORF1p. Using this assay, we screened 1,947 compounds from the natural products library of Target Mol and Selleckchem, among which three compounds, Hydroxyprogesterone, 2,2':5',2â³-Terthiophene and Ethynyl estradiol displayed potency in diminishing LINE-1 ORF1p expression level. Further mechanistic studies indicated the compounds act by affecting LINE-1 RNA transcription. Notably, we demonstrated that the compounds have an inhibitory effect on the proliferation of several lung and breast cancer cell lines. Taken together, we established a high throughput screening system for ORF1p expression inhibitors and the identified compounds provide some clues to the development of a novel anti-tumor therapeutic strategy by targeting ORF1p.
ABSTRACT
Long interspersed element-1 (LINE-1), which is the only autonomous retrotransposon in human genome, makes up about 17% of the human genome. For LINE-1 retrotransposition may result in genome instability, it was strictly restricted by organisms, and its expression was therefore barely detected in normal somatic cells. However, the expression of LINE-1 is a common phenomenon in most tumor or cancer tissues, suggesting a close relationship between LINE-1 expression and cancer development. Differentially expressed LINE-1 in cancer tissues can be used as a biomarker for tumor diagnosis and an important indicator of prognosis after cancer therapeutics. Meanwhile, the feasibility of LINE-1 as a potential drug target for tumor treatment has also been evaluating and verifying in clinicals. In this review, we introduce the application of LINE-1 as a biomarker in tumor diagnosis and prognostic, as well as the research progress in LINE-1 as potential drug target for tumor treatment, in order to provide some references for clinical application in cancer treatment.
