Scientists Develop a New, Powerful Cancer-Fighting Weapon



Atypical cell proliferation is the root cause of one of the biggest global public health issues, cancer. According to new research by a group of scientists lead by Researcher Du Peng of Peking University School of Life Sciences, a plant immune protein has been identified to enable extensive anti-tumor responses by reducing micro-RNA deficit, which offers a potent tool against cancer.

Micro-RNA (miRNA) has been linked to the development of cancer. Argonaute (AGO) can recognize and load mature mammalian miRNA that is double stranded and has a 2-nt 3-terminal overhang in order to create an RNA Induced Silencing Complex (RISC) that controls the expression of target genes. In fact, it is believed that one of the causes of cancer is the dosage reduction of global miRNA.

The aberrant proliferation of cancer cells requires overactivation of the cell cycle. Unexpectedly, a large number of miRNAs can directly target and suppress cell cycle genes to limit cell division. Therefore, restoring the damaged miRNA pathway in tumors would be a novel method of tumor treatment to prevent the growth of tumor cells.

Unlike miRNA, which is produced by a single RNA-dependent RNA polymerase, siRNA is produced from double-stranded RNA substrates (RDR). One of the distinctive basic molecular immune response pathways in plants, RDR1-dependent siRNA is particularly important in the antiviral immune response. Therefore, in order to research its use in translational medicine, Prof. Peng's team plans to carry out plant genetic engineering based on plant RDR1 in mammals from the distinction between animal and plant immune systems.

The research team led by Professor Du Peng recently reported their findings in the journal Cell, revealing that various samples of human primary malignancies and cancer cell lines had a significant accumulation of miRNA isomers that are unable to bind to the 1-nt-shorter 3′ends of the AGO2 complex. These double-stranded free miRNA isomers of AGO2 are modified by RDR1, an ectopically produced plant immune protein, through its single nucleotide tailing, reactivating the damaged miRNA pathway and selectively blocking the cycle of cancer cells in solid tumors and leukemia.

First off, by concentrating on the cell cycle, the RDR1 protein prevents the spread of cancer cells. The authors successfully ectopically expressed the RDR1 gene in human cells after cloning it from the respective plant species Arabidopsis (At) and rice (Os) into a lentivirus vector triggered by Dox. RDR1 in At and Os might disrupt cycle processes in all cancer cell lines, but it had no discernible impact on non-cancer control cells, according to RNA-seq-based Gene Set Enrichment Analysis (GSEA). According to the authors, RDR1 is an exogenous tumor suppressor that may selectively target and thwart the cycle process in cancer cells while having no effect on healthy cells.

While having no impact on non-cancer cell lines, RDR1 in At and Os has a broad-spectrum and targeted inhibition of cancer cell proliferation.

Second, several different malignancies have an accumulation of 3'- terminal short 1-nt miRNA isomers. The scientists claimed that plant RDR1 can restrict cell cycle and proliferation by upregulating global miRNA expression to specifically recover miRNA deficit in cancer cells through AGO2-CLIP of important miRNA pathway constituents. The authors further suggest that the abnormal short 1-nt double-stranded miRNA isomer's ability to enter AGO2 in cancer cells is not as efficient or stable, which may be related to the reduction of miRNA dose in various tumors, through a methodical analysis of published miRNA sequencing data and the miRNA sequencing of AGO2-IP.

Thirdly, single nucleotide tailing by RDR1 restores miRNA isomers in malignancy. The authors explicitly shown through biochemical studies conducted in vitro that rAtRDR1 could change single-stranded miRNA and double-stranded miRNA with 1-nt or 2-nt overhang by 3' terminal single nucleotide but could not modify double-stranded miRNA with flat ends. The researchers established that RDR1, which has nucleotide transferase activity, has the ability to modify short 1-nt double-stranded miRNA isomers that have been isolated from AGO2 by a single nucleotide, restoring their loading efficiency to AGO2, and thereby repairing the cancer's defective miRNA pathway.

Last but not least, RDR1 stops the growth of several mouse solid tumors and leukemia. The anti-tumor impact of plant RDR1 was confirmed by the scientists using immunodeficient mice models and in vivo leukemia. Finally, direct delivery and tumor inhibition at the level of cells in vitro and solid tumors in vivo are achieved by RDR1 protein purified in vitro by nano vesicle package and AAV packed, respectively.

The study gives fresh information about the lowering of global miRNA dose during carcinogenesis by demonstrating for the first time that anomalous 3' terminal short 1-nt miRNA isomers are widely accumulated in a variety of human primary cancers. By fixing miRNA abnormalities in cancer cells with RDR1, we were able to produce a broad-spectrum anti-tumor response. We also created a new method to edit and modify miRNA, turning it into a potent cancer-fighting tool.

The Governmental Natural Science Foundation of China, along with a number of other national organizations and educational laboratories, supported the study.

By PEKING UNIVERSITY 

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