A Plant Immune Protein May be Expected to Completely Cure Cancer!

Posted by Caroline on September 1st, 2022

Cancer, caused by abnormal cell proliferation, is one of the world's major public health problems. Recently, in a research report entitled "A plant immune protein enables broad antitumor response by rescuing microRNA deficiency" published in Cell, Scientists from institutions such as Peking University have found that a special plant immune protein may achieve a broad spectrum of anti-tumor responses by slowing microRNA (miRNA) defects, which may provide a powerful weapon to help protect against human cancer.

miRNAs are thought to be closely related to the carcinogenic process, and there is a 2-nt 3' terminal excess on mature miRNA duplexes in mammals, which can be recognized and loaded by Argonaute (AGO) proteins to form RNA-induced silencing complexes (RISC) and can regulate the expression of targeted genes, and in fact, reduced doses of comprehensive miRNAs are considered to be responsible for inducing cancer. Excessive activation of the cell cycle is necessary for abnormal proliferation of cancer cells, but to the surprise of researchers, many miRNAs can directly target and inhibit cell cycle genes to control cell proliferation, and therefore, repair defective miRNA pathways in tumors may be used as a novel cancer therapy to inhibit tumor cell proliferation.

Unlike miRNAs, siRNAs are derived from double-stranded RNA substrates synthesized by different RNA-dependent RNA polymerases (RDRs), and RDR1-dependent siRNAs in plants are a unique core molecular immune response pathway, especially able to participate in antiviral immune responses, therefore, researchers aim to carry out plant genetic engineering operations based on plant RDR1 in mammals starting from differences in animal and plant immune systems and study their application in the field of translational medicine.

In the article, the researchers introduce that miRNA isoforms at the 1-nt-shorter 3' end that do not effectively bind the AGO2 complex may accumulate widely in different samples of human primary cancers and cancer cell lines, and as ectopically expressed phytoimmune proteins, RDR1 can modify these double-stranded free miRNA isoforms of AGO2 through its single-nucleotide tail, thereby reactivating the defective miRNA pathway and specifically blocking cancer cell cycles in solid tumors and leukemias.

The researchers found that the RDR1 protein could inhibit the proliferation of cancer cells by targeting the cell cycle, and the researchers cloned the RDR1 gene of Arabidopsis (At) and rice (Os) into lentiviral vectors induced by Dox, respectively, while they verified its successful ectopic expression in mammalian cells, and at the molecular level, the results of gene enrichment analysis (GSEA) based on RNA sequencing showed that RDR1 in Arabidopsis and rice could intervene the cell cycle process of all cancer cell lines without significantly damaging the non-cancerous control cells, and the researchers believed that RDR1 was an exogenous tumor suppressor, which could specifically target and intervene the cell cycle of cancer cells, while it did not affect the non-cancerous cells, and RDR1 in Arabidopsis and rice had a broad spectrum and special inhibitory characteristics on the proliferation of cancer cells without damaging the non-cancerous cell lines.v

Short 1-nt miRNA isoforms at the 3 'end accumulate widely in a variety of tumors, and the researchers propose that RDR1 in plants can inhibit cell cycle and cell proliferation by increasing global miRNA expression, thereby restoring miRNA defects in cancer cells by knocking out key components of the miRNA pathway and AGO2-CLIP; i.e. However, systematic analysis of published miRNA sequencing data and miRNA sequencing of AGO2-IP suggests that abnormal short 1-nt duplex miRNA isoforms may not enter AGO2 so effectively and stably in cancer cells, so this may be related to the reduction of miRNA dose in different tumors. In addition, the researchers found that RDR1 can repair miRNA isoforms in cancer cells through a single nucleotide tail, and by performing in vitro biochemical experiments, the researchers could directly prove that rAtRDR1 may modify single-stranded miRNAs and double-stranded miRNAs carrying 1-nt or 2-nt excess through a 3' terminal single nucleotide, but it did not modify double-stranded miRNAs carrying flat ends.

The researchers say RDR1, which has nucleotidyltransferase activity, or short 1-nt double-stranded miNA isoforms that can be isolated from AGO2 by single nucleotide modification, restores its loading efficiency on AGO2 and ultimately repairs defective miRNA pathways in cancer. Finally, RDR1 inhibits the progression of a variety of mouse solid tumors and leukemias, and the researchers verified the anti-tumor effects of plant RDR1 in mouse models of immunodeficiency and leukemia in vivo, and finally, purified RDR1 protein packaged by nanovesicles and loaded by AAV can achieve direct trafficking and tumor inhibition at the level of cells in vitro and solid tumors in vivo, respectively.

In summary, the results of this paper show that researchers have discovered for the first time that abnormal 3'-end short-chain 1-nt miRNA isoforms accumulate in a variety of human primary tumors, thus providing a new research perspective for the overall decrease in miRNA dose during tumorigenesis, and using RDR1, researchers may be able to achieve a broad spectrum of anti-tumor responses by repairing miRNA defects in cancer cells and can develop a novel strategy to edit and manipulate miRNAs, thus making it an effective weapon against cancer.