Since their discovery in the 1950s, transfer RNAs (tRNAs) have been best known for their role in helping the cell make proteins from messenger RNA templates. However, recent studies have led to a previously-unsuspected concept that tRNAs are not always the end product; namely, they further serve as a source of small RNAs. Now researchers from Thomas Jefferson University have discovered a new species of tRNA-derived small RNAs that are produced only in hormonally-driven breast and prostate cancers, and which contribute to cell proliferation. The opensource study is published in the journal Proceedings of the National Academy of Sciences (PNAS).
In the current study an abundance of tRNA fragments was observed in early RNA sequencing studies in cellular transcriptome however, those fragments had often been disregarded as non-functional degradation products. The team state their research is one of several recent studies that bring to light a new role for tRNAs to produce small functional RNAs, in this case, functional tRNA halves. They go on to add that although other tRNA halves have been described before, specifically those that are produced during a cellular stress response, this discovery represents a new and distinct species of tRNA halves that the team have coined SHOT-RNAs, for sex hormone dependent tRNA-derived RNAs.
The researchers state that they discovered these tRNA halves while looking at germline-specific small RNAs in the cells of a silkworm (Bombyx mori). In the cells, the researchers accidentally detected the tRNA halves whose expression was linked to cell proliferation. Since proliferation is a hallmark of cancer cells, the researchers analyzed the involvement of tRNA halves in tumourigenesis.
Using a new TaqMan PCR-based technique, the current study screened a number of cancer cell lines from various tissues, and discovered that tRNA halves were specifically expressed in large quantities in sex hormone-dependent cancers, i.e., estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer that are driven by the hormones estrogen and testosterone. After confirming the dependency of the tRNA halves’ expression on the hormones and their receptors, they coined the new tRNA halves, SHOT-RNAs.
The team explain that SHOT-RNAs contain a terminal modification which prevents their detection by standard RNA-seq method. The modification makes SHOT-RNAs invisible in RNA-seq data and this could be the reason why SHOT-RNAs had not been discovered in spite of their abundance and clear expression specificity in hormone-dependent cancers.
The lab created a novel method called cP-RNA-seq to comprehensively sequence SHOT-RNAs and found that only eight tRNA species produce SHOT-RNAs. They were also able to track the molecule’s function in the cells, and tease apart the other cellular players it interacted with. They discovered, for example, that SHOT-RNAs are created by an enzyme called Angiogenin whose activity is promoted by sex hormone signaling pathways. They also showed that SHOT-RNAs are involved in spurring cell proliferation.
The current study also examined clinical samples from breast cancer patients and found elevated levels of SHOT-RNAs in patients with ER-positive luminal-type cancers, however they were not present in those that were negative for ER expression. The team state that the high expression specificity of SHOT-RNAs implies their potential use as a novel biomarker, and the next steps are to explore relationships between SHOT-RNA expression and prognostic factors.
The researchers note that the SHOT-RNAs are an exciting development in the tRNA field. They go on to add that they are also another example of what appear to be regulators whose presence in a given tissue is modulated by a person’s gender. Discovering such regulators is one of the major foci of the group.
In spite of endocrine therapy to suppress hormone receptor activity or hormone exposure, the team surmise that many patients of hormone-dependent cancers encounter de novo or acquired resistance and require more aggressive treatments. The researchers stress that further studies to understand how SHOT-RNAs promote cell proliferation may lead to the use of SHOT-RNAs as potential target candidates for future therapeutic applications in breast and prostate cancers.
Source: Thomas Jefferson University