New function of non-coding RNA in senescence and cancer
Research from the Cancer Institute of the Japan Foundation for Cancer Research (JFCR), which was published today (August 23, 3:00 p.m. ET) in the leading international scientific journal Proceedings of the National Academy of Sciences of the United States of America, reveals that non-coding RNA derived from pericentromeric repetitive sequences induces the expression of inflammatory genes in senescence and cancer.
Senescence is a state of essentially irreversible cell cycle arrest induced by several stressors, namely aging, obesity, radiotherapy and chemotherapy. Senescent cells that accumulate in vivo during aging communicate with surrounding tissues through the production of pro-inflammatory proteins, called the senescence-associated secretory phenotype (SASP), which plays multiple physiological and pathological roles. In the elderly, SASP inflammatory factors promote many age-related diseases, including cancer. Therefore, elucidating the regulatory mechanism of SASP is essential to develop new preventive and therapeutic strategies against age-related cancer.
A team of JFCR researchers hypothesized that an aberrant chromatin architecture observed in senescent cells may be associated with SASP and began analysis of the interaction of chromatin at the genome and scale. gene expression using next-generation sequencing techniques. They revealed that the region containing pericentromeric repeating sequences called human satellite II (hSATII), which are epigenetically silent in normal cells, showed a particularly open state in senescent cells. In addition, the expression of non-coding RNA (hSATII RNA) was markedly upregulated during cell senescence. Further analysis revealed that hSATII RNA upregulated the expression of inflammatory SASP-like genes by disrupting chromatin interactions in certain regions of the SASP gene through the functional impairment of the CCCTC binding factor (CTCF ), which is important for maintaining genomic integrity.
“Small extracellular vesicles (EVs) secreted by cancer and stromal cells dynamically contribute to tumor incidence and progression non-autonomously in the tumor microenvironment. Surprisingly, the amounts of hSATII RNA were higher in small electric vehicles derived from senescent cells than in those derived from proliferating cells. Thus, our data suggest that hSATII RNA derived from senescent stromal cells is transferred to surrounding cells via small electric vehicles and functions as a SASP-like inflammatory factor in the tumor microenvironment.
In addition, the researchers found that hSATII RNA was highly detectable in cancer cells in surgical samples from patients with primary colon carcinoma. Surprisingly, the hSATII RNA positive cell population was significantly higher among cancer-associated fibroblasts than fibroblasts in normal stromal tissue.
“These findings highlight the novel role of hSATII RNA, which supports tumor development in an autonomous non-cellular manner via the secretion of inflammatory factors like SASP and small electric vehicles. Understanding this molecular mechanism can facilitate the development of new preventive and therapeutic strategies against age-related pathologies in the future. “