Angiogenin promotes colorectal cancer metastasis via tiRNA production

Abstract

Metastasis of colorectal cancer (CRC) is the leading cause of CRC‐associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA‐derived stress‐induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG‐promoted CRC metastasis. Moreover, higher level of a 5′‐tiRNA from mature tRNA‐Val (5′‐tiRNA‐Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG‐tiRNAs‐cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.

The role of Transfer RNA-Derived Small RNAs (tsRNAs) in Digestive System Tumors

“…Investigating the role of tiRNAs/tRFs in tumor progression would improve treatment protocols and disease prognosis. Previous reports demonstrated that elevated ANG in rectal cancer increased 5'-tiRNA-Val levels, and thus established an ANG-tiRNAs-cell invasion/metastasis regulatory axis (52). Such findings provided insights on the mechanism of rectal cancer development and revealed new therapeutic targets for colorectal cancer.…”

“…In clinical case, distant metastasis of DT tumor is a major obstacle to optimal patient prognosis (52). Thus, researchers have been exploring the correlation of tiRNAs/tRFs with the cellular invasion and distant metastasis of DT tumor.…”

“…Thus, researchers have been exploring the correlation of tiRNAs/tRFs with the cellular invasion and distant metastasis of DT tumor. Recent studies showed that colorectal cancer had elevated ANG levels, increased the levels of 5'-tiRNA-Val, 5'-tiRNA-Cys and 5'-tiRNA-Ala, then promoted cancer cell invasion and migration without affecting cellular proliferation (52). Additionally, 5'-tiRNA-Val levels are positively correlated with lymph node metastasis and distant metastasis of colorectal cancer cells (52).…”

tRNA-derived RNA fragments in cancer: current status and future perspectives

“…RUNX1-regulated tRFs and sex hormone-dependent tiRNA (SHOT-RNAs) are associated with cell proliferation of ANG-cleaved tiRNAs. Among them, a 5′-tiRNA from tRNA-Val was highly expressed in CRC patients and was closely related to tumor metastasis [74]. These results provide valuable cues for further insights into the roles of tRFs in colon cancer.…”

“…The discovery of SHOT-RNAs in breast and prostate cancer led to the suggestion that the status of the hormone receptors may impact the production of tRFs in hormone-dependent tumors [66]. In addition, hypoxia-induced tRFs play important roles in BC [32,63] and other stress-induced tiRNAs are also found to be important to breast and colon cancer [65,94]. Interestingly, a recent study showed that in several instances, the abundance of tRFs is regulated without changes in mature tRNA levels.…”