MicroRNA‑486‑5p functions as a tumor suppressor of proliferation and cancer stem‑like cell properties by targeting Sirt1 in liver cancer

Abstract

Cancer stem-like cells (CSCs) are critical for the initiation, progression, chemoresistance and postsurgical recurrence of liver cancer. They are thought to be novel targets for the treatment of liver cancer, however, efficient agents that target liver cancer stem cells (CSCs) have not been identified. MicroRNAs (miRNAs) are small non-coding RNAs that target the 3'untranslated region (3'UTR) of mRNAs. Their dysregulation has been implicated in several types of cancer including liver cancer, but it still remains unknown if they play a role in targeting liver CSCs. We compared the miRNA profiles between liver cancer samples and adjacent non-tumor tissues using The Cancer Genome Atlas (TCGA) datasets. Several miRNAs including miR-486-5p (miR-486) were found to be significantly downregulated in liver cancer tissues. These differentially expressed miRNAs were screened between CSC-enriched tumor spheres and adherent cells. miR-486 was significantly downregulated in tumor spheres and liver cancer samples. Ectopic expression of miR-486 significantly repressed the self-renewal and invasion of CSCs in vitro and tumorigenesis in vivo. Notably, we found that sirtuin 1 (Sirt1) served as a direct target of miR-486. The high expression of Sirt1 was involved in maintaining the self-renewal and tumorigenic potential of liver CSCs. The results of the present study indicated that the miR-486-Sirt1 axis was involved in suppressing CSC traits and tumor progression.

Silencing of miR-486 alleviates LPS-stimulated inflammatory response of macrophages through targeting SIRT1

“…Moreover, we demonstrated that the anti-miR-486-mediated anti-inammatory response in LPSstimulated macrophages was antagonized by SIRT1 inhibition. Similar to our work, SIRT1 was earlier demonstrated to be a direct functional target of miR-486 in erythroleukemia cells, 14 liver cancer stem-like cells 15 and human adipose tissue-derived mesenchymal stem cells. 16 Additionally, recent studies elucidated that several other miRNAs regulated the inammatory responses of macrophages through targeting SIRT1, such as miR-138 and miR-199a.…”

“…12,13 Moreover, SIRT1 was demonstrated to act as a functional target of miR-486 in several other diseases. [14][15][16] However, the effect of interplay between miR-486 and SIRT1 in sepsis remains unclear.…”

Recent Advances in Liver Cancer Stem Cells: Non-coding RNAs, Oncogenes and Oncoproteins

“…miR-365 directly regulated Ras-related C3 botulinum toxin substrate 1 (RAC1) by binding with the mRNA 3 UTR and affected HCC drug resistance (Jiang et al, 2019). In addition, miR-486 directly targeted sirtuin1, which exhibits high expression in self-renewing and tumorigenic LCSCs (Yan et al, 2019).…”

MiR-424-5p regulates cell cycle and inhibits proliferation of hepatocellular carcinoma cells by targeting E2F7

“…Many studies have reported the abnormal expression and biological function of miRNAs in liver cancer. For example, miR-486 is obviously down-regulated in liver cancer, and its ectopic expression can hinder the occurrence of tumor [10]. MiR-498 inhibits growth and metastasis of liver cancer by targeting and down-regulating the expression of ZEB2 [11].…”