Functional characterization of miR-708 microRNA in telomerase positive and negative human cancer cells

Abstract

Activation of a telomere length maintenance mechanism (TMM), including telomerase and alternative lengthening of telomeres (ALT), is essential for replicative immortality of tumor cells, although its regulatory mechanisms are incompletely understood. We conducted a microRNA (miRNA) microarray analysis on isogenic telomerase positive (TEP) and ALT cancer cell lines. Amongst nine miRNAs that showed difference in their expression in TEP and ALT cancer cells in array analysis, miR-708 was selected for further analysis since it was consistently highly expressed in a large panel of ALT cells. miR-708 in TEP and ALT cancer cells was not correlated with C-circle levels, an established feature of ALT cells. Its overexpression induced suppression of cell migration, invasion, and angiogenesis in both TEP and ALT cells, although cell proliferation was inhibited only in TEP cells suggesting that ALT cells may have acquired the ability to escape inhibition of cell proliferation by sustained miR-708 overexpression. Further, cell proliferation regulation in TEP cells by miR708 appears to be through the CARF-p53 pathway. We demonstrate here that miR-708 (i) is the first miRNA shown to be differentially regulated in TEP and ALT cancer cells, (ii) possesses tumor suppressor function, and (iii) deregulates CARF and p21WAF1-mediated signaling to limit proliferation in TEP cells.

Elucidation of how the Mir-23-27-24 cluster regulates development and aging

“…miRNAs also contribute to mechanisms to maintain telomere length, such as telomerase activity and alternative lengthening of telomeres (ALT). For example, MIR708 was shown to be highly expressed in a large panel of cells that underwent ALT, and its overexpression suppressed cell migration, invasion, and angiogenesis 53 .…”

Telomere-related DNA damage response pathways in cancer therapy: prospective targets

“…The activation of telomere maintenance mechanisms, including telomerase and the alternative lengthening of telomeres (ALTs), is essential for tumor cell growth, although its regulatory mechanisms are not completely understood ( Kaul et al, 2021 ). ALT is a BIR-based mechanism that elongates telomeres in a subset of human cancer cells ( Silva et al, 2021 ).…”