miR340 Suppresses the Stem-like Cell Function of Glioma-Initiating Cells by Targeting Tissue Plasminogen Activator

Abstract

Glioma-initiating cells (GIC) have stem-like cell properties thought to be sufficient for recurrence, progression, and drug resistance in glioblastomas. In the present study, we defined miRNA (miR)-340 as a differentially expressed miRNA in human GICs that inhibit GIC-mediated tumorigenesis. Furthermore, we defined tissue plasminogen activator (PLAT) as a critical direct target of miR340 for inhibition. Among miRNAs screened, we found that miR340 expression was decreased in all human GICs and in human glioblastoma tissues, compared with human neural stem cells and normal brain tissues. miR340 overexpression in GICs suppressed their proliferative, invasive, and migratory properties in vitro, triggering cell senescence in vitro and inhibiting GIC-induced tumorigenesis in mouse brains. shRNA-mediated silencing of PLAT in GICs phenocopied the effects of miR340 overexpression in vitro and in vivo, suggesting a potential role for tissue factor in stem-like cell function. Taken together, our results identified miR340 as a tumor suppressor that functions in GIC to enforce PLAT blockade and ablate their stem-like functions.

MicroRNA-340 promotes the tumor growth of human gastric cancer by inhibiting cyclin G2

“…Examination of the expression status, biological function and underlying mechanisms of specific miRNAs in gastric cancer can contribute to the identification of novel biomarkers and therapeutic targets in human gastric cancer. Previous studies have shown that miR-340 plays an important role in human cancers (8)(9)(10)(11)(12)(13)(14). It was found to inhibit the metastatic behavior of breast cancer cells (14) while it decreased the proliferation and promoted the cell apoptosis of prostate cancer cells (13,18).…”

“…MicroRNA-340 (miR-340) has been found to play a critical role in human cancers, including breast (8,9), prostate (10,11), and esophageal cancer (12), hepatocellular carcinoma (13) and glioma (14). Functionally, miR-340 was found to inhibit the migration and invasion of breast cancer cells by inhibiting the Wnt pathway (8).…”

“…In prostate cancer, miR-340 was found to inhibit cell proliferation and promote cell apoptosis by inhibiting high-mobility group nucleosome-binding domain 5 (11). Studies of glioma have shown that miR-340 inhibited the stem-like cell function by targeting tissue plasminogen activator (14). Notably, the expression of miR-340 has been found highly expressed in gastric cancer tissues (15,16).…”

Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway

“…Mouse primary NSCs, NSCL61 cells, human NSCs (hNSCs, Invitrogen), and GICs (hGICs, E2, E3 and E6) were cultured in DMEM/F12 (Gibco, BRL) supplemented with bFGF (10 ng/mL) and EGF (10 ng/mL; NSC medium), as described previously (8)(9)(10)(11)16). For immunostaining, cells were cultured in chamber slides (Nunc) precoated with fibronectin and poly-D-lysine, as described previously (16).…”

“…Using DNA microarray analysis, we compared the gene expression profiles of mGICs with those of their parental cells and identified genes that increased and decreased in mGICs. By evaluating the candidate genes using human GICs (hGICs) and GBM tissues, we have successfully selected potential GIC-specific genes (8)(9)(10)(11).…”