MicroRNA-485 inhibits malignant biological behaviour of glioblastoma cells by directly targeting PAK4

Abstract

Glioblastoma (GBM), which is characterised by rapid growth, cellular heterogeneity, angiogenesis, extensive invasion, hypoxia and necrosis, is the most common histological subtype of glioma in adults. MicroRNA (miRNA) dysregulation is a common feature of human cancers, including GBM. Previous studies have suggested that miRNAs are a novel class of regulatory molecules in various human cancers. Therefore, miRNAs may be investigated as a novel candidate and screening tool in the clinical diagnosis, therapy and prognosis of GBM. Recent accumulating evidence has demonstrated that miRNA‑485 (miR‑485) is involved in the development and progression of several types of human cancers. However, the expression level, exact role and underlying mechanisms of miR‑485 in GBM remain unclear. In this study, miR‑485 was downregulated in both GBM tissue specimens and cell lines. miR‑485 overexpression inhibited GBM cell proliferation, colony formation, migration and invasion; increased apoptosis in vitro; and reduced tumour growth in vivo. In addition, p21‑activated kinase 4 (PAK4) was demonstrated to be a direct and functional target of miR‑485 in GBM. Furthermore, PAK4 was upregulated in GBM tissues and negatively correlated with miR‑485 expression. Moreover, PAK4 knockdown exhibited a similar effect to miR‑485 overexpression in GBM cells. Enforced expression of PAK4 rescued miR‑485 tumour‑suppressor functions in GBM cells. miR‑485 inhibited the activation of the AKT and ERK signalling pathways in GBM. These results indicate that miR‑485 acts as a tumour suppressor in GBM by, at least partially, directly targeting PAK4 and regulating the AKT and ERK signalling pathways. Thus, miR‑485 may be a potential target for the treatment of patients with GBM.

MicroRNA‑663 inhibits the proliferation and invasion of clear cell renal cell carcinoma cells by directly targeting PAK4

“…PAK4 is located at the locus 19q13.2 and it was described as a downstream effector of Ras-related C3 botulinum toxin substrate 1 and cell division control protein 42 homolog (32). PAK4 is upregulated in multiple human cancer types, including colorectal cancer (33), non-small cell lung cancer (34), glioblastoma (35) and gastric cancer (36). PAK4 was implicated in the carcinogenesis and cancer progression by affecting numerous biological processes, including cell proliferation, apoptosis, metastasis and cytoskeletal organisation (37)(38)(39).…”

Linc01234 promotes cell proliferation and metastasis in oral squamous cell carcinoma via miR-433/PAK4 axis

“…Previous studies have reported that dysregulation of PAK4 expression contributes to the development and progression of various tumors [28,29]. Several studies have reported that PAK4 could be regulated by many miRNAs in various cancers, including miR-485 and miR-199a-3p [30][31][32]. In OSCC, PAK4 serves as a super enhancer-associated candidate oncogene and promotes the proliferation of OSCC cells [33].…”

Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression

“…PAK4 belongs to a family of serine/threonine kinases that are involved in cell proliferation and migration and in cytoskeletal organization. PAK4 is amplified/over-expressed in non-Hodgkin lymphoma (28), esophageal cancer (29,30), pancreatic cancer (31)(32)(33)(34)(35), breast cancer (36,37), and other cancers (38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Activated PAK4 a) promotes tumorigenesis in breast cancer via activation of the PI3K/AKT signaling pathway (48), b) promotes liver metastasis by phosphorylation of p53 (49), and c) facilitates the epithelial-mesenchymal transition [EMT] in prostate cancer via phosphorylation of the Slug transcription factor (50).…”