LncRNA MIR4435‐2HG potentiates the proliferation and invasion of glioblastoma cells via modulating miR‐1224‐5p/TGFBR2 axis

Abstract

Glioblastoma (GBM) belongs to the high‐grade (IV) gliomas with extremely poor prognosis. Accumulating evidence uncovered the key roles of long non‐coding RNAs (lncRNAs) in GBM development. This study aimed to determine the biological actions and the clinical relevance of lncRNA MIR4435‐2 Host Gene (MIR4435‐2HG) in GBM. Data from GEPIA database showed that MIR4435‐2HG was up‐regulated in GBM tissues and high expression of MIR4435‐2HG correlated with shorter overall survival of GBM patients. Further experimental assays verified the up‐regulation of MIR4435‐2HG in GBM tissues and cell lines. In vitro cell studies and in vivo animal studies showed that knockdown of MIR4435‐2HG resulted in the inhibition of GBM cell proliferation and invasion and in vivo tumour growth, while MIR4435‐2HG overexpression driven GBM progression. Furthermore, MIR44435‐2HG was found to sponge miR‐1224‐5p and suppress miR‐1224‐5p expression; overexpression of miR‐1224‐5p attenuated the enhancement in GBM cell proliferation and invasion induced by MIR4435‐2HG overexpression. In a subsequent study, miR‐1224‐5p was found to target transforming growth factor‐beta receptor type 2 (TGFBR2) and repressed TGFBR2 expression, and in vitro assays showed that miR‐1224‐5p exerted tumour‐suppressive effects via targeting TGFBR2. More importantly, TGFRB2 knockdown antagonized hyper‐proliferation and invasion of GBM cells with MIR4435‐2HG overexpression. Clinically, the down‐regulation of miR‐1224‐5p and up‐regulation of TGFBR2 were verified in the GBM clinical samples. Taken together, the present study suggests the oncogenic role of MIR4435‐2HG in GBM and underlies the key function of MIR4435‐2HG‐driven GBM progression via targeting miR‐1224‐5p/TGFBR2 axis.

Long Noncoding RNA LINC-PINT Suppresses Cell Proliferation, Invasion, and EMT by Blocking Wnt/β-Catenin Signaling in Glioblastoma

“…LncRNAs have been verified to play a pivotal role in human disease including GBM by an increasing number of studies. For example, LncRNA MIR4435-2HG potentiates the proliferation and invasion of glioblastoma cells via modulating miR-1224–5p/TGFBR2 axis ( Xu et al, 2020 ). LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway ( Han et al, 2019 ), suggesting that LncRNAs could be used as diagnostic biomarkers and potential therapeutic targets in GBM in the future.…”

LncRNA HOXA‐AS3 promotes the malignancy of glioblastoma through regulating miR‐455‐5p/USP3 axis

“…Glioblastoma multiforme (GBM) is a fast‐growing type of aggressive and lethal primary brain tumour 1,2 . Because the pathologic mechanisms of GBM are not fully understood, more research is needed to identify effective predictive biomarkers and therapeutic targets for GBM 2,3 …”

Long non‑coding RNA MIR4435‑2HG promotes the progression of head and neck squamous cell carcinoma by regulating the miR‑383‑5p/RBM3 axis

“…MIR4435-2HG has also been observed to play a role in several cancers through this regulatory mechanism. For example, MIR4435-2HG knockdown suppressed ovarian cancer cell proliferation, invasion, and migration through the miR-128-3p/CDK14 axis (11), MIR4435-2HG promoted the proliferation and invasion of glioblastoma cells by regulating the miR-1224-5p/TGFBR2 axis (12), and MIR4435-2HG acted as a ceRNA to upregulate YAP1 expression by sponging miR-206 and promoted colorectal cancer growth and metastasis (13). To investigate the mechanism of MIR4435-2HG regulation in HNSCC, bioinformatics analysis indicated that miR-383-5p, a tumor suppressor in several types of cancers, including triple-negative breast cancer, ovarian cancer, and gastric cancer (31-33), has potential MIR4435-2HG binding sites.…”

“…For example, MIR4435-2HG knockdown was shown to suppress the proliferation and invasion of ovarian cancer cells (11). MIR4435-2HG expression is upregulated in glioblastoma tissues and is associated with shorter overall survival in patients with glioblastoma (12). In addition, it serves as an oncogene in colorectal cancer, oral squamous cell carcinoma, non-small cell lung cancer, and gastric cancer (10,(13)(14)(15).…”