MicroRNA-197 inhibits cell proliferation by targeting GAB2 in glioblastoma

Abstract

Abstract. Glioblastoma is the most common type of primary brain tumor in adults, and is usually fatal in a short duration. Acquiring a better understanding of the pathogenic mechanisms of glioblastoma is essential to the design of effective therapeutic strategies. Grb2-associated binding protein 2 (GAB2) is a member of the daughter of sevenless/Gab family of scaffolding adapters, and has been reported to be important in the development and progression of human cancer. Previously, it has been reported that GAB2 is expressed at high levels in glioma, and may serve as a useful prognostic marker for glioma and a novel therapeutic target for glioma invasion intervention. Elucidating why GAB2 is overexpressed in glioma, and investigating how to downregulate it will assist in further understanding the pathogenesis and progression of the disease, and to offer novel targets for therapy. The present study used in situ hybridization to detect microRNA (miR)-197 expression levels and Targetscan to predict that the 3'-UTR of GAB2 was targeted by miR-197. Northern blotting and reverse transcription-quantitative polymerase chain reaction were also conducted in the current study. miR-197 is downregulated in glioblastoma tissues, compared with adjacent normal tissues, however it involvement continues to be detected in the disease. The results of the present study demonstrated that miR-197, as a tumor suppressor gene, inhibited proliferation by regulating GAB2 in glioblastoma cells. Furthermore, GAB2 was not only upregulated in glioma, but its expression levels were also associated with the grades of glioma severity. In addition, overexpression of GAB2 suppressed the expression of miR-197 in glioblastoma cells. Therefore, restoration of miR-197 and targeting GAB2 may be used, in conjunction with other therapies, to prevent the progression of glioblastoma. IntroductionMicroRNAs (miRNAs; miRs) are short, non-coding RNAs, which regulate target mRNA by binding predominantly to the 3'-untranslated region (3'-UTR), inducing either translational repression or the degradation of the mRNA target (1-3). Previously, the involvement of miRNAs in the phenotypic modulation of human glioma has been reported. For example, miRNA-21 knockdown disrupts glioma growth in vivo and exhibits synergistic cytotoxicity with neural precursor cell-delivered secretable tumor necrosis factor-related apoptosis-inducing ligand in human glioma (4); miRNA-34a acts as a tumor suppressor in brain tumors and glioma stem cells (5); and miRNA-181a sensitizes human U87MG malignant glioma cells to radiation by targeting B cell lymphoma 2 (6). Although miR-197 is downregulated in glioblastoma, its roles in malignant tumor progression remain to be elucidated (7).Grb2-associated binding protein (GAB)2 belongs to a family of evolutionarily conserved proteins consisting of three mammalian paralogues: GAB1, GAB2 and GAB3; Drosophila melanogaster homolog daughter of sevenless; and Caenorhabditis elegans homolog suppressor of clear. Family members exhibit 40-50% sequence homolog...

MicroRNA-197 inhibits gastric cancer progression by directly targeting metadherin

“…miR-197 serves as a tumour suppressor in tumourigenicity and tumour progression. It has been reported that miR-197 inhibits cell growth and metastasis of glioblastoma (23,39). A previous study revealed that miR-197 upregulation increased the sensitivity of colorectal cancer cells to 5-fluorouracil (40), and another demonstrated that restoration of miR-197 expression represses cell viability, colony formation and cell migration, and induces apoptosis in multiple myeloma (24).…”

Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

“…*P , 0.05, **P , 0.01. (51,52). In the present study, inhibitors of PI3K, MEK, or Jak2 significantly suppressed Gab2-mediated HepG2 cell proliferation and migration.…”

“…Moreover, Gab2 contributes to the angiogenic switch by increasing hypoxia-inducible factor-1α and VEGF levels in melanoma (29). In glioblastoma, both miRNA-197 and miR125a-5p inhibit glioma cell proliferation and invasion by negatively regulating Gab2 (51, 52). In the present study, inhibitors of PI3K, MEK, or Jak2 significantly suppressed Gab2-mediated HepG2 cell proliferation and migration.…”

miR‑197 is downregulated in cervical carcinogenesis and suppresses cell proliferation and invasion through targeting forkhead box M1

“…Therefore, understanding the roles of miRs may be important for providing new insights into the involved molecule mechanism in cancer initiation and development and defining novel markers for cancer prognosis, diagnosis and treatment (19). Previously, miR-197 has been reported to be downregulated in glioblastoma (20), uterine leiomyoma (21), multiple myeloma (22) and esophageal cancer (23), and upregulated in non-small cell lung cancer (24), taxol-resistant ovarian cancer (25) and hepatocellular carcinoma (26).…”

“…For example, restoration of miR-197 decreased cell proliferation through negative regulation of Grb-associated-binding protein 2 (20). In uterine leiomyoma, upregulation of miR-197 inhibited cellular proliferation and promoted cell cycle arrest in G0/G1 phase in vitro (21).…”