miR-29a Negatively Affects Glucose-Stimulated Insulin Secretion and MIN6 Cell Proliferation via Cdc42/ß-Catenin Signaling.

BACKGROUND: Diabetes is a progressive metabolic disease characterized by hyperglycemia. Functional impairment of islet ß cells can occur to varying degrees. This impairment can initially be compensated for by proliferation and metabolic changes of ß cells. Cell division control protein 42 (Cdc42) and the microRNA (miRNA) miR-29 have important roles in ß-cell proliferation and glucose-stimulated insulin secretion (GSIS), which we further explored using the mouse insulinoma cell line MIN6. METHODS: Upregulation and downregulation of miR-29a and Cdc42 were accomplished using transient transfection. miR-29a and Cdc42 expression was detected by real-time PCR and western blotting. MIN6 proliferation was detected using a cell counting kit assay. GSIS under high-glucose (20.0 mM) or basal-glucose (5.0 mM) stimulation was detected by enzyme-linked immunosorbent assay. The miR-29a binding site in the Cdc42 mRNA 3'-untranslated region (UTR) was determined using bioinformatics and luciferase reporter assays. RESULTS: miR-29a overexpression inhibited proliferation (P < 0.01) and GSIS under high-glucose stimulation (P < 0.01). Cdc42 overexpression promoted proliferation (P < 0.05) and GSIS under high-glucose stimulation (P < 0.05). miR-29a overexpression decreased Cdc42 expression (P < 0.01), whereas miR-29a downregulation increased Cdc42 expression (P < 0.01). The results showed that the Cdc42 mRNA 3'-UTR is a direct target of miR-29a in vitro. Additionally, Cdc42 reversed miR-29a-mediated inhibition of proliferation and GSIS (P < 0.01). Furthermore, miR-29a inhibited ß-catenin expression (P < 0.01), whereas Cdc42 promoted ß-catenin expression (P < 0.01). CONCLUSION: By negatively regulating Cdc42 and the downstream molecule ß-catenin, miR-29a inhibits MIN6 proliferation and insulin secretion.

Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases.

Cdc42, a member of the Rho GTPases family, is involved in the regulation of several cellular functions including cell cycle progression, survival, transcription, actin cytoskeleton organization and membrane trafficking. Diabetes is a chronic and metabolic disease, characterized as glycometabolism disorder induced by insulin deficiency related to ß cell dysfunction and peripheral insulin resistance (IR). Diabetes could cause many complications including diabetic nephropathy (DN), diabetic retinopathy and diabetic foot. Furthermore, hyperglycemia can promote tumor progression and increase the risk of malignant cancers. In this review, we summarized the regulation of Cdc42 in insulin secretion and diabetes-associated diseases. Organized researches indicate that Cdc42 is a crucial member during the progression of diabetes, and Cdc42 not only participates in the process of insulin synthesis but also regulates the insulin granule mobilization and cell membrane exocytosis via activating a series of downstream factors. Besides, several studies have demonstrated Cdc42 as participating in the pathogenesis of IR and DN and even contributing to promote cancer cell proliferation, survival, invasion, migration, and metastasis under hyperglycemia. Through the current review, we hope to cast light on the mechanism of Cdc42 in diabetes and associated diseases and provide new ideas for clinical diagnosis, treatment, and prevention.

Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates.

Despite great improvements in the diagnosis and treatment of neoplasms, metastatic disease is still the leading cause of death in cancer patients, with mortality rates still rising. Given this background, new ways to treat cancer will be important for development of improved cancer control strategies. Cdc42 is a member of the Rho GTPase family and plays an important role in cell-to-cell adhesion, formation of cytoskeletal structures, and cell cycle regulation. It thus influences cellular proliferation, transformation, and homeostasis, as well as the cellular migration and invasion processes underlying tumor formation. Cdc42 acts as a collection point for signal transduction and regulates multiple signaling pathways. Moreover, recent studies show that in most human cancers Cdc42 is abnormally expressed and promoting neoplastic growth and metastasis. Regarding possible new treatments for cancer, miRNA and small molecules targeting Cdc42 and related pathways have been recently found to be effective on cancer. In this review, we analyze the newly recognized regulation mechanisms for Cdc42 and Cdc42-related signal pathways, and particularly new treatments using small molecules and miRNAs to inhibit the abnormal overexpression of Cdc42 that may slow down the metastasis process, improve cancer therapy and lead to novel strategies for development of antineoplastic drugs.