Abstract. MicroRNAs (miRNAs/miRs) are a type of highly conserved, small non-coding RNA that are vital to the post-transcriptional regulation of gene expression via base pairing with target mRNA 3'-untranslated regions (3'-UTRs). Several studies have indicated that the abnormal expression of miRNAs occurs frequently in human osteosarcoma (OS). In the present study, the role of miR-26a in the progression and metastasis of OS was investigated using reverse transcription-quantitative polymerase chain reaction, a luciferase activity assay, cell viability assay, in vitro migration and invasion assays, transfection and western blot analysis. miR-26a was upregulated in OS tissues and cell lines, and the expression of miR-26a was indicated to affect the proliferation, migration and invasion of OS Saos-2 cells. At the molecular level, the results showed that glycogen synthase kinase-3β (GSK-3β) was identified as a target of miR-26a, and the ectopic expression of miR-26a inhibited GSK-3β by directly binding to the 3'-UTR. Therefore, the expression of miR-26a was negatively correlated with GSK-3β in the OS tissues. These data suggest that miR-26a is significant in the proliferation of human OS cells due to the direct regulation of Wnt/β-catenin signaling. IntroductionOsteosarcoma (OS) is the most common primary malignant bone tumor, occurring frequently in adolescents and possessing a high malignant severity (1-4). OS is commonly identified on the distal femur and proximal tibia, possessing high rates of recurrence and metastasis, and a poor prognosis. Previously, surgical resection therapy resulted in a poor prognosis for OS patients (2). At present, the molecular pathogenesis and etiology of OS remain unclear. Therefore, the identification of the effector molecules or signaling pathways responsible for regulating tumor growth and metastasis is critical for improving OS treatment.MicroRNAs (miRNAs/miRs) are a type of highly conserved, small non-coding RNA that are vital to the post-transcriptional regulation of gene expression via base pairing with target mRNA 3'-untranslated regions (3'-UTRs) (5,6). Previous studies have indicated that the abnormal expression of miRNAs is closely associated with cell proliferation, apoptosis, metastasis and invasion in human cancers, including OS (7,8). miRNAs function as either tumor suppressors or oncogenes, depending on the role of the target genes. Previous studies have indicated that the inhibition of miR-26a may induce increased apoptosis in primary cultured chronic lymphocytic leukemia cells through suppression of phosphatase and tensin homolog (9). In addition, miR-26a inhibits hepatitis B virus transcription and replication by targeting the host factor cysteine and histidine-rich domain-containing, zinc-binding protein 1 (10).In the present study, the miRNA expression profiles of human OS samples and cell lines were compared with those of adjacent normal skeletal muscle and normal cell lines. miR-26a was indicated to be upregulated in human OS and cell lines, and the expression o...

Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In our study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP-seq and RNA-seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation. *Z.-H.L., M.-L.C., Q.Z. and Y.Z contributed equally to this work. Additional Supporting Information may be found in the online version of this article. hairpin RNA; si: small interfering RNA; STAT3: signal transducers and activators of transcription 3; ZIC: zinc finger protein of the cerebellum

Caterpillar oral secretion (OS) contains active molecules that modulate plant defense signaling. We isolated an effector-like protein (Highly Accumulated Secretory Protein 1, HAS1) from cotton bollworm (Helicoverpa armigera) that is the most highly accumulated secretory protein of the nondigestive components in OS and belongs to venom R-like protein.Elimination of HAS1 by plant-mediated RNA interference reduced the suppression of OS on the defense response in plants. Plants expressing HAS1 are more susceptible to insect herbivory accompanied by the reduced expressions of multiple defense genes.HAS1 binds to the basic helix-loop-helix (bHLH) transcription factors, including GoPGF involved in pigmented gland formation and defense compounds biosynthesis in cotton and MYC3/MYC4 the main regulators in jasmonate (JA) signaling in Arabidopsis. The binding activity is required for HAS1 to inhibit the activation of bHLHs on plant defense gene expressions.Together with our previous study that another venom R-like protein HARP1 in cotton bollworm OS blocks JA signaling by interacting with JASMONATE-ZIM-domain repressors, we conclude that the venom R-like proteins in OS interfere with plant defense in a dual suppression manner. Considering the venom proteins in parasitic wasp assault the immune system of its host animal, our investigation reveals their conserved function in carnivorous and herbivorous insects.