ABSTRACT
Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a-5p/Stat3/hnRNP-A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 expression, hnRNP-A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a-5p, which functionally targets Stat3, whereas hnRNP-A1 blocks the biogenesis of let-7a-5p to counteract its ability to downregulate the Stat3/hnRNP-A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP-A1/PKM2 by let-7a-5p is verified using a breast cancer. These results suggest that let-7a-5p, Stat3, and hnRNP-A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention.
Subject(s)
Breast Neoplasms/pathology , Carrier Proteins/metabolism , Gene Expression Regulation, Neoplastic , Glucose/metabolism , Heterogeneous Nuclear Ribonucleoprotein A1/metabolism , Membrane Proteins/metabolism , MicroRNAs/metabolism , STAT3 Transcription Factor/metabolism , Thyroid Hormones/metabolism , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carrier Proteins/genetics , Cell Proliferation , Feedback, Physiological , Female , Glycolysis , Heterogeneous Nuclear Ribonucleoprotein A1/genetics , Humans , Membrane Proteins/genetics , MicroRNAs/genetics , Prognosis , STAT3 Transcription Factor/genetics , Thyroid Hormones/genetics , Tumor Cells, Cultured , Thyroid Hormone-Binding ProteinsABSTRACT
Understanding the effects of intermolecular interactions on the charge-transport properties of metal/molecule/metal junctions is an important step towards using individual molecules as building blocks for electronic devices. This work reports a systematic electron-transport investigation on a series of "core-shell"-structured oligo(phenylene ethynylene) (Gn-OPE) molecular wires. By using dendrimers of different generations as insulating "shells", the intermolecular π-π interactions between the OPE "cores" can be precisely controlled in single-component monolayers. Three techniques are used to evaluate the electron-transport properties of the Au/Gn-OPE/Au molecular junctions, including crossed-wire junction, scanning tunneling spectroscopy (STS), and scanning tunneling microscope (STM) break-junction techniques. The STM break-junction measurement reveals that the electron-transport pathways are strongly affected by the size of the side groups. When the side groups are small, electron transport could occur through three pathways, including through single-molecule junctions, double-molecule junctions, and molecular bridges between adjacent molecules formed by aromatic π-π coupling. The dendrimer shells effectively prohibit the π-π coupling effect, but at the same time, very large dendrimer side groups may hinder the formation of Au-S bonds. A first-generation dendrimer acts as an optimal shell that only allows electron transport through the single-molecule junction pathway, and forbids the other undesired pathways. It is demonstrated that the dendrimer-based core-shell strategy allows the single-molecule conductance to be probed in a homogenous monolayer without the influence of intermolecular π-π interactions.
