Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis.

Extracellular matrix (ECM) homeostasis is essential for normal tissue function, and its disruption by iatrogenic injury, trauma, or disease results in fibrosis. Skin ECM homeostasis is maintained by a complex process that involves an integration of cytokine and environmental mediators. However, it is unclear, in both normal and disease states, how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. Here we show a consistent downregulation in fatty acid oxidation (FAO) and upregulation of glycolysis in fibrotic skin and in normal skin with abundant ECM. Perturbation of glycolysis and FAO pathway enzymes reveals their reciprocal effects in ECM upregulation and downregulation, respectively. Increasing peroxisome proliferator-activated receptor (PPAR) signalling, an inducer of the FAO pathway, generates a catabolic fibroblast phenotype characterised by inhibition of ECM transcription and enhanced ECM internalization and lysosomal degradation. In contrast, suppression of glycolysis inhibits ECM gene transcription and protein levels, independently of an intact FAO pathway or PPAR signalling. Moreover, we show that CD36, a multifunctional fatty acid transporter, connects the metabolic state of fibroblasts with their capacity for ECM regulation, as internalization and degradation of collagen-1 is abrogated in fibroblasts lacking CD36. Finally, restoring FAO and upregulating CD36 reduces ECM accumulation in murine skin fibrosis. These findings indicate that metabolic perturbation of ECM homeostasis may have broad implications for therapies aimed at ECM regulation, such as fibrosis, regenerative medicine, and ageing.

The complexity of microRNAs in human cancer.

MicroRNAs (miRNAs) are small non-coding RNA molecules that have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. Due to the potential roles of miRNAs in improving cancer prognostic, predictive, diagnostic and therapeutic approaches, they have become an area of intense research focus in recent years. MiRNAs harbor attractive features allowing for translation to the clinical world, such as relatively simple extraction methods, resistance to molecular degradation, and ability to be quantified. Numerous prognostic, predictive and diagnostic miRNA signatures have been developed. To date however, miRNA analysis has not been adopted for routine clinical use. The objectives of this article are to provide an overview of miRNA research and review a selection of miRNA studies in breast cancer, cervical cancer, sarcoma, and nasopharyngeal carcinoma to highlight advances and challenges in miRNA cancer research.

Targeting mitochondrial RNA polymerase in acute myeloid leukemia.

Acute myeloid leukemia (AML) cells have high oxidative phosphorylation and mitochondrial mass and low respiratory chain spare reserve capacity. We reasoned that targeting the mitochondrial RNA polymerase (POLRMT), which indirectly controls oxidative phosphorylation, represents a therapeutic strategy for AML. POLRMT-knockdown OCI-AML2 cells exhibited decreased mitochondrial gene expression, decreased levels of assembled complex I, decreased levels of mitochondrially-encoded Cox-II and decreased oxidative phosphorylation. POLRMT-knockdown cells exhibited an increase in complex II of the electron transport chain, a complex comprised entirely of subunits encoded by nuclear genes, and POLRMT-knockdown cells were resistant to a complex II inhibitor theonyltrifluoroacetone. POLRMT-knockdown cells showed a prominent increase in cell death. Treatment of OCI-AML2 cells with 10-50 µM 2-C-methyladenosine (2-CM), a chain terminator of mitochondrial transcription, reduced mitochondrial gene expression and oxidative phosphorylation, and increased cell death in a concentration-dependent manner. Treatment of normal human hematopoietic cells with 2-CM at concentrations of up to 100 µMdid not alter clonogenic growth, suggesting a therapeutic window. In an OCI-AML2 xenograft model, treatment with 2-CM (70 mg/kg, i.p., daily) decreased the volume and mass of tumours to half that of vehicle controls. 2-CM did not cause toxicity to major organs. Overall, our results in a preclinical model contribute to the functional validation of the utility of targeting the mitochondrial RNA polymerase as a therapeutic strategy for AML.