Hypoxia macrophage-derived exosomal miR-26b-5p targeting PTEN promotes the development of keloids.

Background: Hypoxia is the typical characteristic of keloids. The development of keloids is closely related to the abnormal phenotypic transition of macrophages. However, the role of exosomal microRNAs (miRNAs) derived from hypoxic macrophages in keloids remains unclear. This study aimed to explore the role of hypoxic macrophage-derived exosomes (HMDE) in the occurrence and development of keloids and identify the critical miRNA. Methods: The expression of CD206+ M2 macrophage in keloids and normal skin tissues was examined through immunofluorescence. The polarization of macrophages under a hypoxia environment was detected through flow cytometry. The internalization of macrophage-derived exosomes in human keloid fibroblasts (HKFs) was detected using a confocal microscope. miRNA sequencing was used to explore the differentially expressed miRNAs in exosomes derived from the normoxic and hypoxic macrophage. Subsequently, the dual-luciferase reporter assay verified that phosphatase and tension homolog (PTEN) was miR-26b-5p's target. The biological function of macrophage-derived exosomes, miR-26b-5p and PTEN were detected using the CCK-8, wound-healing and Transwell assays. Western blot assay was used to confirm the miR-26b-5p's underlying mechanisms and PTEN-PI3K/AKT pathway. Results: We demonstrated that M2-type macrophages were enriched in keloids and that hypoxia treatment could polarize macrophages toward M2-type. Compared with normoxic macrophages-derived exosomes (NMDE), HMDE promote the proliferation, migration and invasion of HKFs. A total of 38 differential miRNAs (18 upregulated and 20 downregulated) were found between the NMDE and HMDE. miR-26b-5p was enriched in HMDE, which could be transmitted to HKFs. According to the results of the functional assay, exosomal miR-26b-5p produced by macrophages facilitated HKFs' migration, invasion and proliferation via the PTEN-PI3K/AKT pathway. Conclusions: The highly expressed miR-26b-5p in HMDE promotes the development of keloids via the PTEN-PI3K/AKT pathway.

Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization.

SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy.

Pillared Metal-Organic Framework Initiating Intermolecular Atom-Transfer Radical Addition via Visible-Light-Induced Electron Transfer Activation of Haloalkanes.

Herein, a novel metal-organic framework (MOF) with a pillared-layer structure was rationally synthesized to initiate intermolecular atom-transfer radical addition (ATRA) via photoinduced electron transfer activation of haloalkanes. The MOF synthesized via the controllable pillared-layer method is of excellent visible-light absorption and high chemical stability. Photocatalytic experiments show the atom transfer of various alkyl halides (R-X, X = Cl/Br/I) onto diverse olefins was successfully achieved to produce functional ATRA products. The mechanism and experimental investigations reveal the prepared MOF serves as an efficient photocatalyst with strong reduction potential to activate haloalkane substrates via photoinduced electron transfer, generating a highly reactive alkyl radical to trigger the ATRA reaction. Key events in the ATRA reaction, including alkyl radical photogeneration as well as halide transfer, have been further regulated to achieve preferable photocatalytic performance with higher yields, shorter reaction time, and desirable cycling capability. It is notable that the work is the first report on photoinduced electron transfer activation of halides by a MOF photocatalyst for the ATRA reaction, providing a new blueprint for MOFs to develop photoinduced radical reactions.

Photoactive Metal-Organic Frameworks for the Selective Synthesis of Thioethers: Coupled with Phosphine to Modulate Thiyl Radical Generation.

Metal-organic framework (MOF) materials are intriguing photocatalysts to trigger radical-mediated chemical transformations. We report herein the synthesis and characterization of a series of isomorphic MOFs which show a novel structure, wide visible-light absorption, high chemical stability, and specific redox potential. The prepared MOFs were explored for the photoinduced single-electron oxidation of thiol compounds, generating reactive thiyl radicals to afford thioethers via a convenient thiol-olefin reaction. Importantly, we provide a widely applicable strategy by combing a photoactive MOF with phosphine to modulate the generation of thiyl radical in the reaction, thereby producing a single product of the thioether without the formation of a disulfide byproduct due to the dimerization of thiyl radicals. The photocatalytic reaction takes advantage of this strategy, showing great generality where tens of thiols and olefins have been examined as coupling partners. In addition, the strategy has also been demonstrated to be effective for the reactions catalyzed by other MOFs. Mechanism studies reveal that the selective synthesis of C-S products relies on a synergy between the photoinduced generation of a thiyl radical over the MOF and the in situ cleavage of S-S bond into a S-H bond by phosphine. It is notable that the synthesized MOFs show advanced performance in comparison with classical MOFs. The work not only provides a series of novel MOF photocatalysts that are capable of photoinduced thiol-olefin coupling but also indicates the great potential of MOFs for photochemical transformations mediated by reactive radicals.

PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.

Transforming growth factor ß (TGFß) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGFß signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFß-SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFß signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo In addition, TGFß signaling and TGFß-induced epithelial-mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFß-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFß signaling and NSCLC progression.