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Background and Aims Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE. Approach and Results Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41‐miRNA signature related to HCC recurrence after adjuvant TACE, and miR‐125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR‐125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR‐125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1α)/pAKT loop in vitro and in vivo. miR‐125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB‐1, and blocked an autocrine HIF1α/platelet‐derived growth factor β (PDGFβ)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFβ receptor. The miR‐125b‐loss/HIF1α axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE‐resistant CD24‐positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first‐line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE. Conclusions MiR‐125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.

Chromosomal translocations and activation of the FGF receptor FGFR1 are a feature of stem cell leukemia-lymphoma syndrome (SCLL), an aggressive malignancy characterized by rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. It has been suggested that FGFR1 proteins lose their ability to recruit Src kinase, an important mediator of FGFR1 signaling, as a result of the translocations that delete the extended FGF receptor substrate-2 (FRS2) interacting domain that Src binds. In this study, we report evidence that refutes this hypothesis and reinforces the notion that Src is a critical mediator of signaling from the FGFR1 chimeric fusion genes generated by translocation in SCLL. Src was constitutively active in BaF3 cells expressing exogenous FGFR1 chimeric kinases cultured in vitro as well as in T-cell or B-cell lymphomas they induced in vivo. Residual components of the FRS2 binding site retained in chimeric kinases that were generated by translocation were sufficient to interact with FRS2 and activate Src. The Src kinase inhibitor dasatinib killed transformed BaF3 cells and other established murine leukemia cell lines expressing chimeric FGFR1 kinases, significantly extending the survival of mice with SCLL syndrome. Our results indicated that Src kinase is pathogenically activated in lymphomagenesis induced by FGFR1 fusion genes, implying that Src kinase inhibitors may offer a useful option to treat of FGFR1-associated myeloproliferative/lymphoma disorders.

Angiogenesis contributes fundamentally to embryonic development, tissue homeostasis, and wound healing. Basic fibroblast growth factor (FGF2) is recognized as the first proangiogenic molecule discovered, and it facilitates angiogenesis by activating FGF receptor 1 (FGFR1) signaling in endothelial cells. However, the precise roles of FGFR and the FGF/FGFR signaling axis in angiogenesis remain unclear, especially because of the contradictory phenotypes of in vivo FGF and FGFR gene deficiency models. Our previous study results suggested a potential role of posttranslational small ubiquitin-like modifier modification (SUMOylation), with highly dynamic regulatory features, in vascular development and disorder. Here, we identified SENP1-regulated endothelial FGFR1 SUMOylation at conserved lysines responding to proangiogenic stimuli, while SENP1 functioned as the deSUMOylase. Hypoxia-enhanced FGFR1 SUMOylation restricted the tyrosine kinase activation of FGFR1 by modulating the dimerization of FGFR1 and FGFR1 binding with its phosphatase PTPRG. Consequently, it facilitated the recruitment of FRS2α to VEGFR2 but limited additional recruitment of FRS2α to FGFR1, supporting the activation of VEGFA/VEGFR2 signaling in endothelial cells. Furthermore, SUMOylation-defective mutation of FGFR1 resulted in exaggerated FGF2/FGFR1 signaling but suppressed VEGFA/VEGFR2 signaling and the angiogenic capabilities of endothelial cells, which were rescued by FRS2α overexpression. Reduced angiogenesis and endothelial sprouting in mice bearing an endothelial-specific, FGFR1 SUMOylation-defective mutant confirmed the functional significance of endothelial FGFR1 SUMOylation in vivo. Our findings identify the reversible SUMOylation of FGFR1 as an intrinsic fine-tuned mechanism in coordinating endothelial angiogenic signaling during neovascularization; SENP1-regulated FGFR1 SUMOylation and deSUMOylation controls the competitive recruitment of FRS2α by FGFR1 and VEGFR2 to switch receptor-complex formation responding to hypoxia and normoxia angiogenic environments.

Angiogenesis is involved in development, reproduction, wound healing, homeostasis and other pathophysiological events. Imbalanced angiogenesis predisposes patients to various pathological processes, such as angiocardiopathy, inflammation and tumorigenesis. MicroRNAs (miRNAs) have been found to be important in regulating cellular processing and physiological events including angiogenesis. However, the role of miRNAs that regulate angiogenesis (angiomiRs) is not fully understood. Here, we observed a downregulation of the miR-196 family in endothelial cells upon hypoxia. Functionally, miR-196b-5p inhibited the angiogenic functions of endothelial cells in vitro and suppressed angiogenesis in Matrigel plugs and skin wound healing in vivo. Mechanistically, miR-196b-5p bound onto the 3'UTR of HMGA2 mRNA and repressed the translation of HMGA2, which in turn represses HIF1α accumulation in endothelial cells upon hypoxia. Together, our results establish the role of endothelial miR-196b-5p as an angiomiR that negatively regulates endothelial growth in angiogenesis via the hypoxia/miR-196b-5p/HMGA2/HIF1α loop. MiR-196b-5p and its regulatory loop could be an important addition to the molecular mechanisms underlying angiogenesis and may serve as potential targets for anti-angiogenic therapy.

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<p>PDF file - 138K</p>

<p>PDF file - 138K</p>