Long noncoding RNAs (lncRNAs) have important roles in diverse biological processes. Our previous study has revealed that lncRNA-MALAT1 deregulation is implicated in the pathogenesis of diabetes-related microvascular disease, diabetic retinopathy (DR). However, the role of MALAT1 in retinal vasculature remodeling still remains elusive. Here we show that MALAT1 expression is significantly upregulated in the retinas of STZ-induced diabetic rats and db/db mice. MALAT1 knockdown could obviously ameliorate DR in vivo, as shown by pericyte loss, capillary degeneration, microvascular leakage, and retinal inflammation. Moreover, MALAT1 knockdown could regulate retinal endothelial cell proliferation, migration, and tube formation in vitro. The crosstalk between MALAT1 and p38 MAPK signaling pathway is involved in the regulation of endothelial cell function. MALAT1 upregulation represents a critical pathogenic mechanism for diabetes-induced microvascular dysfunction. Inhibition of MALAT1 may serve as a potential target for anti-angiogenic therapy for diabetes-related microvascular complications.

EML4-ALK gene rearrangements define a unique subset of non-small cell lung cancer (NSCLC) patients and the clinical success of the ALK inhibitor crizotinib in this population has become a paradigm for molecularly-targeted therapy. Here we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, resulting in greater in vitro potency, superior antitumor efficacy and prolonged animal survival compared to crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a NSCLC patient with crizotinib-resistant disease. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinases were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.