Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted CLIC1 spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a PIP2-rich microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli resulting in suppressed lung metastasis in mice. This study reveals an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.
The effects of Ganoderma lucidum polysaccharides (GL-PS) on renal complication in streptozotocin-induced diabetic mice have been investigated in the present study. C57BL/6J mice were made diabetic by injection of streptozotocin and GL-PS (125 and 250 mg kg-1) was administered for 8 weeks. Body weight was monitored every week. Serum glucose, creatinine (Cr), blood urea nitrogen (BUN), triglyceride (TG) and urinary albumin excretion (UAE) were measured after 8 weeks of treatment. Glomerular size and mesangial matrix index were assayed by morphometric analysis. Renal expression of transforming growth factor-beta1 (TGF-beta1) were determined by immunochemistry. Renal malondialdehyde (MDA) level and superoxide dismutase (SOD) activities were also evaluated. GL-PS was able to reduce the serum Cr and BUN levels and UAE compared with diabetic model mice in a dose-dependent manner. Increasing serum glucose and triglyceride levels in diabetic mice could also be lowered by GL-PS. Moreover, GL-PS had the capacity to improve the renal morphometric changes and oxidative stress state of diabetic mice. In summary, GL-PS can improve the metabolic abnormalities of diabetic mice and prevent or delay the progression of diabetic renal complications.
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