No abstract

Although gradients play an essential role in guiding the function of tissues, achieving synchronous regeneration of gradient tissue injuries remains a challenge. Here, a gradient bimetallic (Cu and Zn) ion–based hydrogel was first constructed via the one-step coordinative crosslinking of sulfhydryl groups with copper and zinc ions for the microstructure reconstruction of the tendon-to-bone insertion. In this bimetallic hydrogel system, zinc and copper ions could not only act as crosslinkers but also provide strong antibacterial effects and induce regenerative capacity in vitro. The capability of hydrogels in simultaneously promoting tenogenesis and osteogenesis was further verified in a rat rotator cuff tear model. It was found that the Cu/Zn gradient layer could induce considerable collagen and fibrocartilage arrangement and ingrowth at the tendon-to-bone interface. Overall, the gradient bimetallic ion–based hydrogel ensures accessibility and provides opportunities to regenerate inhomogeneous tissue with physiological complexity or interface tissue.

Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.

Taken together, our data reveal that up-regulation of LOXL4 expression is a frequent event in GC progression, contributes to tumor cell proliferation and metastasis, and LOXL4 may be a potential independent prognostic marker and therapeutic target for GC.