Comprehensive analysis of the oncogenic and immunological role of FAP and identification of the ceRNA network in human cancers.

Fibroblast activation protein-alpha (FAP) is a transmembrane serine protease involving in tissue remodeling. Previous studies report that FAP is highly expressed in certain tumors and participated in oncogenesis. However, there is still lack of systematic and in-depth analysis of FAP based on clinical big data. Here, we comprehensively map the FAP expression profile, prognostic outcome, genetic alteration, immune infiltration across over 30 types of human cancers through multiple datasets including TCGA, CPTAC, and cBioPortal. We find that FAP is up-regulated in most cancer types, and increased FAP expression is associated with advanced pathological stages or poor prognosis in several cancers. Furthermore, FAP is significantly correlated with the infiltration of cancer-associated fibroblasts, macrophages, myeloid dendritic cells, as well as endothelia cells. Immunosuppressive checkpoint proteins or cytokines expression, microsatellite instability and tumor mutational burden analysis also indicate the regulation role of FAP in tumor progression. Gene enrichment analysis demonstrates that ECM-receptor interaction as well as extracellular matrix and structure process are linked to the potential mechanism of FAP in tumor pathogenesis. The ceRNA network is also constructed and identified the involvement of LINC00707/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30d-5p/FAP, as well as AC026356.1/hsa-miR-30d-5p/FAP axis in tumor progression. In conclusion, our study offers new insights into the oncogenic and immunological role of FAP from a pan-cancer perspective, providing new clues for developing novel targeted anti-tumor strategies.

Morin Treatment Delays the Ripening and Senescence of Postharvest Mango Fruits.

A 0.005% and 0.01% morin treatment was applied to treat mango fruits stored under ambient conditions (25 ± 1 °C) with 85-90% relative humidity, and the effects on quality indexes, enzyme activity related to antioxidation and cell wall degradation, and gene expressions involved in ripening and senescence were explored. The results indicate that a 0.01% morin application effectively delayed fruit softening and yellowing and sustained the nutritional quality. After 12 days of storage, the contents of soluble sugar and carotenoid in the treatment groups were 68.54 mg/g and 11.20 mg/100 g, respectively, lower than those in control, while the vitamin C content in the treatment groups was 0.58 mg/g, higher than that in control. Moreover, a morin application successively enhanced the activity of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD), but reduced the activity of polygalacturonase (PG) and pectin lyase (PL). Finally, real-time PCR and correlation analysis suggested that morin downregulated the ethylene biosynthesis (ACS and, ACO) and signal transduction (ETR1, ERS1, EIN2, and ERF1) genes, which is positively associated with softening enzymes (LOX, EXP, ßGal, and EG), carotenoid synthesis enzymes (PSY and, LCYB), sucrose phosphate synthase (SPS), and uncoupling protein (UCP) gene expressions. Therefore, a 0.01% morin treatment might efficiently retard mango fruit ripening and senescence to sustain external and nutritional quality through ethylene-related pathways, which indicates its preservation application.

Targeting platelet-derived growth factor receptor ß inhibits the proliferation and motility of human pterygial fibroblasts.

Background: Pterygium, a common eye disease with high postoperative recurrence, lacks effective therapeutic strategies. Therefore, it's urgent to identify specific targets to develop rationally targeted molecular drugs for the pterygial therapy. Methods: The cell proliferation and motility were studied in both the primary human pterygial fibroblasts (hPFs) and an ex vivo pterygium model. hPFs transfected with the pCMV3-PDGFRB plasmid, PDGFRB siRNA and CRISPR/Cas9 system were used to determine the role of PDGFR-ß in pterygial fibroblasts functions. Western blotting, immunohistochemistry and immunofluorescence were performed to evaluate the expression of the key proteins. Results: PDGFR-ß expression in the pterygial stroma and primary hPFs was significantly higher than that in the conjunctiva and human conjunctival fibroblasts. PDGF-BB promoted the proliferation, migration and invasion of hPFs, which can be significantly suppressed by sunitinib via inhibition of the PDGFR-ß/extracellular signal-regulated kinase (ERK) pathway. In the ex vivo model, the knockout of PDGFRB and sunitinib treatment blocked the proliferation and motility of fibroblasts in the pterygial stroma via the suppression of PDGFR-ß/ERK pathway. Conclusion: This study demonstrates that PDGFR-ß may be a potential therapeutic target for pterygium, and inhibition of PDGFR-ß by sunitinib is a promising and effective approach for pterygium treatment.

Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents.

Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.

Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating ß-catenin.

Epithelial-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis; thus, developing EMT inhibitors may be a feasible treatment for metastatic PCa. Here, we discovered that arenobufagin and four other bufadienolides suppressed PC3 cell EMT. These compounds modulated EMT marker expression with elevating E-cadherin and reducing ZEB1, vimentin and slug expression, and attenuated the migration and invasion of PC3 cells. Among these five compounds, arenobufagin exhibited the most potent activity. We found that the mRNA and protein expression of ß-catenin and ß-catenin/TCF4 target genes, which are related to tumor invasion and metastasis, were down-regulated after arenobufagin treatment. Overexpression of ß-catenin in PC3 cells antagonized the EMT inhibition effect of arenobufagin, while silencing ß-catenin with siRNA enhanced the inhibitory effect of arenobufagin on EMT. In addition, arenobufagin restrained xenograft tumor EMT, as demonstrated by decreased mesenchymal marker expression and increased epithelial marker expression, and reduced the tumor metastatic foci in lung. This study demonstrates a novel anticancer activity of arenobufagin, which inhibits PC3 cell EMT by down-regulating ß-catenin, thereby reducing PCa metastasis. In addition, it also provides new evidence for the development of arenobufagin as a treatment for metastatic prostate cancer.