Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ-binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO-1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane-associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/ß-catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing ß-catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/ß-catenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/ß-catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression.
Membrane Proteins/metabolism , Uterine Cervical Neoplasms/metabolism , Wnt Signaling Pathway/physiology , Adaptor Proteins, Signal Transducing/metabolism , Cell Line, Tumor , Cell Movement/genetics , China , Female , Gene Expression Regulation, Neoplastic , Human papillomavirus 18/metabolism , Human papillomavirus 18/pathogenicity , Humans , Membrane Proteins/genetics , Neoplasm Invasiveness/genetics , Oncogene Proteins, Viral/metabolism , Papillomavirus Infections , Repressor Proteins/metabolism , Transcription Factors/metabolism , Uterine Cervical Neoplasms/physiopathology , Wnt Signaling Pathway/genetics , beta Catenin/metabolism
The Mas receptor has been reported to promote migration and invasion of clear cell renal cell carcinoma (ccRCC) cells via Ang-(1-7)-dependent AKT signaling. However, the mechanism underlying the regulation of Mas function remains unknown. Here, eight PDZ domain-containing proteins were identified as Mas interactors using surface plasmon resonance (SPR) coupled to mass spectrometry (MS). NHERF4 was the only downregulated gene across multiple independent ccRCC datasets. GST pull-down and co-immunoprecipitation assays confirmed physical interaction between NHERF4 and Mas. Using NHERF4 overexpression and knockdown assays, we found that NHERF4 inhibited Mas-induced migration, invasion and in vivo metastasis of ccRCC cells. Mechanistically, NHERF4 suppressed Mas-stimulated AKT phosphorylation and the PLC/Ca2+ response. We further demonstrated that NHERF4 compromised Mas-mediated migration and invasion of ccRCC cells via regulation of the PLC/AKT signaling axis. Analysis of the ccRCC dataset revealed that low levels of NHERF4 expression were correlated with higher TNM stage, and independently predicted poor prognosis of ccRCC patients. Overall, our study identified NHERF4 as a novel regulator of ccRCC invasiveness, and a prognostic biomarker, which may be beneficial for determining optimal therapeutic strategies for ccRCC patients.
Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , Phosphoproteins/metabolism , Proto-Oncogene Mas/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , Sodium-Hydrogen Exchangers/metabolism , Animals , COS Cells , Carcinoma, Renal Cell/pathology , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , HEK293 Cells , Humans , Kidney Neoplasms/pathology , Phosphorylation/physiology
A series of monomethoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) diblock copolymers were synthesized, and mPEG-PLA micelle was fabricated and used as a nanocarrier for solubilization and delivery of a promising anticancer drug ethaselen. Ethaselen was efficiently encapsulated into the micelles by the dialysis method, and the solubility of ethaselen in water was remarkably increased up to 82 µg/mL before freeze-drying. The mean diameter of ethaselen-loaded micelles ranged from 51 to 98 nm with a narrow size distribution and depended on the length of PLA block. In vitro hemolysis study indicated that mPEG-PLA copolymers and ethaselen-loaded polymeric micelles had no hemolytic effect on the erythrocyte. The enhanced antitumor efficacy and reduced toxic effect of ethaselen-loaded polymeric micelle when compared with ethaselen-HP-ß-CD inclusion were observed at the same dose in H22human liver cancer cell bearing mouse models. These suggested that mPEG-PLA polymeric micelle nanoparticles had great potential as nanocarriers for effective solubilization of poorly soluble ethaselen and further reducing side effects and toxicities of the drug.
