Wnt/ß-catenin Signaling Inhibitors.

The Wnt/ß-catenin signaling pathway plays a crucial role in the development, tissue homeostasis, angiogenesis, and carcinogenesis of cancer. Mutations and excessive activation of the Wnt/ß-catenin signaling pathway in cancer cells and cancer stem cells lead to drug resistance and recurrence of cancer in patients treated with conventional chemotherapy and radiotherapy. Upregulation of proangiogenic factors is persistently induced by hyperactivated Wnt/ß-catenin signaling during tumor angiogenesis. Furthermore, mutations and hyperactivated Wnt/ß-catenin signaling are associated with worse outcomes in several human cancers, including breast cancer, cervical cancer, and glioma. Therefore, mutations and hyperactivation of Wnt/ß-catenin signaling create challenges and limitations in cancer treatment. Recently, in silico drug design as well as high-throughput assays and experiments have demonstrated the promising anticancer efficacy of chemotherapeutics, such as blocking the cancer cell cycle, inhibiting cancer cell proliferation and endothelial cell angiogenesis, inducing cancer cell apoptosis, removing cancer stem cells, and enhancing immune responses. Compared to conventional chemotherapy and radiotherapy, small-molecule inhibitors are considered the most promising therapeutic strategy for targeting the Wnt/ß-catenin signaling pathway. Herein, we review the current small-molecule inhibitors of the Wnt/ß-catenin signaling pathway, focusing on Wnt ligands, Wnt receptors, the ß-catenin destruction complex, ubiquitin ligases and proteasomal destruction complex, ß-catenin, ß-catenin-associated transcriptional factors and coactivators, and proangiogenic factors. We describe the structure, mechanisms, and functions of these small molecules during cancer treatment in preclinical and clinical trials. We also review several Wnt/ß-catenin inhibitors reported to exhibit anti-angiogenic effects. Finally, we explain various challenges in the targeting of the Wnt/ß-catenin signaling pathway in human cancer treatment and suggest potential therapeutic approaches to human cancer.

miR-200a targets Gelsolin: A novel mechanism regulating secretion of microvesicles in hepatocellular carcinoma cells.

Microvesicle biogenesis is a highly regulated process. Aberrant release of microvesicles from cancer cells have been associated with their invasiveness and prognosis. However, the mechanism of aberrant release remains poorly understood. Herein, we found that hepatocellular carcinoma cells shed more microvesicles than normal hepatocytes and miR-200a were shown to inhibit the release of microvesicles in hepatocellular carcinoma cells. Then, we confirmed that miR-200a might target Gelsolin and change cytoskeleton to regulate microvesicles secretion. Further miR-200a may inhibit the proliferation of adjacent cells by inhibiting the release of microvesicles. Collectively, our findings indicate that miR-200a regulated the microvesicle biogenesis involved in the hepatocellular carcinoma progression.

Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3.

The overall biological role and clinical significance of long non-coding RNA H19 in colorectal cancer (CRC) remain largely unknown. Here, we firstly report that the lncRNA H19 recruits eIF4A3 and promotes the CRC cell proliferation. We observed higher expression of H19 was significantly correlated with tumor differentiation and advanced TNM stage in a cohort of 83 CRC patients. Multivariate analyses revealed that expression of H19 served as an independent predictor for overall survival and disease-free survival. Further experiments revealed that overexpression of H19 promoted the proliferation of CRC cells, while depletion of H19 inhibited cell viability and induced growth arrest. Moreover, expression profile data showed that H19 upregulated a series of cell-cycle genes. Using bioinformatics prediction and RNA immunoprecipitation assays, we identified eIF4A3 as an RNA-binding protein that binds to H19. We confirmed that combining eIF4A3 with H19 obstructed the recruitment of eIF4A3 to the cell-cycle gene mRNA. Our results suggest that H19, as a growth regulator, could serve as a candidate prognostic biomarker and target for new therapies in human CRC.