Advanced prostate cancers are known to acquire not only invasive capabilities but also significant resistance to chemotherapy-induced apoptosis. To understand how microRNAs (miRNAs) may contribute to prostate cancer resistance to apoptosis, we compared microRNA expression profiles of a benign prostate cancer cell line WPE1-NA22 and a highly malignant WPE1-NB26 cell line (derived from a common lineage). We found that miR-205 and miR-31 are significantly downregulated in WPE1-NB26 cells, as well as in other cell lines representing advanced-stage prostate cancers. Antiapoptotic genes BCL2L2 (encoding Bcl-w) and E2F6 are identified as the targets of miR-205 and miR-31, respectively. By downregulating Bcl-w and E2F6, miR-205 and miR-31 promote chemotherapeutic agents-induced apoptosis in prostate cancer cells. The promoter region of the miR-205 gene was cloned and was found to be hypermethylated in cell lines derived from advanced prostate cancers, contributing to the downregulation of the gene. Treatment with DNA methylation inhibitor 5-aza-2′-deoxycytidine induced miR-205 expression, downregulated Bcl-w, and sensitized prostate cancer cells to chemotherapy-induced apoptosis. Thus, downregulation of miR-205 and miR-31 has an important role in apoptosis resistance in advanced prostate cancer.

The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). However, the relationship between PAK5 and E47 has not been explored. In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation, which decreased cell-cell cohesion, increased cell migration and invasion in vitro and promoted metastasis in a xenograft model. Furthermore, phosphorylation of E47 facilitated its accumulating in nucleus in an importin α-dependent manner, and enhanced E47 binding to E-cadherin promoter directly, leading to inhibition of E-cadherin transcription. In contrast, PAK5-knockdown resulted in blockage of HGF-induced E47 phosphorylation, attenuated association of E47 with importin α and decreased E47 binding to E-cadherin promoter. In addition, we demonstrated a close correlation between PAK5 and phospho-Ser39 E47 expression in colon cancer specimens. More importantly, high expression of phospho-E47 was associated with an aggressive phenotype of colon cancer and nuclear phospho-E47 staining was found in certain cases of colon cancer with metastasis. Collectively, E47 is a novel substrate of PAK5, and PAK5-mediated phosphorylation of E47 promotes EMT and metastasis of colon cancer, suggesting that phosphorylated E47 on Ser39 may be a potential therapeutic target in progressive colon cancer.

Purpose: To determine the expression of circRTN4 in gastric cancer (GC) and its role in tumor progression. Methods: GEO dataset GSE93541 was analyzed using GEO2R. Starbase website was used to predict the combination of miRNA and circRTN4. The relationship between circRTN4 and prognosis was analyzed using Kaplan-Meier Plotter database, while expression levels of circRTN4, miR-424-5p, and LATS2 were assessed by quantitative real time-polymerase chain reaction (qRT-PCR). CCK8, EDU, Transwell, and Western blot were used to assess GC  proliferation, migration, invasion, and stemness. Lastly, co-transfection of miR-424-5p or si-LAST2 was reversely used to demonstrate the regulatory effect  of circRTN4 on the progression of gastric cancer cells. Significantly downregulated circRTN4 in GC was screened, and the combined miR-424-5p  and downstream gene LATS2 were predicted by Starbase. Results: The average relative expression of circRTN4 mRNA in GC tissues was significantly lower than in adjacent tissues. MiR-424-5p was highly  expressed in tumor tissues, while LATS2 decreased (p < 0.05). Low expression of circRTN4 was associated with a low survival rate in patients. pLCDH- circRTN4 significantly inhibited the proliferation of gastric cancer cells (p < 0.05). Overexpression of circRTN4 inhibited the migration and invasion of  tumor cells, while pLCDH-circRTN4 reduced the ability of GC stem cells and expressions of MMP2 and OCT4. Conclusion: Expression of circRTN4 decreases in GC, and contributes to the development and progression of this disease by increasing the levels of  LATS2 and binding with miR-424-5p. This suggests that circRTN4 may serve as a promising prognostic marker as well as a potential therapeutic target for  gastric cancer