HMGA2 promotes breast cancer metastasis by modulating Hippo-YAP signaling pathway.

BACKGROUND: Breast cancer is the most common cancer in women, and triple-negative breast cancer (TNBC) accounts for about 15-20% of all breast cancer. High mobility group AT-hook 2 (HMGA2) is overexpressed in some tumors and closely associated with patients' prognosis. However, the mechanisms involved in the regulation of HMGA2 in TNBC still remain unclear. METHODS: In this study, HMGA2 level in TNBC cell lines was analyzed by western blot. After knockdown of HMGA2 expression by RNA interference in TNBC cell lines MDA-MB-231 and SUM149, wound healing and transwell assays were conducted to examine the effects of HMGA2 on migration and invasion. Tumor metastasis was assessed in amouse xenograft model invivo. Furthermore, expression levels of epithelial-mesenchymal transition (EMT) biomarkers and involvement of the Hippo-YAP pathway were detected by western blot. RESULTS: Compared to normal breast epithelial cells, the expression levels of HMGA2 were significantly increased in TNBC cell lines (all P< .05). Downregulation of HMGA2 dramatically inhibited the migration and invasion of MDA-MB-231 and SUM149 cells (all P< .01) invitro, and suppressed the tumor metastasis of nude mice xenograft model invivo. Western blot analysis revealed alterations in EMT biomarkers: the expression of mesenchymal markers N-cadherin, Vimentin and Snail were decreased, while the expression of epithelial marker E-cadherin was increased. Downregulated expression of HMGA2 attenuated Hippo-YAP related protein expression and the stability of YAP. CONCLUSIONS: HMGA2 is highly expressed in TNBC cells. Downregulation of HMGA2 inhibits the migration and invasion of TNBC and invivo tumor metastasis mediated through inhibition of EMT and Hippo-YAP pathway.

Upregulation of MicroRNA-21 promotes tumorigenesis of prostate cancer cells by targeting KLF5.

Prostate cancer (PCa) is the second frequently newly diagnosed cancer in men. Androgen deprivation therapy has been widely used to inhibit PCa growth but eventually fails in many patients. Androgen receptor and its downstream molecules like microRNAs could be promising therapeutic targets. We aimed to investigate the involvement of miR-21 in PCa tumorigenesis. We found that miR-21 was an unfavorable factor and correlated positively with tumor grade in PCa patients from TCGA database. MiR-21 was more highly expressed in androgen-independent PCa cells than in androgen-dependent PCa cells. Overexpression of miR-21 promoted androgen-dependent and -independent PCa cell proliferation, migration, invasion, and resistance to apoptosis. Furthermore, increased miR-21 expression promoted mouse xenograft growth. We identified nine genes differentially expressed in PCa tumors and normal tissue which could be potential targets of miR-21 by bioinformatic analyses. We demonstrate that miR-21 directly targeted KLF5 and inhibited KLF5 mRNA and protein levels in PCa. STRING and functional enrichment analysis results suggest that GSK3B might be regulated by KLF5. Our findings demonstrate that miR-21 promotes the tumorigenesis of PCa cells by directly targeting KLF5. These biological effects are mediated through upregulation of GSK3B and activation of the AKT signaling pathway.

miR-30a can inhibit DNA replication by targeting RPA1 thus slowing cancer cell proliferation.

Cell proliferation was inhibited following forced over-expression of miR-30a in the ovary cancer cell line A2780DX5 and the gastric cancer cell line SGC7901R. Interestingly, miR-30a targets the DNA replication protein RPA1, hinders the replication of DNA and induces DNA fragmentation. Furthermore, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) were phosphorylated after DNA damage, which induced p53 expression, thus triggering the S-phase checkpoint, arresting cell cycle progression and ultimately initiating cancer cell apoptosis. Therefore, forced miR-30a over-expression in cancer cells can be a potential way to inhibit tumour development.