The dysregulation of miRNAs has been increasingly recognized as a critical mediator of cancer development and progression. Here, we show that frequent deletion of the locus is associated with poor prognosis in primary breast cancer. Forced expression of miR-135a decreased breast cancer progression, while inhibition of miR-135a with a specific miRNA sponge elicited opposing effects, suggestive of a tumor suppressive role of miR-135a in breast cancer. Estrogen receptor alpha (ERα) bound the promoter of for its transcriptional activation, whereas tamoxifen treatment inhibited expression of miR-135a in ERα breast cancer cells. miR-135a directly targeted and, forming a negative feedback loop to inhibit ERα signaling. This regulatory feedback between miR-135a and ERα demonstrated that miR-135a regulated the response to tamoxifen. The tamoxifen-mediated decrease in miR-135a expression increased the expression of miR-135a targets to reduce tamoxifen sensitivity. Consistently, miR-135a expression was downregulated in ERα breast cancer cells with acquired tamoxifen resistance, while forced expression of miR-135a partially resensitized these cells to tamoxifen. Tamoxifen resistance mediated by the loss of miR-135a was shown to be partially dependent on the activation of the ERK1/2 and AKT pathways by miR-135a-targeted genes. Taken together, these results indicate that deletion of the locus and decreased miR-135a expression promote ERα breast cancer progression and tamoxifen resistance. Loss of miR-135a in breast cancer disrupts an estrogen receptor-induced negative feedback loop, perpetuating disease progression and resistance to therapy. http://cancerres.aacrjournals.org/content/canres/78/17/4915/F1.large.jpg .
Hypoxia has been reported to regulate the cancer stem cell (CSC) population yet the underlying mechanism is poorly characterized. Herein, we show that Artemin (ARTN), a member of the glial cell derived neurotrophic factor family of ligands, is a hypoxia-responsive factor and is essential for hypoxia-induced CSC expansion in hepatocellular carcinoma (HCC). Clinically, elevated expression of ARTN in HCC was associated with larger tumor size, faster relapse and shorter survival. In vitro, HCC cells with forced expression of ARTN exhibited reduced apoptosis, increased proliferation, epithelial-mesenchymal transition (EMT) and enhanced motility. Additionally, ARTN dramatically increased xenograft tumor size and metastasis in vivo. Moreover, ARTN also enhanced tumorsphere formation and the tumor initiating capacity of HCC cells, consequent to expansion of the CD133+ CSC population. ARTN transcription was directly activated by hypoxia-induced factor-1α (HIF-1α) and hypoxia induced ARTN promoted EMT and increased the CSC population via AKT signaling. We herein identify a novel HIF-1α/ARTN axis promoting CSC-like behavior in hypoxic environments which implicates ARTN as a valuable therapeutic target for HCC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.