Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a poor prognosis. The microRNA‐200 (miR‐200) family has been associated with breast cancer metastasis. However, the epigenetic mechanisms underlying miR‐200b repression in TNBC are not fully elucidated. In this study, we found that MYC proto‐oncogene, bHLH transcription factor (MYC) and DNA methyltransferase 3A (DNMT3A) were highly expressed in TNBC tissues compared with other breast cancer subtypes, while miR‐200b expression was inhibited significantly. We demonstrated that MYC physically interacted with DNMT3A in MDA‐MB‐231 cells. Furthermore, we demonstrated that MYC recruited DNMT3A to the miR‐200b promoter, resulting in proximal CpG island hypermethylation and subsequent miR‐200b repression. MiR‐200b directly inhibited DNMT3A expression and formed a feedback loop in TNBC cells. MiR‐200b overexpression synergistically repressed target genes including zinc‐finger E‐box‐binding homeobox factor 1, Sex determining region Y‐box 2 (SOX2), and CD133, and inhibited the migration, invasion and mammosphere formation of TNBC cells. Our findings reveal that MYC can collaborate with DNMT3A on inducing promoter methylation and miR‐200b silencing, and thereby promotes the epithelial to mesenchymal transition and mammosphere formation of TNBC cells.
Accumulating evidence has indicated that long noncoding RNAs (lncRNAs) play pivotal roles in the processes of cancer occurrence, progression, and treatment. FAM83A-AS1 is a novel onco-lncRNA involved in various cancers. Nevertheless, the biological function and underlying mechanism of FAM83A-AS1 in lung adenocarcinoma (LUAD) remain largely unclear. In this study, we found FAM83A-AS1 to be upregulated in LUAD tissues and closely associated with tumor size, lymph node metastasis, and TNM stage. In addition, high FAM83A-AS1 expression correlated positively with a poor prognosis. Functional investigation revealed that FAM83A-AS1 promotes LUAD cell proliferation, migration, invasion and the epithelial-mesenchymal transition (EMT) in vitro and tumor growth in vivo. Mechanistically, FAM83A-AS1 functions as an endogenous sponge of miR-150-5p by directly targeting it, removing inhibition of MMP14, a target of miR-150-5p. Furthermore, rescue assays demonstrated that FAM83A-AS1 enhances cell migration, invasion and EMT by modulating the miR-150-5p/MMP14 pathway. Collectively, we conclude that the novel FAM83A-AS1/miR-150-5p/MMP14 axis regulates LUAD progression, suggesting an innovative therapeutic strategy for this cancer.
BackgroundLCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.MethodsCellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.ResultsThe expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.ConclusionThus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.
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.