No abstract

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.

Purpose: Evidence indicates that long noncoding RNAs (lncRNA) possess important roles in various cellular processes and that dysregulation of lncRNAs promotes tumor progression. However, the expression patterns and biological functions of many specific lncRNAs in breast cancer remain to be determined. Methods: Quantitative real-time polymerase chain reaction was performed to detect Linc00460, miR-489-5p and FGF7 expression. Protein levels were determined using Western blot. MTT and colony formation assay were used to measure cell proliferation. Transwell assays were conducted to determine cell migration and invasion. Luciferase reporter assays were carried out to assess the interaction between miR-489-5p and Linc00460 or FGF7. Biotin pull-down assay was used to detect the direct interaction between miR-489-5p and Linc00460. In vivo experiments were performed to measure tumor formation and lung metastasis. Results: We demonstrated that lncRNA Linc00460 was upregulated in breast cancer, and its expression level was positively associated with lymphatic metastasis and poor overall survival. Forced expression of Linc00460 increased, whereas Linc00460 silencing decreased, breast cancer cell viability, migration and invasion both in vitro and in vivo. Linc00460 was identified as a direct target of miR-489-5p, which further targeted FGF7 and exerted oncogenic functions in breast cancer. Mechanistically, Linc00460 served as a competing endogenous RNA of FGF-7 mRNA by sponging miR-489-5p, resulting in upregulated FGF7 expression and AKT activity. Notably, forced expression of miR-489-5p abrogated Linc00460-mediated oncogenic behavior and activation of the FGF7-AKT pathway in breast cancer cells. Conclusion: We have demonstrated that Linc00460 promotes breast cancer progression partly through the miR-489-5p/FGF7/AKT axis.

MicroRNAs (miRNAs) typically bind to unstructured miRNA-binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR-1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5′ untranslated region (UTR) and this interaction enhances the stability of both molecules. miR-1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR-1254-targeting sites act as both a functional RNA motif-sensing unit, and an independent RNA functional unit that enhances miR-1254 expression. Artificially designed miRNA enhancers, termed “miRancers”, can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5′ UTR as a natural miRancer of endogenous miR-1254 re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer-like motif-containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.

Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The functional and mechanistic implications of this subpopulation plasticity remain largely unknown. Herein, it is demonstrated that the breast cancer stem cell (BCSC) secretome autonomously compresses the stem cell population. Co-implantation with BCSCs decreases the tumor-initiating capacity yet increases metastasis of accompanying cancer cells, wherein DKK1 is identified as a pivotal factor secreted by BCSCs for such functions. DKK1-promotes differentiation is indispensable for disseminated tumor cell metastatic outgrowth. In contrast, DKK1 inhibitors substantially relieve the metastatic burden by restraining metastatic cells in the dormant state. DKK1 increases the expression of SLC7A11 to protect metastasizing cancer cells from lipid peroxidation and ferroptosis. Combined treatment with a ferroptosis inducer and a DKK1 inhibitor exhibits synergistic effects in diminishing metastasis. Hence, this study deciphers the contribution of CSC-regulated phenotypic plasticity in metastatic colonization and provides therapeutic approaches to limit metastatic outgrowth.

The dysregulation of miRNAs is a crucial characteristic of human cancers. Herein, we observed frequent amplification of the MIR191/425 locus in breast cancer, which is correlated with poor survival outcome. We demonstrated that the miR-191/425 cluster binds the 3'UTR of the DICER1 transcript and post-transcriptionally represses DICER1 expression, thereby impairing global microRNAs biogenesis. Functionally, the forced expression of miR-191 or miR-425 stimulated the proliferation, survival, migration and invasion of breast cancer cells, while the inhibition of miR-191 or miR-425 suppressed these oncogenic behaviors of breast cancer cells, in a manner dependent on miR-191/425-mediated downregulation of DICER1. Furthermore, the miR-191/425 cluster promoted breast tumor growth, invasion and metastasis in vivo. The let-7 family of miRNAs was downregulated upon forced expression of miR-191 or miR-425, with a corresponding increase in the levels of let-7 target, HMGA2. The forced expression of let-7 partially abrogated the miR-191/425-mediated oncogenic effects in breast cancer cells, suggestive of let-7 as a downstream effector of the miR-191/425-DICER1 axis. Collectively, we proposed that the inhibition of global miRNA processing, through miR-191/425-mediated downregulation of DICER1, promotes breast cancer progression.

No abstract

Orthopyroxene (opx) is an important mineral in petrologic models for the upper mantle. Its elastic properties are fundamental for understanding the chemical composition and geodynamics of the upper mantle. Here we calculate the elastic properties of orthoenstatite (MgSiO3), the Mg end‐member orthopyroxene under upper mantle pressure and temperature conditions using first principle calculations with local density approximation. Bulk and shear moduli increase nonlinearly with pressure at mantle temperatures, but the shear modulus and VS show very weak pressure dependence in comparison with VP. Compared to other major minerals in the upper mantle, orthoenstatite has the lowest compressional velocities (VP), shear velocities (VS), and VP/VS ratio down to the depth of approximately 300 km. The enrichment of opx in the upper mantle can cause the unusually low VP/VS observed in the mantle wedge.