Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger ...protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. ...Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.
Selective introduction of fluorine into molecules by the cleavage of inert C−H bonds is of central academic and synthetic interest, yet remains challenging. Given the central role of alcohols in ...organic chemistry as the most ubiquitous building blocks, a versatile and selective C(sp3)−H and C(sp2)−H fluorination of simple alcohols, enabled by novel designed exo‐directing groups, is described. C(sp2)−H bond fluorination was achieved by using a simple acetone oxime as auxiliary, whereas a new, modular and easily accessible bidentate auxiliary was developed for the efficient and site‐selective fluorination of various primary methyl, methylene, and benzylic C(sp3)−H bonds. Fluorinated alcohols can readily be accessed by the removal of auxiliaries, and significantly expands the synthetic prospect of the present procedure.
A versatile and selective C(sp3)−H and C(sp2)−H fluorination of simple alcohols, enabled by an exo‐directing group (DG) is described. C(sp2)−H bond fluorination was achieved by using simple acetone oxime as an auxiliary, whereas a new and modularly accessible bidentate auxiliary was developed for the efficient and site‐selective fluorination of C(sp3)−H bonds. The auxiliary is removable and demonstrates broad substrate scope and excellent selectivity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The molecular underpinnings behind malignant progression of breast cancer from a localized lesion to an invasive and ultimately metastatic disease are incompletely understood. Here, we report that ...F-box only protein 22 (FBXO22) plays a dual role in mammary tumorigenesis and metastasis. FBXO22 was upregulated in primary breast tumors and promoted cell proliferation and colony formation
and xenograft tumorigenicity
Surprisingly, FBXO22 suppressed epithelial-mesenchymal transition (EMT), cell motility, and invasiveness
and metastatic lung colonization
Clinical data showed that expression levels of FBXO22 were associated with favorable clinical outcomes, supporting the notion that metastasis, rather than primary cancer, is the major determinant of the mortality of patients with breast cancer. Mechanistic investigations further revealed that FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner. Importantly, expression of SNAIL rescued FBXO22-mediated suppression of EMT, cell migration, and invasion. A patient-derived tryptophan-to-arginine mutation at residue 52 (W52R) within the F-box domain impaired FBXO22 binding to the SKP1-Cullin1 complex and blocked FBXO22-mediated SNAIL degradation, thus abrogating the ability of FBXO22 to suppress cell migration, invasion, and metastasis. Collectively, these findings uncover an unexpected dual role for FBXO22 in mammary tumorigenesis and metastatic progression and delineate the mechanism of an oncogenic mutation of FBXO22 in breast cancer progression.
These findings highlight the paradoxical roles of FBXO22 in breast cancer, as it promotes breast tumor cell proliferation but prevents EMT and metastasis.
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The ALK gene encodes a transmembrane tyrosine kinase receptor. ALK is physiologically expressed in the nervous system during embryogenesis, but its expression decreases postnatally. ALK first emerged ...in the field of oncology in 1994 when it was identified to fuse to NPM1 in anaplastic large‐cell lymphoma. Since then, ALK has been associated with other types of cancers, including non‐small‐cell lung cancer (NSCLC). More than 19 different ALK fusion partners have been discovered in NSCLC, including EML4, KIF5B, KLC1, and TPR. Most of these ALK fusions in NSCLC patients respond well to the ALK inhibitor, crizotinib. In this paper, we reviewed fusion partner genes with ALK, detection methods for ALK‐rearrangement (ALK‐R), and the ALK‐tyrosine kinase inhibitor, crizotinib, used in NSCLC patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary ...conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation.
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circRNAs are covalently closed continuous loops that exhibit multiple biological functions. This review summarizes recent advances in circRNAs’ regulatory roles in parental gene expression, including transcription and splicing regulation, ceRNA mechanisms, mRNA traps, and translational/post-translational regulation. It may provide new perspectives for the understanding and further investigation of circRNAs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Determining the reputation of academic journals is an crucial issue. The Author Affiliation Index (AAI) was proposed as a novel indicator for judging journal quality in many academic disciplines. ...Nevertheless, the original AAI has several potential limitations, some of which have been discussed and addressed in previous studies. In this paper, we modified the original AAI by incorporating diversity of top-notch institutions, namely the AAID, exploring how institutional diversity is related to journal quality assessment. We further conducted a quality assessment of 263 education journals indexed in the Social Sciences Citation Index (SSCI) by applying the AAID, AAI and weighted AAI. We find that the AAID ranking possesses a low correlation coefficient with the Journal Impact Factor (JIF) and Eigenfactor Score (ES). That is to say, the AAID rating has not reached a good agreement with the most popular ranking indicators JIF and ES for journals in the field of education. Moreover, we analyze the reasons for the highest AAID from the structure of complex networks. Overall, the AAID is an alternative indicator for evaluating the prestige of journals from a new perspective.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast ...cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g.,
, and
), we identify two novel missense variants in
(rs13047478,
= 4.52 × 10
) and
(rs3810151,
= 7.60 × 10
) and one new noncoding variant at 7q21.11 (
< 5 × 10
).
and
possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (
< 5.00 × 10
) associated with the expression of genes
and
in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes
(
= 8.39 × 10
) and
(
= 3.77 × 10
) in human blood samples.
and
, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.
Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer.
.
Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an
...CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.
This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target.
.
•Phase change behaviors of nanoscale liquid films are studied via MD simulations.•A critical thickness is proposed to distinguish the macro-micro boiling transition.•The critical thickness is found ...to be 10.34 nm for water.
Two main reasons including practical and scientific significance continuously motivate the studies of explosive boiling of nanoscale liquid films. Whether the nanoscale explosive boiling agrees with classical nucleation theory is still an open issue. In this work, we study the effects of surface wettability on the explosive boiling of nanoscale liquid films using molecular dynamics simulations. A critical film thickness is proposed to address the debate of whether the classical nucleation theory fails in nanoscale boiling. The explosive boiling modes and dynamics are summarized with the phase diagram based on various simulation cases, considering the effects of surface wettability, film thickness, and surface superheat. When the films thickness exceeds the critical thickness, hydrophobic surfaces are more favorable for explosive boiling, which still agrees with the classical nucleation theory. However, a much higher superheat is required to trigger the explosive boiling of a thin liquid film when its thickness is less than the critical thickness on hydrophobic surfaces, which consists with previous molecular dynamics simulations. Furthermore, we also find that the explosive boiling is trigged faster for films on hydrophilic surfaces than those on hydrophobic surfaces with the same superheat owing to the lower Kapitza thermal resistance. With such heat transfer superiority, hydrophilic surfaces can heat liquid films faster to explosion. The deliveries of this work and the concept of the critical thickness might help to understand the still fledgling field of nanoscale boiling phase change and its relevant mechanisms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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