Eccrine porocarcinoma in the tempus of an elderly woman: A case report.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin tumor that mainly affects the elderly population. Tumors often present with slow growth and a good prognosis. EPCs are usually distinguished from other skin tumors using histopathology and immunohistochemistry. However, surgical management alone may be inadequate if the tumor has metastasized. However, currently, surgical resection is the most commonly used treatment modality. CASE SUMMARY: A seventy-four-year-old woman presented with a slow-growing nodule in her left temporal area, with no obvious itching or pain, for more than four months. Histopathological examination showed small columnar and short spindle-shaped cells; thus, basal cell carcinoma was suspected. However, immunohistochemical analysis revealed the expression of cytokeratin 5/6, p63 protein, p16 protein, and Ki-67 antigen (40%), and EPC was taken into consideration. The skin biopsy was repeated, and hematoxylin and eosin staining revealed ductal differentiation in some cells. Finally, the patient was diagnosed with EPC, and Mohs micrographic surgery was performed. We adapted follow-up visits in a year and not found any recurrence of nodules. CONCLUSION: This case report emphasizes the diagnosis and differentiation of EPC.

Genomic characters of Anaplasma bovis and genetic diversity in China.

The emergence of Anaplasma bovis or A. bovis-like infection in humans from China and the United States of America has raised concern about the public health importance of this pathogen. Although A. bovis has been detected in a wide range of ticks and mammals in the world, no genome of the pathogen is available up to now, which has prohibited us from better understanding the genetic basis for its pathogenicity. Here we describe an A. bovis genome from metagenomic sequencing of an infected goat in China. Anaplasma bovis had the smallest genome of the genus Anaplasma, and relatively lower GC content. Phylogenetic analysis of single-copy orthologue sequence showed that A. bovis was closely related to A. platys and A. phagocytophilum, but relatively far from intraerythrocytic Anaplasma species. Anaplasma bovis had 116 unique orthogroups and lacked 51 orthogroups in comparison to other Anaplasma species. The virulence factors of A. bovis were significantly less than those of A. phagocytophilum, suggesting less pathogenicity of A. bovis. When tested by specific PCR assays, A. bovis was detected in 23 of 29 goats, with an infection rate up to 79.3% (95% CI: 64.6% ∼94.1%). The phylogenetic analyses based on partial 16S rRNA, gltA and groEL genes indicated that A. bovis had high genetic diversity. The findings of this study lay a foundation for further understanding of the biological characteristics and genetic diversity of A. bovis, and will facilitate the formulation of prevention and control strategies.

PIN1P1 is activated by CREB1 and promotes gastric cancer progression via interacting with YBX1 and upregulating PIN1.

Long noncoding RNAs (lncRNAs) play critical roles in the carcinogenesis and progression of cancers. However, the role and mechanism of the pseudogene lncRNA PIN1P1 in gastric carcinoma remain unclear. The expression and effects of lncRNA PIN1P1 in gastric cancer were investigated. The transcriptional regulation of CREB1 on PIN1P1 was determined by ChIP and luciferase assays. The mechanistic model of PIN1P1 in gastric cancer was further explored by RNA pull-down, RIP and western blot analysis. PIN1P1 was overexpressed in gastric cancer tissues, and upregulated PIN1P1 predicted poor prognosis in patients. CREB1 was directly combined with the promoter region of PIN1P1 to promote the transcription of PIN1P1. CREB1-mediated enhanced proliferation, migration and invasion could be partially reversed by downregulation of PIN1P1. Overexpressed PIN1P1 promoted the proliferation, migration and invasion of gastric cancer cells, whereas decreased PIN1P1 showed the opposite effects. PIN1P1 directly interacted with YBX1 and promoted YBX1 protein expression, leading to upregulation of PIN1, in which E2F1 may be involved. Silencing of YBX1 during PIN1P1 overexpression could partially rescue PIN1 upregulation. PIN1, the parental gene of PIN1P1, was elevated in gastric cancer tissues, and its upregulation was correlated with poor patient outcomes. PIN1 facilitated gastric cancer cell proliferation, migration and invasion. To sum up, CREB1-activated PIN1P1 could promote gastric cancer progression through YBX1 and upregulating PIN1, suggesting that it is a potential target for gastric cancer.

LncRNA LY6E-DT and its encoded metastatic-related protein play oncogenic roles via different pathways and promote breast cancer progression.

Abnormal long noncoding RNA (lncRNA) expression plays an important role in tumor invasion and metastasis. Here, we show that lncRNA LY6E divergent transcript (LY6E-DT) levels are increased in breast cancer (BC) tissues. Transcription factor SP3 binds directly to the LY6E-DT promoter, activating its transcription. Moreover, LY6E-DT N6-methyladenosine modification by methyltransferase-like protein 14 (METTL14) promotes its expression, dependent on the "reader" insulin-like growth factor 2 mRNA binding protein 1(IGF2BP1)-dependent pathway. Notably, we discovered that the lncRNA LY6E-DT encodes a conserved 153-aa protein, "Metastatic-Related Protein" (MRP). Both LY6E-DT and MRP promote BC invasion and metastasis, and MRP expression could distinguish BC patients with lymph node metastasis from those without. Mechanistically, MRP binds heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC), enhancing the interaction between HNRNPC and epidermal growth factor receptor (EGFR) mRNA, increasing EGFR mRNA stability and protein expression and subsequently activating the phosphatidylinositol 3­kinase/protein kinase B signaling (PI3K) pathway. LncRNA LY6E-DT promotes the interaction between Y box binding protein 1 (YBX1) and importin α1 and increases YBX1 protein entry into the nucleus, where it transcriptionally activates zinc finger E-box-binding homeobox 1(ZEB1). Our findings uncover a novel regulatory mechanism underlying BC invasion orchestrated by LY6E-DT and its encoded MRP.

Circ_0004771 Promotes Hypoxia/Reoxygenation Induced Cardiomyocyte Injury via Activation of Mitogen-Activated Protein Kinase Signaling Pathway.

This study aimed to observe the mechanism and effect of circ_0004771 on cardiomyocyte injury in acute myocardial infarction (AMI). The differences in circ_0004771 expression in the blood of AMI patients and healthy volunteers were observed by Real-Time Quantitative Reverse Transcription-Polymerase Chain Reaction. AMI cell models were constructed by hypoxia/reoxygenation (H/R)-induced injury in human cardiomyocytes (AC16 cells). The changes of circ_0004771 expression in AMI cells were observed. After transfection with the knockdown or overexpression of circ_0004771 vector in AMI cells, Cell Counting Kit-8 (CCK-8) assay and propidium iodide/FITC-Annexin V staining were performed to detect cell proliferation and apoptosis levels, extracellular lactate dehydrogenase (LDH) activity, malondialdehyde (MDA) concentration, and superoxide dismutase (SOD) activity. Expression levels of Mitogen-activated protein kinase (MAPK) signaling pathway-related proteins (p-MEK1/2, MEK1/2, p-ERK1/2, ERK1/2), and endoplasmic reticulum (ER) stress proteins (GRP78 and CHOP-1) were observed in each group of cells by western blot method. The expression level of circ_0004771 was significantly reduced in both clinical samples and cells of AMI. When circ_0004771 was knocked down in AMI cells, it resulted in a decrease in cell proliferation level and significant increase in apoptosis level. The inhibition of circ_0004771 expression caused leakage of LDH in AMI cells, accumulation of intracellular MDA, and inhibition of SOD activity. In addition, the knockdown of circ_0004771 significantly increased the levels of p-MEK1/2, p-ERK1/2, GRP78, and CHOP-1 in H/R-induced AC16 cells. However, the overexpression of circ_0004771 resulted in the opposite result as when circ_0004771 was knocked down. A low level of circ_0004771 in AMI activates the MAPK signaling pathway in cardiomyocytes as well as encourages intracellular oxidative stress and ER stress, thereby inhibiting cell proliferation and promoting apoptosis.

Epidemiological and phylogenetic characteristics of emerging Anaplasma capra: A systematic review with modeling analysis.

Anaplasma capra, an emerging tick-borne pathogen, has caused a lot of concern since initially recognized in goats and patients in China in 2015, and has been reported in a wide range of domestic and wild animals as well as ticks worldwide, posing a threat to public health. In this systematic review, we established a comprehensive database to acquire the distribution and prevalence status of this pathogen, and collected all sequences of A. capra to summarize the details of genetic diversity by phylogenetic analysis. We also predicted the possible global distribution of A. capra by using ecological niche model. A. capra has been known to distribute in 18 countries across Asia, Europe and Africa. A total of 19 species of mammals from seven families have been reported as hosts, and domestic ruminants including goats, sheep and cattle were the major hosts. At least 8 tick species of 4 genera have been reported to carry A. capra, and Haemaphysalis longicornis was most commonly infected. Sheep and Rhipicephalus microplus had the highest positive rates among animals and ticks. Phylogenetic analysis based on gltA and groEL genes revealed that A. capra could primarily be divided into two clusters related to geographic location and animal hosts. The predictive model showed that the most suitable habitats for presence of A. capra were mainly located in Asia and eastern Europe. These cumulative data regarding A. capra of our study lay a foundation for the subsequent exploration of this emerging tick-borne pathogen.

Base-Exchange Enabling the Visualization of SARM1 Activities in Sciatic Nerve-Injured Mice.

Enzymes are important in homeostasis in living organisms. Since abnormal enzyme activities are highly associated with many human diseases, detection of in vivo activities of a specific enzyme is important to study the pathology of the related diseases. In this work, we have designed and synthesized a series of new small-molecule-activatable fluorescent probes for the imaging of Sterile Alpha and TIR Motif-containing 1 (SARM1) activities based on its transglycosidase activities (base-exchange reactions of NAD+). Probe 1a was found to undergo base-exchange reactions with NAD+ in the presence of activated SARM1 but not CD38 nor NADase and formed a highly emissive product AD-1a [about a 100-fold fluorescence enhancement in 20 min with a 150 nm (5665 cm-1) Stokes shift and a 100 nm (3812 cm-1) red shift]. This probe exhibited a higher reactivity and sensitivity than those commonly used for SARM1 imaging. The utilities of 1a have also been demonstrated in live-cell imaging and detection of in vivo activities of SARM1 in a sciatic nerve injury mouse model.

A conformation-specific nanobody targeting the nicotinamide mononucleotide-activated state of SARM1.

Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is an autoinhibitory NAD-consuming enzyme that is activated by the accumulation of nicotinamide mononucleotide (NMN) during axonal injury. Its activation mechanism is not fully understood. Here, we generate a nanobody, Nb-C6, that specifically recognizes NMN-activated SARM1. Nb-C6 stains only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN, and partially activates SARM1 in vitro and in cells. Cryo-EM of NMN/SARM1/Nb-C6 complex shows an octameric structure with ARM domains bending significantly inward and swinging out together with TIR domains. Nb-C6 binds to SAM domain of the activated SARM1 and stabilized its ARM domain. Mass spectrometry analyses indicate that the activated SARM1 in solution is highly dynamic and that the neighboring TIRs form transient dimers via the surface close to one BB loop. We show that Nb-C6 is a valuable tool for studies of SARM1 activation.

Construction of Water-Stable Rare-Earth Organic Frameworks with Ambient High Proton Conductivity Based on Zirconium Sandwiched Heteropolytungstate.

Water-stable proton-conducting materials owning excellent performances at ambient temperatures are currently one of the crucial challenges. Herein, four water-stable three-dimensional polyoxometalate-based rare-earth organic frameworks have been successfully synthesized and formulated as H{Ln4(L)2(H2O)21[Zr3(OH)3(PW9O34)2]}·15H2O (1-3) (Ln = La (1), Ce (2), Pr (3); L = 3,5-pyridine dicarboxylic acid), which are the first examples of MOFs constructed by a zirconium sandwiched polyoxoanion. There are abundant coordinated water molecules functionalizing the PrIII centers, and simultaneously, plenty of lattice water molecules are fitted into the channel of the framework. A continuous H-bonding network is found between the architectures and plays an important role in stabilizing the structure. Benefiting from the consecutive H-bonding networks, compounds 1-3 showed high proton conductivities at ambient temperature (up to 1.05 × 10-3 S·cm-1 under 98% RH) by a synergistic effect of the combined components.

CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis.

Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

Linc01133 contributes to gastric cancer growth by enhancing YES1-dependent YAP1 nuclear translocation via sponging miR-145-5p.

The long intergenic non-coding RNA linc01133 is reported to be oncogenic in various malignancies. However, the role and mechanism of linc01133 in regulating gastric cancer growth is still not clear. In the present study, we found that linc01133 was significantly upregulated in gastric cancer tissues compared to non-tumorous gastric tissues. Linc01133 over-expression significantly correlated with tumor size and tumor differentiation in gastric cancer patients. The expression of linc01133 was regulated by c-Jun and c-Fos collaboratively. In both in vitro and in vivo studies, linc01133 was shown to promote gastric cancer cell growth. Linc01133 localized in the cytoplasm and functioned as an endogenous competing RNA of miR-145-5p to upregulate the expression of YES1, which was proved to be the target gene of miR-145-5p. By promoting YES1-dependent YAP1 nuclear translocation, linc01133 upregulated the expression of the key cell cycle regulators CDK4, CDK6 and cyclin D1 to promote G1-S phase transition. Thus, our study unveiled the function and mechanism of linc01133 regulating cell cycle progression in gastric cancer.

lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus.

Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma.

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

New insights into long non-coding RNAs in breast cancer: Biological functions and therapeutic prospects.

Breast cancer (BC) has become one of the most common malignant tumors in the world, seriously endangering women's health and life. However, the underlying molecular mechanisms of BC remain unclear. Over the past decade, long non-coding RNAs (lncRNAs) were gradually discovered and appreciated to play pivotal regulatory role in the progression of BC. It has been demonstrated that lncRNAs are implicated in regulating plenty of biological phenomena including cell proliferation, apoptosis, invasion and metastasis by interacting with DNA, RNA or proteins. In addition to these, the function of lncRNAs in tumor resistance has increasingly attracted more attention. In this review, we summarized the emerging impact of lncRNAs on the occurrence and progression of human BC, specifically focusing on the functions and mechanisms of them, with the aim of exploring the potential value of lncRNAs as oncogenic drivers or tumor suppressors. Furthermore, the potential clinical application of lncRNAs as diagnostic biomarkers and therapeutic targets in BC was also discussed.

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate.

Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.

Identification of prognostic claudins signature in hepatocellular carcinoma from a hepatocyte differentiation model.

BACKGROUND: Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management. METHODS: Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients. RESULTS: A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts. CONCLUSIONS: In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.

Development of an oncogenic dedifferentiation SOX signature with prognostic significance in hepatocellular carcinoma.

BACKGROUND: Gradual loss of terminal differentiation markers and gain of stem cell-like properties is a major hall mark of cancer malignant progression. The stem cell pluripotent transcriptional factor SOX family play critical roles in governing tumor plasticity and lineage specification. This study aims to establish a novel SOX signature to monitor the extent of tumor dedifferentiation and predict prognostic significance in hepatocellular carcinoma (HCC). METHODS: The RNA-seq data from The Cancer Genome Atlas (TCGA) LIHC project were chronologically divided into the training (n = 188) and testing cohort (n = 189). LIRI-JP project from International Cancer Genome Consortium (ICGC) data portal was used as an independent validation cohort (n = 232). Kaplan-Meier and multivariable Cox analyses were used to examine the clinical significance and prognostic value of the signature genes. RESULTS: The SOX gene family members were found to be aberrantly expressed in clinical HCC patients. A five-gene SOX signature with prognostic value was established in the training cohort. The SOX signature genes were found to be closely associated with tumor grade and tumor stage. Liver cancer dedifferentiation markers (AFP, CD133, EPCAM, and KRT19) were found to be progressively increased while hepatocyte terminal differentiation markers (ALB, G6PC, CYP3A4, and HNF4A) were progressively decreased from HCC patients with low SOX signature scores to patients with high SOX signature scores. Kaplan-Meier survival analysis further indicated that the newly established SOX signature could robustly predict patient overall survival in both training, testing, and independent validation cohort. CONCLUSIONS: An oncogenic dedifferentiation SOX signature presents a great potential in predicting prognostic significance in HCC, and might provide novel biomarkers for precision oncology further in the clinic.

A 4-microRNA signature predicts lymph node metastasis and prognosis in breast cancer.

Recent findings have reported that human microRNAs (miRNAs) could serve as prognostic biomarkers in various cancers. We aimed to identify miRNAs that were associated with lymph node metastasis (LNM) and prognosis in breast cancer patients. A miRNA microarray covering 2019 mature miRNAs was used to identify differentially expressed miRNAs in 9 patients with LNM and 3 patients without LNM. Thirty-five differentially expressed miRNAs were identified, of which 10 significantly were up-regulated, whereas the other 25 were down-regulated in tissues with LNM compared with those without LNM. Seven miRNAs were subjected to quantitative real-time polymerase chain PCR (qRT-PCR) reaction, and 4 miRNAs (miR-191-5p, miR-214-3p, miR-451a, and miR-489) were validated in a total of 159 patients including a training set (n = 64) and a validation set (n = 95). The 4 miRNAs were used to construct a miRNA signature by logistic regression. Risk scores derived from the 4-miRNA signature were calculated to stratify the patients into high- or low-risk groups. Patients with high-risk scores had poorer overall survival and disease-free survival than did those with low-risk scores. The miRNA signature was an independent prognostic factor. MiR-191-5p increased, whereas miR-214-3p, miR-451a, and miR-489 inhibited cell proliferation, migration, and invasion abilities. The 4-miRNA signature may be a reliable prognostic and predictive tool for metastasis and survival in breast cancer patients.

MiR-1268b confers chemosensitivity in breast cancer by targeting ERBB2-mediated PI3K-AKT pathway.

Chemoresistance represents a major obstacle to effective therapy for breast cancer. Emerging evidences associated aberrantly expressed miRNAs with tumor development and chemoresistance. MiR-1268b has never been studied in any cancers before, and its roles in mediating tumor progression and drug resistance are still unclear. Selected from miRNA microarray and confirmed by real-time quantitative PCR (RT-qPCR), miR-1268b was found to be significantly upregulated in drug sensitive and ERBB2 negative tissues, as well as in breast cancer patients with low clinical stage. And miR-1268b had a higher expression in chemosensitive breast cancer cell lines, compared with the chemoresistant cell line. Moreover, the results revealed that miR-1268b induced breast cancer cell apoptosis and increased cell chemosensitivity. ERBB2 was demonstrated to be the target gene of miR-1268b by dual-luciferase reporter assays, western blot, and immunocytochemistry. Furthermore, PI3KCA, AKT, BCL2 in the ERBB2-PI3K-AKT signaling pathway were found to be downstream effectors of miR-1268b. In conclusion, miR-1268b increased chemosensitivity, at least in part, via modulation of PI3K-AKT pathway by targeting ERBB2. MiR-1268b may serve as a potential therapeutic target for patients with breast cancers.