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The tyrosinase inhibitory peptides screened from pearl shell meat hydrolysate can effectively inhibit tyrosinase activity and reduce melanin content.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis.Implications:This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.

Table S1. Frequencies of mTOR promoter polymorphisms in patients with breast cancer and healthy controls Table S2. Frequency distribution of mTOR haplotypes and their associations with the risk of developing breast cancer Table S3. Association of mTOR haplotypes with clinicopathological parameters in patients with breast cancer Table S4. Association of mTOR polymorphisms with clinicopathological parameters in patients with breast cancer Table S5. Association of mTOR polymorphisms with therapeutic response to neoadjuvant chemotherapy (n=131) Figure S1. The impact of forced expression of pcmTOR-Ht1 or pcmTOR-Ht2 on cell proliferation and cell cycle and chemoresistance to PTX in MCF7/PTX cells. Figure S2. Plasma concentration of PTX detection by using UPLC-MS/MS method.

Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.

Isosteviol has been indicated as a cardiomyocyte protector. However, the underlying mechanism remains unclear. Thus, we sought to confirm the protective effect of isosteviol after myocardial infarction in a model of permanent coronary artery occlusion and investigate the potential proangiogenic activity in vitro and in vivo. A 4-week permanent coronary artery occlusion rat model was generated, and the protective effect of isosteviol was evaluated by echocardiographic imaging and hemodynamics assays. The coronary capillary density was tested by immunochemistry and micro-computed tomography (μCT) imaging. The effect of isosteviol on endothelial cells was determined in human umbilical vein endothelial cells (HUVECs) in vitro and Tg (kdrl: EGFP) zebrafish in vivo. We also examined the expression of related transcription factors by real-time polymerase chain reaction (RT-qPCR). Isosteviol increased ejection fraction (EF), fractional shortening (FS), cardiac systolic index (CI), maximum rate of increase of left ventricular pressure (Max dp/dt), and left ventricular systolic pressure (LVSP) by 32%, 40%, 25%, 26%, and 10%, respectively, in permanent coronary artery occlusion rats. Interestingly, it also promoted coronary capillary density by 2.5-fold. In addition, isosteviol promoted the proliferation and branching of HUVECs in vitro. It also rescued intersegmental vessel (ISV) development and improved endothelial cell proliferation by approximately fivefold (4-6) in zebrafish embryos in vivo. Isosteviol also upregulated the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in zebrafish by fourfold and 3.5-fold, respectively. Our findings suggest that isosteviol is a proangiogenic agent and that this activity is related to its protective effects against myocardial ischemia. After using the permanent coronary artery occlusion model, we demonstrated that isosteviol promotes angiogenesis directly and increases capillary density in myocardial ischemia rats. Isosteviol promotes angiogenesis in zebrafish in vivo and increases vascular endothelial cell proliferation in HUVECs and zebrafish. The angiogenesis activity of isosteviol may be correlated with VEGFA and HIF-1α signaling.

Background Cancer stem cells (CSCs) have been considered as a potential therapeutic target for cervical carcinoma. CD 276 is a well-known immune check point molecular, but its relationship with cervical CSCs was still unclear. Methods HeLa cell lines were obtained as cervical carcinoma in vitro model. HeLa cell Sphere formation culture was performed and CD276, OCT4 and SOX2 expression were determined by RT-qPCR. Transiently transfection and siRNA interference were used to modify CD276 expression. HeLa cell colony has been counted and cell proliferation was assessed by MTT assay. The relationship between CD276 and chemotherapy resistance of HeLa cell were evaluated by cisplatin treatment. Additionally, the mice model of xenograft tumor was established and CD276’s function was evaluated in vivo. Results Here, we demonstrate that the expression of CD276 is positively correlated with the amount of sphere-forming cells in HeLa cell lines. Overexpression of CD276 causes the inhibition of HeLa cells’ sphere formation, colony formation and cell viability. Meanwhile, the downregulation of CD276 leads to the other way. We also demonstrate that CD276 contributes to the chemotherapy resistance in the cell line. Furthermore, we verify the CD276’s function on HeLa xenotransplantation mice model. Conclusions These results suggest that CD276 elevates the self-renewal capacity of HeLa CSCs.

Under the condition of thin interbeds with great lateral changes in terrestrial basins, a seismic meme inversion method is established based on the analysis of seismic sedimentology technology. The relationship between seismic waveform and high-frequency well logs is established through dynamic clustering of seismic waveform to improve the vertical and horizontal resolution of inversion results; meanwhile, by constructing the Bayesian inversion framework of different seismic facies, the real facies controlled inversion is realized. The forward model verification results show that the seismic meme inversion can realize precise prediction of 3 m thick thin interbeds, proving the rationality and high precision of the method. The application in the Daqing placanticline shows that the seismic meme inversion could identify 2 m thin interbeds, and the coincidence rates of inversion results and drilling data were more than 80%. The seismic meme inversion method can improve the accuracy of reservoir prediction and provides a useful mean for thin interbeds prediction in terrestrial basins.

A growing number of studies have focused on the involvement of non-coding RNAs (ncRNAs) in the internal ribosome entry site (IRES)-mediated translation in tumorigenesis; however, the underlying mechanisms in colorectal cancer (CRC) remain elusive. In this study, we show that LINC00473 (LNC473) exerted its functions as a tumor suppressor in promoting apoptotic protease-activating factor 1 (APAF1) IRES activity through competitively sponging miR574-5p and miR15b-5p in CRC initiation and pathogenesis. Specifically, LNC473 and its downstream target APAF1 were significantly downregulated accompanied by upregulated miR574-5p and miR15b-5p in CRC cells and tissues, which had a significant prognostic impact on clinical outcomes in our CRC cohort (n = 157). Furthermore, ectopic LNC473 significantly sponged endogenous miR574-5p or miR15b-5p and thereby inhibited cell proliferation and colony formation capacity, and it accelerated cell apoptosis through activating the APAF1-CASP9-CASP3 pathway. Notably, LNC473 overexpression resulted in dramatic promotion of APAF1 IRES activity and translation, whereas rescue experiments confirmed the recovery by the existence of LNC473 and miR574/15b-5p. Mechanistically, LNC473 overexpression promoted IRES binding domain exposure and removed the constraints controlling from miR574-5p and miR15b-5p, and subsequently enhanced IRES-mediated APAF1 expression in vitro and in vivo. Therefore, our results uncover a novel LNC473-miR574/miR15b-APAF1 signaling axis, which provides new targets and crosstalk regulation mechanism for CRC prevention and treatment., Graphical Abstract, The authors show that LNC473 is critically involved in the tumorigenesis, progression, and prognosis in CRC by competitively sponging hsa-miR574/miR15b-5p, yet it regulates APAF1 IRES-mediated translation initiation. The novel signaling axis will provide strong support for finding efficient molecular biomarkers and pathways for CRC diagnosis and treatment.

Emerging evidence suggests that dysregulation of long non‐coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up‐regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up‐regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC‐like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR‐148a‐3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/β‐catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC‐like properties of BCSCs by as a molecular sponge for miR‐148a‐3p to increase WNT1 expression, offering a new target for breast cancer therapy.

Glabridin, extracted from Glycyrrhiza glabra L., is widely used for the treatment of hyperpigmentation because of its anti-inflammatory and antioxidant activities and its ability to inhibit melanin synthesis. This led to the strict regulation of its quality and safety. However, traditional quality control methods used for plant extracts cannot reflect the product quality owing to multiple unknown impurities, which necessitates the further analysis of impurities.The study identified the toxic impurities of glabridin and their toxicological mechanism.In total, 10 glabridin samples from different sources were quantified using high-performance liquid chromatography. Sample toxicities were evaluated using zebrafish and cell models. To identify impurities, samples with different toxicity were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry. The toxicity of related impurities was verified in the zebrafish model. Phalloidin stain was used to evaluate subtle changes in myofibril alignment.Although glabridin content in the samples was similar, there were significant differences in toxicity. The results were verified using four different mammalian cell lines. Higher contents of glabrone and glabrol were identified in the sample with the highest toxicity. In the zebrafish model, the addition of glabrol reduced the LCGlabrol, but not glabrone, was identified as a key impurity that increased glabridin toxicity. This finding indicates that controlling glabrol content is necessary during glabridin product production.

Single-chemical thresholds cannot comprehensively evaluate the risk of chemical mixture exposure in indoor air. Moreover, a large number of researches have focused on short-term and high-concentration co-exposure scenarios related to different species, based on diverse endpoints, which hampers the application and improvement of existing risk evaluation models of chemical mixture exposures. More importantly, current risk evaluation models are not user-friendly for construction practitioners who do not have sufficient toxicological knowledge. Therefore, in this study, an inhalation experiment system and a hazard index (HI) were developed to investigate the risks associated with low-concentration and long-term inhalation exposure scenarios of formaldehyde and benzene, individually and combined, based on Drosophila melanogaster mortality. The results showed that the system exhibited good reproducibility in providing stable exposure concentrations during D. melanogaster life cycle. Furthermore, in a range of experimental concentrations, the interaction between formaldehyde and benzene was additive or synergistic, which was concentration- and ratio-dependent. This study is of great significance in harmonising and providing toxicity data under long-term and low-concentration exposure scenarios, which is beneficial for establishing a new user-friendly risk evaluation model for indoor chemical mixture exposures. It should be noted that the proposed HI value could indicate the hazard degrees of long-term inhalation exposures of formaldehyde and benzene, individually and combined, to D. melanogaster. However, the applicability of this index requires further experiments to evaluate the exposure risks of other volatile organic compounds (VOCs) to D. melanogaster.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5–mTOR–CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5–mTOR–CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis. Implications: This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5–mTOR–CCND1/ABCB1 axis.

Doxorubicin (DOX) is a powerful anthracycline antibiotic agent which is widely used to treat various types of cancers. Despite efficacy, it displays severe cardiotoxic side effects. Discovery of novel and effective protective agents against DOX-induced cardiotoxicity has been a subject of great interest. Herein, we report the synthesis of two series of analogues of Isosteviol (ISV) 1 with modifications at C-16, C-19 positions as the first series and at C-15, C-16 positions as the other series. Interestingly second series analogues have shown a potential protective effect against DOX-induced cardiotoxicity in zebrafish embryos in vivo. Further, we have demonstrated that the synthesized new analogues of ISV, prevented the morphological distortions caused due to DOX cardiotoxicity in zebrafish heart and the associated cardiac impairments.

Background ACTL8 is a member of the CT antigens. There are only few studies on the role of ACTL8 in malignant tumors. The aim of this study is to investigate the expression and clinical significance of ACTL8 protein in colorectal cancer (CRC). Materials and methods Human CRC tissues and cell lines, and paired adjacent non-tumor tissues and human intestinal epithelial cell lines were obtained to evaluate the expression of ACTL8. The association between protein expression of ACTL8 and clinicopathological parameters and prognosis of CRC patients was examined. The biological functions of ACTL8 in the invasion and metastasis of CRC were determined by wound healing and transwell invasion assays after silencing of ACTL8 in CRC cell lines. The potential target genes of ACTL8 were also identified by quantitative reverse transcription PCR and Western blotting after silencing of ACTL8 in CRC cell lines. Results It was found that ACTL8 was upregulated in human CRC tissues and cell lines. The expression of ACTL8 was positively associated with poor differentiation, invasion and metastasis, postoperative infection, and poor prognosis, but negatively associated with proximal margin length. In addition, silencing of ACTL8 significantly decreased the capacity of invasion and migration in HT29 and SW620 CRC cell lines. Moreover, silencing of ACTL8 significantly decreased the expression of TRIM29 in HT29 and SW620 CRC cell lines. Conclusion These results suggest that ACTL8 plays a key role in the invasion and metastasis of CRC, and TRIM29 may be involved in the ACTL8-mediated poor prognosis of CRC.

Ovarian cancer stem cells (OCSCs) are sources of tumor chemoresistance and recurrence. A hypoxic microenvironment contributes to the chemoresistance of cancer stem cells (CSCs), but the underlying mechanism is not fully understood yet. Here, we show that increased HIF-2α expression is associated with enhanced stemness of OCSCs and poor outcomes in ovarian cancer patients. OVCAR-3 and CAOV-3 sphere-forming (OVCAR-3 S and CAOV-3 S) cells with OCSC-like properties showed strong resistance to adriamycin (ADR). Hypoxia (1% O2 ) induced high expression of both HIF-1α and especially HIF-2α, and increased the resistance of OVCAR-3 S and CAOV-3 S cells to ADR. Notably, treatment with ADR further increased the expression of HIF-2α, but not that of HIF-1α. Knockdown of HIF-2α expression substantially attenuated the resistance of OVCAR-3 S and CAOV-3 S cells to ADR, and the HIF-2α overexpression had the opposite effect. Furthermore, in mouse models xenografted with OCSCs, HIF-2α depletion significantly inhibited tumor growth and sensitized OCSCs to ADR in vivo. Mechanistically, HIF-2α directly promotes transcription/expression of BCRP, a gene encoding a transporter protein responsible for pumping drugs (e.g., ADR) out of cells, which in turn increases drug resistance due to increased drug transportation. Collectively, our studies reveal a novel drug-resistant mechanism in ovarian cancer by which hypoxia (and ADR treatment)-induced HIF-2α overexpression endows OCSCs with resistance to ADR by promoting BCRP expression and ADR transportation. Therefore, targeting the HIF-2α/BCRP axis holds therapeutic potential for treating drug-resistant ovarian cancer.

Simple Summary Fear extinction is the driving mechanism to reduce the fear response, and it is the basis of exposure-based cognitive-behavioral therapy. Butyrylcholinesterase (BChE) seems to be involved in regulating cognitive function, and its relationship with fear extinction memory has not been reported. BChE knockout mice and wild-type mice with administration of (R)-bambuterol, a BChE inhibitor, were used in this study. In addition to immunohistochemistry and metabolite analysis using mass spectrometry imaging, the influence of age on the conditioned fear test, Morris water maze experiment, and open field test were carefully evaluated. Our results showed that BChE inhibition accelerates the fear extinction memory in mice and delays the cognitive decline in the early stages of aging. Abstract Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer’s disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3–10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline.

Tumor metastasis is a complex and multistep process and its exact molecular mechanisms remain unclear. We attempted to find novel microRNAs (miRNAs) contributing to the migration and invasion of breast cancer cells. In this study, we found that the expression of miR-487a was higher in MDA-MB-231breast cancer cells with high metastasis ability than MCF-7 breast cancer cells with low metastasis ability and the treatment with transforming growth factor β1 (TGF-β1) significantly increased the expression of miR-487a in MCF-7 and MDA-MB-231 breast cancer cells. Subsequently, we found that the transfection of miR-487a inhibitor significantly decreased the expression of vimentin, a mesenchymal marker, while increased the expression of E-cadherin, an epithelial marker, in both MCF-7 cells and MDA-MB-231 cells. Also, the inactivation of miR-487a inhibited the migration and invasion of breast cancer cells. Furthermore, our findings demonstrated that miR-487a directly targeted the MAGI2 involved in the stability of PTEN. The down-regulation of miR-487a increased the expression of p-PTEN and PTEN, and reduced the expression of p-AKT in both cell lines. In addition, the results showed that NF-kappaB (p65) significantly increased the miR-487a promoter activity and expression, and TGF-β1 induced the increased miR-487a promoter activity via p65 in MCF-7 cells and MDA-MB-231 cells. Moreover, we further confirmed the expression of miR-487a was positively correlated with the lymph nodes metastasis and negatively correlated with the expression of MAGI2 in human breast cancer tissues. Overall, our results suggested that miR-487a could promote the TGF-β1-induced EMT, the migration and invasion of breast cancer cells by directly targeting MAGI2.

Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPR

Butyrylcholinesterase (BChE) efficiently hydrolyzes acetylcholine (ACh) at high concentrations when acetylcholinesterase (AChE) is substrate-inhibited. Recent studies have shown that BChE also has a function that is independent of ACh, but it has not been fully explored. Low BChE expression is accompanied with higher stress-induced aggression and ghrelin levels in stress models, and BChE knockout mice exhibit cognitive and memory impairments. However, the role of BChE in posttraumatic stress disorder (PTSD) remains unclear. In the present study, we investigated the role of BChE in contextual fear memory and its regulatory effect on the expression of factors related to the glutamate (Glu)-glutamine (Gln) cycle via knockdown studies. We used AAVs and lentiviruses to knockdown BChE expression in the mouse hippocampal CA1 region and C8D1A astrocytes. Our behavioral data from those mice injected with AAV-shBChE in the hippocampal CA1 region showed strengthened fear memory and increased dendritic spine density. Elevated Glu levels and glutamine synthetase (GS) enzyme activity were detected in contextual fear conditioned-BChE knockdown animals and astrocytes. We observed that an AAV-shBChE induced lowering of BChE expression in the hippocampus CA1 enhanced contextual fear memory expression and promoted the astrocytic Glu-Gln cycle but did not elevate ACh-hydrolyzing activity. This study provides new insight into the regulatory role of BChE in cognition and suggests potential target for stress-related psychiatric disorder such as posttraumatic stress disorder (PTSD) where patients experience fear after exposure to severe life-threatening traumatic events.

Additional file 2. Supplementary materials and methods.

Additional file 3 Figure S1. The expression and correlation analysis between ZFAS1 and snoRNP complex based on the TCGA database. Figure S2. The (m) RNA expression of ZFAS1, NOP58, SNORD12C, and SNORD78 in CRC tissues and matched tumor-adjacent controls (n = 30). Figure S3. The correlation analysis of ZFAS1, NOP58, SNORD12C/78 expression in 30 paired CRC and control tissues. Figure S4. The effect of ZFAS1 on cell proliferation and apoptosis in CRC cells. Figure S5. The correlation of ZFAS1 and NOP58 expression and prognosis evaluation in CRC patient tissues. Figure S6. The 2′-O-Me activity levels after interfering ZFAS1 and/or NOP58 expression. Figure S7. The 2′-O-Me activities mediated by SNORD12C and SNORD78 after silencing SNORD12C and SNORD78.

Additional file 1: Table S1.Short hairpin RNAs (shRNAs) sequence against ZFAS1. Table S2.Short hairpin RNAs (shRNAs) sequence against NOP58. Table S3. The reaction assays of qRT-PCR method. Table S4. Primers used in qRT-PCR assays. Table S5. Probes used in situ hybridization (ISH) assay. Table S6. RNA probes used for RNA pull-down assays. Table S7. Primers used in site-specific 2′-O-methylation for RTL-P assay. Table S8. RTL-P assays for rRNA 2′-O-methylation. Table S9. Probes used in site-specific 2′-O-methylation for double-stranded primer based on single-stranded toehold (DPBST) assays. Table S10. Double-stranded primer based on single-stranded toehold (DPBST) assays. Table S11. Data of LncRNAs cluster in Heat map analysis. Table S12. Data of snoRNAs cluster in Heat map analysis. Table S13. Data of mRNAs cluster in Heat map analysis. Table S14. The enriched target genes intersected by ZFAS1, SNORD12C/78 in GO analysis. Table S15. Prognostic information of included colorectal cancer patients (n = 157). Table S16. Multivariate COX regression analysis of the association of ZFAS1 and NOP58 expression with DFS and OS in CRC patients.

The pTEN/AKT/mTOR signaling pathways play a critical role in balancing cell proliferation, differentiation, and survival. Recent studies researched the associations of core genes in the pTEN/AKT/mTOR pathway polymorphisms with the cancer susceptibility; however, the results are inconclusive. Therefore, a systematically meta-analysis was performed to evaluate the association between the five SNPs (mTOR rs2295080 and rs2536, AKT1 rs2494750 and rs2494752, pTEN rs701848) and cancer risk by systematic review of the literature in 31 eligible studies. The results showed a significant decreased risk between rs2295080 TG, GG genotype, and GG/TG genotypes and overall cancer [TG vs.TT: OR(95% CI) = 0.82(0.76, 0.89), GG/TG vs. TT: OR(95% CI) = 0.82(0.76, 0.88), and GG vs. TG/TT: OR(95% CI) = 0.67(0.51, 0.88)] and the subgroup of urinary system cancer and digestive system cancer. Moreover, the SNP rs701848 CC, TC genotype showed significantly increased the overall cancer risk both in dominant model [CC/TC vs. TT: OR(95% CI) = 1.25(1.15, 1.36)] and recessive model [CC vs. TC/TT: OR(95% CI) = 1.20(1.09, 1.32)], and digestive system cancer and urinary system cancer. In addition, AG genotype and GG/AG genotype of rs2494752 was associated with increased risk of cancer. Therefore, this meta-analysis provided genetic risk factors for carcinogenesis and the most valid cancer prevalence estimate for Asian population.

Background Increasing evidence supports the role of small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs) as master gene regulators at the epigenetic modification level. However, the underlying mechanism of these functional ncRNAs in colorectal cancer (CRC) has not been well investigated. Methods The dysregulated expression profiling of lncRNAs-snoRNAs-mRNAs and their correlations and co-expression enrichment were assessed by GeneChip microarray analysis. The candidate lncRNAs, snoRNAs, and target genes were detected by in situ hybridization (ISH), RT-PCR, qPCR and immunofluorescence (IF) assays. The biological functions of these factors were investigated using in vitro and in vivo studies that included CCK8, trans-well, cell apoptosis, IF assay, western blot method, and the xenograft mice models. rRNA 2′-O-methylation (Me) activities were determined by the RTL-P assay and a novel double-stranded primer based on the single-stranded toehold (DPBST) assay. The underlying molecular mechanisms were explored by bioinformatics and RNA stability, RNA fluorescence ISH, RNA pull-down and translation inhibition assays. Results To demonstrate the involvement of lncRNA and snoRNAs in 2′-O-Me modification during tumorigenesis, we uncovered a previously unreported mechanism linking the snoRNPs NOP58 regulated by ZFAS1 in control of SNORD12C, SNORD78 mediated rRNA 2′-O-Me activities in CRC initiation and development. Specifically, ZFAS1 exerts its oncogenic functions and significantly up-regulated accompanied by elevated NOP58, SNORD12C/78 expression in CRC cells and tissues. ZFAS1 knockdown suppressed CRC cell proliferation, migration, and increased cell apoptosis, and this inhibitory effect could be reversed by NOP58 overexpression in vitro and in vivo. Mechanistically, the NOP58 protein could be recognized by the specific motif (AAGA or CAGA) of ZFAS1. This event accelerates the assembly of SNORD12C/78 to allow for further guiding of 2′-O-Me at the corresponding Gm3878 and Gm4593 sites. Importantly, silencing SNORD12C or 78 reduced the rRNAs 2′-O-Me activities, which could be rescued by overexpression ZFAS1, and this subsequently inhibits the RNA stability and translation activity of their downstream targets (e.g., EIF4A3 and LAMC2). Conclusion The novel ZFAS1-NOP58-SNORD12C/78-EIF4A3/LAMC2 signaling axis that functions in CRC tumorigenesis provides a better understanding regarding the role of lncRNA-snoRNP-mediated rRNAs 2′-O-Me activities for the prevention and treatment of CRC.

Background The long non-coding RNA H19 plays critical roles in cancer occurrence, development, and progression. The present study is for the first time to evaluate the association of genetic variations in the H19 promoter region with advanced colorectal cancer (CRC) susceptibility, environmental factors, and clinical outcomes. Methods 16 single-nucleotide polymorphisms (SNPs) were identified in the H19 gene promoter by DNA sequencing, and 3 SNPs among which including rs4930101, rs11042170, and rs2735970 further expanded samples with 572 advanced CRC patients and 555 healthy controls. Results We found that harboring SNP [rs4930101 (P = 0.009), rs2735970 (P = 0.003), and rs11042170 (P = 0.003)] or carrying more than one combined risk genotypes significantly increased the risk for CRC [P 1 vs. ≤ 1) and family history of cancer demonstrated significant interactions. Furthermore, a remarkably worse clinical outcome was found in combined risk genotypes (> 1 vs. ≤ 1), especially in CRC patients with body weight ≥ 61 kg, smoking, and first-degree family history of cancer (Log-rank test: P = 0.006, P = 0.018, and P = 0.013, respectively). More importantly, the multivariate Cox regression analyses further verified that combined risk genotypes > 1 showed a prognostic risk factor for CRC patients with body weight ≥ 61 kg (P = 0.002), smoking (P = 0.008), and family history of cancer (P = 0.006). In addition, MDR analysis consistently revealed that the combination of selected SNPs and nine known risk factors showed a better prediction prognosis and represented the best model to predict advanced CRC prognosis. Conclusion 3 SNPs of rs4930101, rs11042170, and rs27359703 among 16 identified SNPs of H19 gene remarkably increased CRC risk. Furthermore, the combined risk genotypes had a significant impact on environmental factors and clinical outcomes in the advanced CRC patients with body weight ≥ 61 kg, ever-smoking, and first-degree family history of cancer. These data suggest that H19 promoter SNPs, especially these combined SNPs might be more potentially functional biomarkers in the prediction of advanced CRC risk and prognosis.

Objective Multiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and ABCG2 gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy. Methods In this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes (XPA rs10817938, XPA rs2808668, XPC rs2607775, and WRN rs1346044) and ABCG2 gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay. Results Regarding interaction with environmental factors, ABCG2 rs2231142 and the first-degree family history of cancer and XPC rs2607775 or ABCG2 rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, XPA rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (P=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (P=0.001) and OS (P

Additional file 1. Additional tables.

Moesin, a cytoskeletal protein belonging to the ezrin-radixin-moesin family serves important roles in cell motility, invasion and metastasis. Moesin has been demonstrated to be of prognostic significance in tumor progression, due to its role in the metastatic process; however, its role in breast cancer is not well characterized. In the present study, the moesin expression was determined using immunohistochemistry in 404 and 46 patients with breast cancer and fibroadenoma, respectively, and the associations between moesin expression and the clinical parameters and prognostic values were analyzed. The positive rate of moesin protein expression was 47.8% (193/404) in breast cancer tissues, which was significantly higher than in fibroadenoma tissues (15.2%, 14/46). Overexpression of moesin was significantly associated with advanced clinical stage (P=0.002), positive lymph node metastasis (P

OBJECTIVE Previous studies have revealed the association of multidrug resistance with histone deacetylases inhibitors treatment in cancer cells. But little data were available for the correlation of histone deacetylases and drug-resistant-related proteins in breast cancer tissue. This study aimed to exploring the association of histone deacetylases expression with clinicopathological features, drug-resistant-related proteins, prognosis and therapeutic responses in breast cancer patients. METHODS We performed immunohistochemistry to study the expression of HDAC1 and HDAC2 in 226 breast cancer and 34 breast fibroadenoma patients, and the expression of breast cancer resistance protein, P-glycoprotein, lung resistance protein and multidrug resistance protein in 226 breast cancer. RESULTS In breast cancer, HDAC2 expression was significantly increased than in fibroadenoma (P = 0.015), and correlated with lymph node metastasis (P = 0.002), advanced clinical stages (P = 0.016) and high histological grade (P = 0.001). Significant positive correlations were found between HDAC2 and Ki67, HDAC1 and multidrug resistance protein, HDAC2 and breast cancer resistance protein, HDAC2 and multidrug resistance protein. HDAC2 positive expression was associated with shorter overall survival (P = 0.035) of breast cancer patients. In addition, HDAC2-positive expression was significantly associated with shorter overall survival in multidrug resistance protein-positive patients (P = 0.034), but not in multidrug resistance protein-negative patients (P = 0.530). HDAC2-positive expression was associated with shorter survival in patients who received chemotherapy containing anthracyclines (overall survival, P = 0.041; disease-free survival, P = 0.084), but not in patients who received chemotherapy without anthracyclines (overall survival, P = 0.679; disease-free survival, P = 0.708). CONCLUSIONS HDAC2 overexpression correlated with the metastasis, progression and the increased Ki67, multidrug resistance protein expression in breast cancer, and HDAC2 could be a prognostic factor of breast cancer patients, especially the patients who received anthracyclines therapy.

Recent studies suggest that the nanorods consisting of europium hydroxide could promote angiogenesis. In this study, it is sought to determine if additional types of nanoparticles are capable of enhancing angiogenesis and in addition, understand the underlying mechanisms. For this reason, a method is employed that combines a high throughput in vitro cell based screen coupled with an in vivo validation using vascular specific green fluorescent protein reporter transgenic zebrafish for examining proangiogenesis activity. After screening multiple types of nanoparticles, it is discovered that four of them, Eu(III) (OH)3 rods (Eu rods), Eu(III) (OH)3 spheres (Eu spheres), Tb(III) (OH)3 rods (Tb rods), and Tb(III) (OH)3 spheres (Tb spheres), are the most effective in promoting angiogenesis. It is also showed that ionic forms of europium nitrate [Eu(NO3 )3 ] (Eu) and terbium nitrate [Tb(NO3 )3 ] (Tb), the two lanthanide elements for these four nanoparticles, are also capable of enhancing angiogenesis. However, this effect is further enhanced by nanoparticle synthesis. Finally, it is demonstrated that reactive oxygen species H2 O2 is a key factor in the process of proangiogenesis by lanthanide elemental nanoparticles.

The novel uniform Fe 3 O 4 @C@Mn 3 O 4 multilayer core–shell porous spheres for used in lithium–ion batteries (LIBs) have been synthesized with utilizing bovine serum albumin (BSA) as carbon source by hydrothermal process. Fe 3 O 4 porous spheres are coated by carbon and Mn 3 O 4 nanolayer, when manganese ion and iron ion could be adsorbed on BSA. It is indicated that chelation of protein and metal is constructed between the metal ions and the atom with lone pair electrons on the surface of the protein amino acid. And the chelation is connected by the nitrogen atoms in histidine of BSA and the Fe 2+ , Mn 2+ in the metal ions. As an anode material for LIBs, Fe 3 O 4 @C@Mn 3 O 4 core–shell nanostructure particles show a high initial capacity of 1261 mAh g −1 at the current density of 0.1 C, a reversible capacity of approximately 987 mAh g −1 after 200 cycles, which possess excellent cycling stability. The enhanced electrochemical properties are mainly ascribed to the core/shell architecture between the different metal oxides with carbon interlayer, which can effectively improve the electric conductivity, active phase, the synergy between different metal oxides. And also, the porous structure could help anodes for buffering the dramatic volume change of active material for improving electrochemical performance for LIBs.

Xuzhou is located in the northwest of Jiangsu Province, at the junction of the four provinces of Sulu, Henan and Anhui. It belongs to a warm temperate and semi-humid climate. Based on the field investigation in Xuzhou area, a total of 1037 species, 595 genera and 144 families of vascular plants were obtained. The flora has certain importance and particularity in Jiangsu area. Based on the analysis of the species diversity of vascular plants and their floristic characteristics and geographical components, it is found that there are a lot of vascular plants in Xuzhou, most of which are distributed in the world and north temperate zone, and the tropical distribution also accounts for a certain proportion, which shows that the flora is mainly the type of transition from tropical to temperate, At the same time, its flora also has some ancient elements.