DNA-Modulated and Mechanoresponsive Excitonic Couplings Reveal Chiroptical Correlation of Conformation, Tension, and Dynamics of DNA Self-Assembly.

Study of the conformational and mechanical behaviors of biomolecular assemblies is vital to the rational design and realization of artificial molecular architectures with biologically relevant functionality. Here, we revealed DNA-modulated and mechanoresponsive excitonic couplings between organic chromophores and verified strong correlations between the excitonic chiroptical responses and the conformational and mechanical states of DNA self-assemblies irrespective of fluorescence background interference. Besides, the excitonic chiroptical effect allowed sensitive monitoring of DNA self-assembled nanostructures due to small molecule bindings or DNA strand displacement reactions. Moreover, we developed a new chiroptical reporter, a DNA-templated dimer of an achiral cyanine5 and an intrinsically chiral BODIPY, that exhibited unique multiple-split spectral line shape of exciton-coupled circular dichroism, largely separated response wavelengths, and enhanced anisotropy dissymmetry factor (g-factor). These results shed light on a promising chiroptical spectroscopic tool for studying biomolecular recognition and binding, conformation dynamics, and soft mechanics in general.

Concomitant high expression of BRAFV600E, P-cadherin and cadherin 6 is associated with High TNM stage and lymph node metastasis in conventional papillary thyroid carcinoma.

CONTEXT AND OBJECTIVE: BRAFV600E mutation is the most common activating mutation associated with aggressive behaviours in human tumours including conventional papillary thyroid carcinoma (cPTC). P-cadherin and cadherin 6 have been shown to be mesenchymal-associated cadherins and promote cancer cell invasion and metastasis. The purpose of this study was to examine BRAFV600E, P-cadherin and cadherin 6 expressions in cPTC and to assess the association of their expression with clinicopathological indicators. METHODS: BRAFV600E, P-cadherin and cadherin 6 protein expressions in 80 cPTCs, 61 nodular hyperplasia and 76 normal thyroid tissues were examined by immunohistochemistry. The correlation of their protein expression with clinicopathological indicators of cPTC was statistically analysed. RESULTS: Protein expression of BRAFV600E, P-cadherin and cadherin 6 was upregulated in cPTC. High protein expression of BRAFV600E, P-cadherin and cadherin 6 was significantly correlated with high TNM stage and lymph node metastasis (LNM) (P < 0·001). Furthermore, BRAFV600E, P-cadherin and cadherin 6 protein expressions were correlated with one another. BRAFV600E high expression combined with both P-cadherin and cadherin-6 high expressions had stronger correlation with high TNM stage and LNM when compared with BRAFV600E high expression combined with either P-cadherin or cadherin-6 high expression (P = 0·042, 0·017 for TNM stage and P = 0·003, 0·006 for LNM, respectively) and only BRAFV600E high expression (P < 0·001 for both TNM stage and LNM). CONCLUSIONS: Concomitant high expression of BRAFV600E, P-cadherin and cadherin 6 is strongly associated with high TNM stage and LNM in cPTC.

Versixanthones A-F, Cytotoxic Xanthone-Chromanone Dimers from the Marine-Derived Fungus Aspergillus versicolor HDN1009.

Six unusual xanthone-chromanone dimers, versixanthones A-F (1-6), featuring different formal linkages of tetrahydroxanthone and 2,2-disubstituted chroman-4-one monomers, were isolated from a culture of the mangrove-derived fungus Aspergillus versicolor HDN1009. The absolute configurations of 1-6, representing the central and axial chirality elements or preferred helicities, were established by a combination of X-ray diffraction analysis, chemical conversions, and TDDFT-ECD calculations. The interconversion of different biaryl linkages between 1 and 4 and between 2 and 3 in DMSO by a retro-oxa-Michael mechanism provided insight into the formation of the xanthone-chromanone dimers and supported the assignments of their absolute configurations. Compounds 1-6 exhibited cytotoxicities against the seven tested cancer cell lines, with the best IC50 value of 0.7 µM. Compound 5 showed further inhibitory activity against topoisomerase I.

[Contemplation and suggestion on the medical device adverse event reporting program].

The number of medical device adverse events reported to national monitoring center increased greatly year by year, but the reporting system still existed some deficiencies which resulting in confusion when filling the forms, especially those selections about relationship evaluation. This paper proposed amendments about event-evaluation process according to the characteristics of medical device adverse events reported in China, in order to perform timely and effectively regulation on different types of adverse events for different purposes.

First identification of multidrug-resistant Acinetobacter bereziniae isolates harboring bla NDM-1 from hospitals in South China.

This study is a first report on the identification of multidrug-resistant (MDR) Acinetobacter bereziniae among non-baumannii acinetobacters that had previously escaped automated laboratory detection, and characterize their clinical courses of infection at two tertiary-care hospitals in Shenzhen city, China (2015-2017). Herein, definitive identification by PCR was performed with universal and species-specific primers targeting 16S rDNA and rpoB genes, respectively, followed by Sanger sequencing and blast analysis. Antimicrobial susceptibility of A. bereziniae isolates was assessed accordingly. Three of the five identified A. bereziniae isolates exhibited carbapenem-resistance and were subjected to a multiplex PCR assay to detect drug-resistance genes. Sequences of the rpoB amplicon were aligned with curated sequences from global databases for phylogenetic analysis on evolutionary relations. Five clinical isolates of A. bereziniae were thereby re-identified, whose infections were primarily nosocomial. Automated identification and susceptibility testing systems (Phoenix-100 and VITEK 2) proved insufficient for discriminating A. bereziniae from other acinetobacters such as Acinetobacter baumannii and Acinetobacter guillouiae. Among these isolates, three exhibited carbapenem-resistant phenotypes indistinguishable from that of carbapenem-resistant A. baumannii. The carbapenem-resistant A. bereziniae isolates were subsequently confirmed to carry a bla NDM-1 (New Delhi metallo-ß-lactamase-1) gene downstream of ISAba125. Phylogenetic analysis revealed that A. bereziniae isolates evolved slowly but independently in local habitats. A. bereziniae isolates are difficult to distinguish by traditional automated detection systems. PCR-based identification via amplification and sequencing of selected house-keeping genes provides sufficient resolution for discriminating the isolates.

Diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1.

Effusin A (1), a spirobicyclic N,O-acetal derivative with an unprecedented 3',3a',5',6'-tetrahydrospiro[piperazine-2,2'-pyrano[2,3,4-de]chromene] ring system, and a spiro-polyketide-diketopiperazine hybrid dihydrocryptoechinulin D (2) were isolated from a mangrove rhizosphere soil derived fungus, Aspergillus effuses H1-1. Their structures were determined by detailed spectroscopic analysis. Effusin A (1) and dihydrocryptoechinulin D (2) occurred as racemates, the enantiomers of which were separated and characterized by online HPLC-ECD analysis and their absolute configurations were determined by the solution TDDFT ECD calculation approach. The cytotoxic effects of 1 and 2 were preliminarily evaluated and 2 showed potent activity on P388 cells with an IC(50) value of 1.83 µM. The target of racemic 2 was also investigated and the (12R,28S,31S)-2 enantiomer showed selectivity against topoisomerase I.

DNA-Binding and Topoisomerase-I-Suppressing Activities of Novel Vanadium Compound Van-7.

Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 µM. Van-7 significantly suppressed the growth of cancer cell lines with IC(50) at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison.

Analysis of anti-M antibody status and blood transfusion strategy in Hunan, China.

Background: By analyzing the detection rate of anti-M antibody in patients with the MNS blood group system in the Hunan area, we aimed to explore its clinical significance and blood transfusion strategy. Methods: We retrospectively analyzed the clinical data of patients who had been confirmed to contain anti-M antibodies through serological methods such as the saline tube method and cassette anti-human globulin method. Results: Irregular antibody screening tests had been applied to 94,452 patients, from which 652 results were positive. Among those positive patients, 93 cases were positive for anti-M antibodies, accounting for 14.26% of the positive rate of irregular antibodies; 11 cases had a blood transfusion history, accounting for 11.8%; 59 cases had a pregnancy history, accounting for 63.4%; and 2 cases had a transplant history, accounting for 2.2%. The patients with anti-M antibodies included 23 pregnant woman, accounting for 24.7%, and 19 tumor patients, accounting for 20.4%. A total of 66 cases were immunoglobulin M (IgM) + immunoglobulin G (IgG) class, accounting for 71.0%, 26 cases were IgM class, accounting for 28.0%, and 1 case was IgG class, accounting for 1.0%. Conclusions: The detection rates of anti-M antibody in the Hunan area and unexpected antibodies in literature reports are mainly related to a pregnancy history, and the type of antibody is predominantly IgM + IgG class. The clinical significance of anti-M antibody cannot be ignored, and three media should be used for cross-matching of blood wherever possible to ensure the safety of blood transfusion.

Brefeldin A Induces Apoptosis, Inhibits BCR-ABL Activation, and Triggers BCRABL Degradation in Chronic Myeloid Leukemia K562 Cells.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). OBJECTIVE: This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. METHODS: We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. RESULTS: BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. CONCLUSION: Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Tyndall-Effect-inspired assay with gold nanoparticles for the colorimetric discrimination and quantification of mercury ions and glutathione.

This work initially reports a new nanosening method for simple, sensitive, specific, visual detection of mercury (II) (Hg2+) and glutathione (GSH) using the Tyndall Effect (TE) of the same colloidal gold nanoparticle (GNP) probes for efficient colorimetric signaling amplification. For the TE-inspired assay (TEA) method, arginine (Arg) molecules are pre-modified on the GNPs' surfaces (Arg-GNPs). Upon the Hg2+ introduction, it can be specifically coordinated with the terminal -NH2 and -COOH groups of the Arg molecules to make the Arg-GNPs aggregate, producing a significantly-enhanced TE signal in the reaction solution after its irradiation by a 635-nm red laser pointer pen. On the other hand, the introduction of the GSH results in the production of the original Arg-GNPs' weak TE response, as it is able to bind such metal ion via mercury-thiol reactions to inhibit the above aggregation. Under the optimal conditions, the utility of the new TEA method is well demonstrated to quantitatively detect the Hg2+ and GSH with the aid of a smartphone as a portable TE reader during the linear concentration ranges of 50-3000 and 10-3000 nM, respectively. The detection limits for the Hg2+ and GSH are estimated to be as low as ∼3.5 and ∼0.3 nM, respectively. The recovery results obtained from the detection of Hg2+ in the complex tap and pond water samples and the assay of GSH in real human serum and urine samples are also satisfactory.

On-site, rapid and visual method for nanomolar Hg2+ detection based on the thymine-Hg2+-thymine triggered "double" aggregation of Au nanoparticles enhancing the Tyndall effect.

This work describes a new nanosensor for the simple, rapid, portable, colorimetric analysis of mercury(ii) (Hg2+) ions by combining the sensitive Tyndall effect (TE) of colloidal Au nanoparticles (AuNPs) with specific thymine-Hg2+-thymine (T-Hg2+-T) coordination chemistry for the first time. For the TE-inspired assay (TEA), in the presence of Hg2+ in a sample, the analyte can selectively mediate the hybridization of three types of flexible single-stranded DNAs (ssDNAs) to form stable rigid double-stranded DNAs (dsDNAs) via the T-Hg2+-T ligand interaction. Subsequent self-assembly of the dsDNAs with terminal thiol groups on the AuNPs' surfaces led to their "double" aggregation in addition to the lack of sufficient ssDNAs as the stabilizing molecules in a high-salt solution, resulting in a remarkably enhanced TE signal that positively relied on the Hg2+ level. The results demonstrated that such a TEA method enabled rapid naked-eye qualitative analysis of 625 nM Hg2+ within 10 min with an inexpensive laser pointer pen as an inexpensive handheld light source to generate the TE response. Making use of a smartphone for portable TE readout could further quantitatively detect the Hg2+ ions in a linear concentration range from 156 to 2500 nM with a limit of detection as low as 25 nM. Moreover, the developed equipment-free nanosensor was also used to analyze the Hg2+ ions in real samples including tap water, drinking water, and pond water, the obtained recoveries were within the range of 93.68 to 108.71%. To the best of our knowledge, this is the first report of using the AuNPs and functional nucleic acids to design a TE-based biosensor for the analysis of highly toxic heavy metal ions.

A novel strategy for sensitive and rapid detection of ascorbic acid via the Tyndall effect of cobalt hydroxide nanoflakes.

Cobalt oxyhydroxide (CoOOH) nanoflakes, as nanoenzymes and fluorescence quenchers, have been widely used in colorimetric and fluorescent analysis. However, their promising light scattering property-the Tyndall effect (TE)-has never been applied in biosensors and biological analysis to date. Herein, we report for the first time a novel strategy for point-of-care detection of ascorbic acid (AA) with the TE of CoOOH nanoflakes providing colorimetric signaling. In this detection system, CoOOH nanoflakes exhibit a strong red TE signal under the illumination of a hand-held 635 nm laser pointer pen. However, the introduction of AA could induce a significant decrease of the TE because it could reduce CoOOH into Co2+ and results in the degradation of the CoOOH nanoflakes. The changes in the TE intensity could be read-out using a smartphone for the portable quantitative analysis of AA. The results showed that this CoOOH nanoflake-based TE-inspired assay (TEA) exhibited a good linear range from 0.25 µM to 40 µM for AA, with a detection limit of 12 nM. It also showed high selectivity toward AA over common potential interfering species. Importantly, this method possessed the advantages of simple operation, low consumption of time and equipment-free analysis and was successfully applied to the detection of AA in vitamin C tablets.

Structural insights into the inhibition of bacterial RecA by naphthalene polysulfonated compounds.

As a promising target for alternative antimicrobials, bacterial recombinase A (RecA) protein has attracted much attention for its roles in antibiotic-driven SOS response and mutagenesis. Naphthalene polysulfonated compounds (NPS) such as suramin have previously been explored as antibiotic adjuvants targeting RecA, although the underlying structural bases for RecA-ligand interactions remain obscure. Based on our in silico predictions and documented activity of NPS in vitro, we conclude that the analyzed NPS likely interact with Tyr103 (Y103) and other key residues in the ATPase activity center (pocket A). For validation, we generated recombinant RecA proteins (wild-type versus Y103 mutant) to determine the binding affinities for RecA protein interactions with suramin and underexamined NPS in isothermal titration calorimetry. The corresponding dissociation constants (K d) ranged from 11.5 to 18.8 µM, and Y103 was experimentally shown to be critical to RecA-NPS interactions.

Nucleosome Assembly Protein 1-Like 3 Enhances Cisplatin Resistance of Ovarian Cancer Cell by Activating Transforming Growth Factor-Beta Pathway.

Chemotherapy resistance is one of the main reasons for tumor-related death. In particular, ovarian cancer patients often acquire drug resistance after chemotherapy. In this study, we found that the histone chaperone, nucleosome assembly protein 1-like 3 (NAP1L3), was significantly upregulated in tissues with cisplatin resistance compared with cisplatin-sensitive tissues. Patients with high NAP1L3 levels had poor prognosis, suggesting that NAP1L3 might regulate ovarian cancer resistance. Colony formation and terminal deoxynulceotidyl transferase nick-end-labeling (TUNEL) assays showed cells with high NAP1L3 had high cisplatin resistance, whereas cells with low NAP1L3 had poor cisplatin resistance. NAP1L3 overexpression significantly increased cisplatin resistance, whereas NAP1L3 knockdown significantly reduced cisplatin resistance, suggesting that NAP1L3 promoted cisplatin resistance. Mechanistically, gene set enrichment analysis and luciferase reporter assays showed that NAP1L3 regulated the transforming growth factor-beta (TGF-ß) pathway. NAP1L3 overexpression increased the phosphorylation and nuclear translocation of SMAD family member 2 (SMAD2) and SMAD3, confirming that NAP1L3 activated the TGF-ß pathway. Therefore, NAP1L3 might represent a novel target to overcome ovarian cancer chemoresistance.

miR-421 promotes the viability of A549 lung cancer cells by targeting forkhead box O1.

MicroRNA (miR)-421 has been reported to serve various important roles in numerous types of cancer, including neuroblastoma and gastric cancer. However, to the best of our knowledge, few reports have determined the role of miR-421 in lung cancer. The aim of the current study was to analyze the expression levels of miR-421 in A549 lung cancer cells, to determine the target gene of miR-421, and to investigate the function and mechanism of miR-421 in cellular cytotoxicity. miR-421 expression levels were analyzed in A549 lung cancer cells using reverse transcription-quantitative PCR, a MTT assay was performed to determine the effect of miR-421 on A549 cell cytotoxicity and the protein expression levels of forkhead box O1 (FOXO1) were determined via western blotting. The target gene of miR-421 was predicted and verified using TargetScan and a dual-luciferase reporter assay, respectively. The results revealed that miR-421 expression levels were significantly upregulated in A549 lung cancer cell lines compared with the normal cells (P<0.01). Additionally, it was discovered that miR-421 promoted A549 cell viability (P<0.01) compared with A549 transfected with negative control. miR-421 was also identified to bind to the 3'-untranslated region of FOXO1. In A549 cells transfected with miR-421-mimics, the expression levels of phosphorylated (p)-AKT, p-glycogen synthase kinase-3ß, p-retinoblastoma and cyclin D1 were significantly upregulated (P<0.01), whereas the expression levels of FOXO1 and p21 were significantly downregulated (P<0.01) compared with the control group. In conclusion, the results of the present study suggested that miR-421 may promote the viability of A549 lung cancer cells by targeting FOXO1 and modulating cell cycle, indicating that targeting miR-421 and FOXO1 may represent future therapeutic strategies for the treatment of patients with lung cancer.

Computational elucidation of the binding mechanisms of curcumin analogues as bacterial RecA inhibitors.

Antimicrobial resistance (AMR) presents as a serious threat to global public health, which urgently demands action to develop alternative antimicrobial strategies with minimized selective pressure. The bacterial SOS response regulator RecA has emerged as a promising target in the exploration of new classes of antibiotic adjuvants, as RecA has been implicated in bacterial mutagenesis and thus AMR development through its critical roles in error-prone DNA repair. The natural product curcumin has been reported to be an effective RecA inhibitor in several Gram-negative bacteria, but details on the underlying mechanisms are wanting. In order to bridge the gap in how curcumin operates as a RecA inhibitor, we used computational approaches to model interactions between RecA protein and curcumin analogues. We first identified potential binding sites on E. coli RecA protein and classified them into four major binding pockets based on biological literature and computational findings from multiple in silico calculations. In docking analysis, curcumin-thalidomide hybrids were predicted to be superior binders of RecA compared with bis-(arylmethylidene)acetone curcumin analogues, which was further confirmed by MMGBSA calculations. Overall, this work provides mechanistic insights into bacterial RecA protein as a target for curcumin-like compounds and offers a theoretical basis for rational design and development of future antibiotic adjuvants.

Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus.

DNA topoisomerase I (Topo I) is an important anticancer drug target, and xanthone dimers are considered to be a new kind of Topo I inhibitor chemotypes. Based on the characteristics of dimeric xanthone structures, five new dimeric xanthones (1-5) and two known SAD isomers (6 and 7) were isolated from the mangrove-derived fungus Aspergillus vericolor. The absolute configurations of compounds 1-7, entailing both central and axial chirality elements, were established by a combination of ECD comparison, chemical conversions, and biogenetic considerations. Compounds 1-7 possessed high structural diversity and exhibited cytotoxicity at different levels. The selected new compounds 1, 2, and 5 showed Topo I inhibition properties and the most potent compound 1, an atropisomer of compound 2, was confirmed to inhibit Topo I-mediated DNA relaxation by targeting Topo I, thereby, arresting the cell cycle process and inducing necrosis in cancer cells. Molecular docking studies showed that compound 1 could bind DNA by π-π interaction and DNA Topo I by hydrogen bonds to form a ternary complex.

GPER/ERK&AKT/NF-κB pathway is involved in cadmium-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells.

The higher incidence of thyroid cancer in women during reproductive years compared with men and the increased risk associated with the therapeutic use of estrogen have strongly suggested that estrogen may be involved in the occurrence and development of thyroid cancer. Cadmium (Cd) is a potent metalloestrogen that disrupts the endocrine system by mimicking the effects of 17ß-estradiol (E2). In the present study, we demonstrate that similar to E2 and G1, a specific agonist for G protein-coupled estrogen receptor (GPER), Cd induces the proliferation, invasion and migration of human WRO and FRO thyroid cancer cells that have endogenous GPER. Moreover, like E2 and G1, Cd leads to a rapid activation of ERK/AKT, and then nuclear translocation of NF-κB, increased expression of cyclin A and D1, and secretion of IL-8, all of which are significantly attenuated by GPER blockage or knock-down in both WRO and FRO cells. Furthermore, the Cd-induced proliferation, invasion and migration are suppressed either by specific inhibitors for GPER, ERK, AKT and NF-κB, or by knock-down of GPER. These results suggest that GPER/ERK&AKT/NF-κB signaling pathway is involved in the Cd-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells.

MicroRNA-610 suppresses the proliferation of human glioblastoma cells by repressing CCND2 and AKT3.

Previous studies have shown that microRNA (miR)-610 is crucial in a variety of biological processes in various types of human cancer cells. However, the role of this microRNA in glioblastoma (GBM) is presently unclear. In this study, the role of miR­610 in cell proliferation was investigated in GBM. It was demonstrated that miR­610 expression is markedly downregulated in GBM cells and GBM tissues compared with normal human astrocytes (NHAs) and normal brain tissue, respectively. Ectopic expression of miR­610 reduced the proliferation and anchorage­independent growth of GBM cells, whereas inhibition of miR­610 promoted this effect. Bioinformatics analysis further revealed cyclin D2 (CCND2) and AKT3, putative tumor promoters, as potential targets of miR­610. Data from reporter assays showed that miR­610 directly binds to the 3'­untranslated region of CCND2 and AKT3 mRNA, and represses their expression at the transcriptional and translational levels. In conclusion, the data provide compelling evidence that miR­610 functions as an anti­onco­miRNA, which is important in inhibiting cell proliferation in GBM, and its anti­oncogenic effects are mediated chiefly through direct suppression of CCND2 and AKT3 expression.

Up-regulation of Hsp27 by ERα/Sp1 facilitates proliferation and confers resistance to apoptosis in human papillary thyroid cancer cells.

17ß-estradiol (E2) has been suggested to play a role in the development and progression of papillary thyroid cancer. Heat shock protein 27 (Hsp27) is a member of the Hsp family that is responsible for cell survival under stressful conditions. Previous studies have shown that the 5'-promoter region of Hsp27 gene contains a specificity protein-1 (Spl) and estrogen response element half-site (ERE-half), which contributes to Hsp27 induction by E2 in breast cancer cells. However, it is unclear whether Hsp27 can be up-regulated by E2 and which estrogen receptor (ER) isoform and tethered transcription factor are involved in this regulation in papillary thyroid cancer cells. In the present study, we demonstrated that Hsp27 can be effectively up-regulated by E2 at mRNA and protein levels in human K1 and BCPAP papillary thyroid cancer cells which have more than two times higher level of ERα than that of ERß. The up-regulation of Hsp27 by E2 is mediated by ERα/Sp1 and ERß has repressive effect on this ERα/Sp1-mediated up-regulation of Hsp27. Moreover, we showed that the up-regulation of Hsp27 by ERα/Sp1 facilitates proliferation and confers resistance to apoptosis through interaction with procaspase-3. Targeting this pathway may be a potential strategy for therapy of papillary thyroid cancer.