The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

The androgen receptor （AR） plays an important role in the development and progression of prostate cancer （PCa）. Androgen deprivation therapy is initially effective in blocking tumor growth, but it eventually leads to the hormonerefractory state. The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear. Several PCa cell lines were established to study the role of AR in PCa, but the results were often inconsistent or contrasting in different cell lines, or in the same cell line grown under different conditions. The cellular and molecular alteration of epithelial cells and their microenvironments are complicated, and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR. In this paper, we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa. We also discuss the advantages of widely used epithelium-stroma co-culture systems, xenograft mouse models, and genetically engineered PCa mouse models. The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.

Comparative Molecular Field Analysis(CoMFA) of Curcumin-related Compounds for Anticancer Activity

Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis （CoMFA） in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values （R12= 0.911, R22= 0.985） and cross-validation coefficient values （q2= 0.580, q22= 0.722）. Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.

Preoperative [18]fluorodeoxyglucose-positron emission tomography/computed tomography in early stage breast cancer: Rates of distant metastases

AIM To investigate rates of distant metastases(DM) detected with [18]fluorodeoxyglucose-positron emissiontomography/computed tomography(^(18)FDG-PET/CT) in early stage invasive breast cancer.METHODS We searched the English language literature databases of PubM ed, EMBASE, ISI Web of Knowledge, Web of Science and Google Scholar, for publications on DM detected in patients who had ^(18)FDG-PET/CT scans as part of the staging for early stages of breast cancer(stage Ⅰ?and Ⅱ), prior to or immediately following surgery. Reports published between 2011 and 2017 were considered. The systematic review was conducted according to the PRISMA guidelines.RESULTS Among the 18 total studies included in the analysis, the risk of DM ranged from 0% to 8.3% and 0% to 12.9% for stage Ⅰ?and Ⅱ invasive breast cancer, respectively. Among the patients with clinical stage Ⅱ, the rate of occult metastases diagnosed by ^(18)FDG-PET/CT was 7.2%(range, 0%-19.6%) for stage ⅡA and 15.8%(range, 0%-40.8%) for stage ⅡB. In young patients(< 40-yearold), ^(18)FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology(i.e., triple-negative receptors and poorly differentiated grade).CONCLUSION Young patients with poorly differentiated tumors and stage ⅡB triple-negative breast cancer may benefit from ^(18)FDG-PET/CT at initial staging to detect occult DM prior to surgery.

Experimental therapeutics in prostate cancer： where are Ne now and where do we need to go

The explosion of new therapeutics in metastatic castrate-resistant prostatecancer （mCRPC） is unprecedented, but much more work needs to be done before we are satisfied. Six phase III trials with an overall survival impact have now been reported （Table 1）.1-6 Four of these trials were exclusively or predominantly in the mCRPC post-docetaxel space （MDV3100, abiraterone, 223radium and cabazitaxel）. The 223radium trial also uniquely offered therapy to patients who were unsuitable for or refused docetaxel. The sipuleucel-T trial focused on mCRPC patients who were asymptomatic or minimally symptomatic; most of these patients were chemotherapy naive.

Cancer-associated fibroblasts express CD1d and activate invariant natural killer T cells under cellular stress

Invariant natural killer T(iNKT)cells are part of the family of unconventional T cells,and they recognize glycolipid antigens presented on the MHC class I like molecule CD1^([1]).In humans there are five CD1 molecules named CD1a to CD1e,whereas mice use only CD1d for lipid presentation.Functionally,iNKT cells can elicit both cytotoxicity similarly to conventional CD8 T cells and secrete cytokines that influence the adaptive immune response including providing direct T cell help to B cells^([2]).In the context of tumors,they can use both release of granzyme B and use Fas-mediated mechanisms for killing of tumor cells.As iNKT cells use a restricted TCR repertoire and CD1 molecules are non-heterogenous the risk of graft vs host disease is limited and thus these T cells have been an attractive option for off the shelf immunotherapy to treat cancer^([3]).

Activins and activin antagonists in hepatocellular carcinoma

In many parts of the world hepatocellular carcinoma (HCC)is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood.There is increasing evidence that activins,which are members of the transforming growth factorβ(TGFβ)superfamily of growth and differentiation factors,could play important roles in liver carcinogenesis.Activins are disulphide-linked homo- or heterodimers formed from four differentβsubunits termedβA,βB,βC,andβE,respectively.Activin A, the dimer of twoβA subunits,is critically involved in the regulation of cell growth,apoptosis,and tissue architecture in the liver,while the hepatic function of other activins is largely unexplored so far.Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG,and at the cell membrane antagonistic coreceptors like Cripto or BAMBI.Additionally,in the intracellular space inhibitory Smads can modulate and control activin activity.Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation,fibrosis and development of cancer.The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

Use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease

This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer＇s disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer＇s disease.The effect of curcumin on Alzheimer＇s disease involves multiple signaling pathways：anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer＇s disease.

dentification of testosterone-/androgen receptor-regulated genes in mouse Sertoli cells

Androgen and androgen receptor （AR） play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear. To identify AR target genes in Sertoli cells, we analyzed the gene expression profiles of testis between mice lacking AR in Sertoli cells （S-AR-/y） and their littermate wild-type （WT） mice. Digital gene expression analysis identified 2276 genes downregulated and 2865 genes upregulated in the S-AR-/y mice testis compared to WT ones. To further nail down the difference within Sertoli cells, we first constructed Sertoli cell line TM4 with stably transfected AR （named as TM4/AR） and found androgens failed to transactivate AR in Sertoli TM4 and TM4/AR cells. Interestingly, additional transient transfection of AR-cDNA resulted in significant androgen responsiveness with TM4/AR cells showing 10 times more androgen sensitivity than TM4 cells. In the condition where maximal androgen response was demonstrated, we then analyzed gene expression and found the expression levels of 2313 genes were changed more than twofold by transient transfection of AR-cDNA in the presence of testosterone. Among these genes, 603 androgen-/ AR-regulated genes, including 164 upregulated and 439 downregulated, were found in both S-AR-/y mice testis and TM4/AR cells. Using informatics analysis, the gene ontology was applied to analyze these androgen-/AR-regulated genes to predict the potential roles of androgen/AR in the process of spermatogenesis. Together, using gene analysis in both S-AR-/y mice testis and TM4/AR cells may help us to better understand the androeen/AR signals in Sertoli cells and their influences in spermatogenesis.

Prospects for inhibiting the post-transcriptional regulation of gene expression in hepatitis B virus

There is a continuing need for novel antivirals to treat hepatitis B virus(HBV) infection, as it remains a ma-jor health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral life-cycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing anti-viral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regula-tory element identified 20 years ago promotes nucleo-cytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5' end of the poly-cistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regu-late gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.

The Management of Maxillary Squamous Cell Carcinoma―A Retrospective Study

Introduction: Squamous cell carcinoma (SCC) is the predominant neoplastic tumor that occurs in the oral cavity. SCC arising from the maxillary gingiva, hard palate and maxillary alveolus is relatively rare. Since soft tissue barrier is thin, the diagnosis of cancer in these regions is usually ulcerative and invasive to the underlying bone already in the early stages of the disease. The aim of the present study was to retrospectively evaluate our data regarding the management of loco-regional lymph nodes and the efficacy of neck dissection in the clinically negative neck when maxillary squamous cell carcinoma is diagnosed. Furthermore, we wish to establish the role of prophylactic neck dissection and T stage from which it should be implemented. Methods: Archival records of oncological patients that were treated for SCC of the maxillary alveolus, hard palate and gingiva were collected. Overall 20 patients met the inclusion criteria, 11 men and 9 women. Average age of first diagnosis was 68 years. Results: At initial examination, 2 patients (10%) had clinically positive lymph nodes and undergone therapeutic neck dissection. The remaining 18 patients had clinically N0 necks. Five patients (28%) had occult positive lymph nodes following prophylactic neck dissection. One of the patients had a primary resection with no neck treatment. This patient eventually developed metastases in the neck two month post-surgery (occult disease). The overall positive lymph nodes in maxillary squamous cell carcinoma were 40% (8/20) with an occult metastasis rate of 33% (6/18). Disease specific mortality was 45% (9/20). Conclusion: In the present study, the majority of patients that were diagnosed with occult metastatic disease were either large tumors (T4, 60%) or with moderate to poor differentiation (mood-poor 80%). We conclude that patients who are present with a high grade (moderate-poor) large or invasive maxillary SCC (T2-T4), a prophylactic selective neck dissection (levels I-III) should be performed.

Dynamic epi-transcriptomic landscape mapping with disease progression in estrogen receptor-positive breast cancer

Dear Editor,The molecular determinants that drive breast cancer progression to metastasis are complex and partly controlled by nucleic acid epi-modifications[1].Although DNA-methyl modifications in breast cancer metastasis have been well described,there is limited understanding of the role of RNA methylation in advanced disease[2].This study aimed to provide an understanding on the role of the epitranscriptome in estrogen receptor-positive(ER+)breast cancer progression to metastasis.

Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively researched.The continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early stage.In this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural peroxidase.The peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol substrate.By integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting EBV-IgAs.Importantly,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC screening.The sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ELISA.Additionally,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection process.In conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of SANzyme.Our innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

Frequent Mutation of rs13281615 and Its Association with PVT1 Expression and Cell Proliferation in Breast Cancer

The q24 band of chromosome 8 （8q24） is frequently amplified in human cancers including breast cancer, and several SNPs （single nucleotide polymorphisms） at 8q24, including rs13281615, have been identified for their association with cancer risks. These SNPs are in a ＂gene desert＂ region, and their functions in cancer development remain to be illustrated, although several of the SNPs appear to influence the genes in the ＂desert＂ in a long-range manner, including the v-myc avian myelocytomatosis viral oncogene homolog （MYC） and the non- protein coding plasmacytoma variant translocation 1 （PVT1）, both of which have been implicated in human cancers. In the current study, we examined rs13281615 for its potential role in breast cancer using normal and cancer tissues from 121 Chinese women with breast cancer. In addition to confirming the association of the GG genotype of rs 13281615 with breast cancer risk, we found that germline GG genotype was significantly associated with estrogen receptor （ER） positivity, higher tumor grade and higher proliferation index. We also found frequent somatic mutations （22/121 or 18.2%） of this SNP in breast cancer. Interestingly, the majority of the mutations （17/22 or 77%） involved a G→ A change, resulting in a decrease in the number of cancers with the GG risk genotype and subsequent loss of GG association with higher tumor grade and proliferation index in cancers. Furthermore, PVT1 expression was increased in cancers, and the increase was associated with the GG genotype of rs13281615. These results suggest that the GG genotype of SNP rs13281615 plays a role in breast cancer likely by influencing PVT1 expression, and that during oncogenesis, ＂protective＂ mutations could occur.

PPARγ2 functions as a tumor suppressor in a translational mouse model of human prostate cancer

Peroxisome proliferator-activated receptorsγ(PPARγ)is a master regulator that controls energy metabolism and cell fate.PPARγ2,a PPARγisoform,is highly expressed in the normal prostate but expressed at lower levels in prostate cancer tissues.In the present study,PC3 and LNCaP cells were used to examine the benefits of restoring PPARγ2 activity.PPARγ2 was overexpressed in PC3 and LNCaP cells,and cell proliferation and migration were detected.Hematoxylin and eosin(H&E)staining was used to detect pathological changes.The genes regulated by PPARγ2 overexpression were detected by microarray analysis.The restoration of PPARγ2 in PC3 and LNCaP cells inhibited cell proliferation and migration.PC3-PPARγ2 tissue recombinants showed necrosis in cancerous regions and leukocyte infiltration in the surrounding stroma by H&E staining.We found higher mixed lineage kinase domain-like(MLKL)and lower microtubule-associated protein 1 light chain 3(LC3)expression in cancer tissues compared to controls by immunohistochemistry(IHC)staining.Microarray analysis showed that PPARγ2 gain of function in PC3 cells resulted in the reprogramming of lipid-and energy metabolism-associated signaling pathways.These data indicate that PPARγ2 exerts a crucial tumor-suppressive effect by triggering necrosis and an inflammatory reaction in human prostate cancer.

The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

Signaling pathways downstream to receptor tyrosine kinases:targets for cancer treatment

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.

Insights from the degradation mechanism of cyclin D into targeted therapy of the cancer cell cycle

The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradation of cyclin D1-3 and provide important insights for the targeted therapy of the cancer cell cycle.

Corrigendum to‘New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs.non-stem/progenitor cells’

In this article,there were errors in the images presented in Figure 3Ab(bottom left)and Figure 5D(2nd and 4th columns).These were caused by miss-insertion of the images during preparation of the manuscript for submission.Since raw data of the images in Figure 5D were lost,the authors re-performed the whole experiment and provided new similar results(both images and quantitation graphs)for an update.The corrected Figure 3Ab left panel and updated Figure 5D are shown as below.The details have been corrected only in this corrigendum to preserve the published version of record.The authors assure that the original results or conclusions are not altered and they apologize for the mistake.

Microscopic tumor foci in axillary lymph nodes may reveal the recurrence dynamics of breast cancer

Dear Editor,In early breast cancer,the prognostic value of the num-ber of macroscopically metastasized axillary nodes has been recognized in earlier reports[1].However,the impact of microscopic tumour cell deposits on the sur-vival outcome of early breast cancer patients is still debated[2].This issue has gained increasing attention since the implementation of sentinel node biopsy in axil-lary node staging for tailoring breast cancer treatments,and the status of the single resected node would deter-mine the clinical decision of whether or not to perform the axillary lymph node dissection[3].Moreover,this issue raises more questions on whether to administer primary or adjuvant systemic treatment for patients with lymph nodes bearing isolated tumour cells(pN0[i+])or micrometastases(pN1mi).Despite the wide debate on the clinical treatment dilemma encountered by early breast cancer patients with microscopic tumour cell deposits,the biology underlying different pathologi-cal presentations at microscopic level(pN0,pN0[i+],pN1mi)and the disease outcomes remain poorly known.In an attempt to shed some light on this topic,we have analyzed,in the context of dormancy-based metastasis development model[4],early breast cancer patients con-ventionally classified as pN0(tumour foci with largest diameter≤2 mm)[5]by systematically reassessing their tumor recurrence dynamics following primary tumour resection at a single institution.