Cell Neoplastic Transformation Research Articles

Immunophenotypic aberrant hematopoietic stem cells in myelodysplastic syndromes: a biomarker for leukemic progression

Myelodysplastic syndromes (MDS) comprise hematological disorders that originate from the neoplastic transformation of hematopoietic stem cells (HSCs). However, discrimination between HSCs and their neoplastic counterparts in MDS-derived bone marrows (MDS-BMs) remains challenging. We hypothesized that in MDS patients immature CD34+CD38− cells with aberrant expression of immunophenotypic markers reflect neoplastic stem cells and that their frequency predicts leukemic progression. We analyzed samples from 68 MDS patients and 53 controls and discriminated HSCs from immunophenotypic aberrant HSCs (IA-HSCs) expressing membrane aberrancies (CD7, CD11b, CD22, CD33, CD44, CD45RA, CD56, CD123, CD366 or CD371). One-third of the MDS-BMs (23/68) contained IA-HSCs. The presence of IA-HSCs correlated with perturbed hematopoiesis (disproportionally expanded CD34+ subsets beside cytopenias) and an increased hazard of leukemic progression (HR = 25, 95% CI: 2.9–218) that was independent of conventional risk factors. At 2 years follow-up, the sensitivity and specificity of presence of IA-HSCs for predicting leukemic progression was 83% (95% CI: 36–99%) and 71% (95% CI: 58–81%), respectively. In a selected cohort (n = 10), most MDS-BMs with IA-HSCs showed genomic complexity and high human blast counts following xenotransplantation into immunodeficient mice, contrasting MDS-BMs without IA-HSCs. This study demonstrates that the presence of IA-HSCs within MDS-BMs predicts leukemic progression, indicating the clinical potential of IA-HSCs as a prognostic biomarker.

Transformation of Odontogenic Cysts to Neoplasms - A Systematic Review.

Odontogenic cysts have the potential to transform into neoplasms. However, the characteristics of those which transformed to neoplastic tissues have not been well described and the exact causes of that phenomenon are not yet clear. This study aims to describe characteristics of odontogenic cysts that transformed into neoplasms and to look for their potential etiologies. English-written studies indexed in PubMed, Science Direct, and Proquest were assessed using keywords verified by Medical Subject Headings: 'Odontogenic Cyst' and 'Neoplastic Cell Transformation'. Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines were used as guidance. Following steps in PRISMA guidelines, 19 articles were fully reviewed (three case series and 16 case reports) with 27 subjects of 16 males (59%) and 11 females (41%) from 15 to 86 years old. Cystic origins were eight dentigerous cysts, four odontogenic keratocysts, two residual cysts, one radicular cyst, one calcifying odontogenic cyst, one follicular cyst, one glandular odontogenic cyst, and nine unspecified odontogenic cysts that transformed to ameloblastoma (3 cases) and carcinoma (24 cases). Neoplastic transformations of odontogenic cysts arose from epithelial remnants of inadequate odontogenic cyst removal and chronic inflammation due to infection. However, the exact causes of their transformations remain unclear. Therefore, careful removal of odontogenic cysts and regular postoperative follow-ups are key to prevent recurrence and neoplastic transformation. Future studies are needed to investigate potential causes of neoplastic transformation of odontogenic cysts.

A double-edged sword in tumor angiogenesis and progression. Dual roles of mast cells, macrophages, and neutrophils.

Inflammatory cells act in concert with tumor cells, stromal cells, and endothelial cells to create an environment that is critical for the survival, development, and diffusion of the tumor. Under a variety of conditions, inflammatory cells are capable of polarization under their tumoricidal (growth arresting) or tumorigenic (growth promoting) forms. In this context, two major subsets of mast cells, macrophages, and neutrophils, have been described. This article is focused on the description of these different sub-populations and to the analysis of arrays of common and specific mediators involved in their action in the context of tumor growth. Different databases, including PubMed/MEDLINE, Scopus, and Google Scholar, were searched to review and analyze relevant literature concerning the different sub-populations of mast cells, macrophages, and neutrophils, and arrays of common and specific mediators involved in their action in the context of tumor growth.The analysis of the literature data confirm that the microenvironment can inhibit tumor growth and suppress or revert the malignant phenotype. Incorrect signals from the microenvironment can lead to initiation and promotion of neoplastic transformation of normal cells, and once tumor is formed, it modifies the stroma and initiates an inflammatory reaction and an immune response.

Structure and chemopreventive activity of fucoidans from the brown alga Alaria angusta

Six fucoidan fractions were isolated from the brown alga Alaria angusta. Structures of enzymatic hydrolysis products of the fraction 1AaF2 (Fuc:Gal ~ 1:1; 33 % of sulfates) by fucanase from Wenyingzhuangia fucanilytica were studied by chemical and instrumental (NMR spectroscopy and mass-spectrometry) methods. It was shown that 1AaF2 consisted of two structurally different fucoidans: a sulfated 1,3;1,4-α-L-fucan and an enzyme-resistant sulfated and acetylated complex fucogalactan (Fuc:Gal ~ 1:2; 19 % of sulfates) 1AaF2_HMP containing extended 1,3-linked fucose and 1,3/1,4-linked galactose fragments (up to 5 residues). The fractions 1AaF2 and 1AaF2_HMP were a non-cytotoxic, possessed dose-dependent chemopreventive effect on EGF-induced neoplastic cell transformation of mouse normal epidermal JB6 Cl41 cells and inhibited the colony formation of human melanoma SK-MEL-28 cells.

Understanding Mechanisms of RKIP Regulation to Improve the Development of New Diagnostic Tools.

Simple SummaryRaf Kinase Inhibitor protein is a protein that governs multiple intracellular signalling involved primarily in the progression of tumours and the development of metastases. In this review, we discussed the main mechanisms that regulate the expression and activity of RKIP with the aim of identifying the link between the transcriptional, post-transcriptional and post-translational events in different tumour settings. We also tried to analyse the studies that have measured the levels of RKIP in biological fluids in order to highlight the possible advantages and potential of RKIP assessment to obtain an accurate diagnosis and prognosis of various tumours.One of the most dangerous aspects of cancer cell biology is their ability to grow, spread and form metastases in the main vital organs. The identification of dysregulated markers that drive intracellular signalling involved in the malignant transformation of neoplastic cells and the understanding of the mechanisms that regulate these processes is undoubtedly a key objective for the development of new and more targeted therapies. RAF-kinase inhibitor protein (RKIP) is an endogenous tumour suppressor protein that affects tumour cell survival, proliferation, and metastasis. RKIP might serve as an early tumour biomarker since it exhibits significantly different expression levels in various cancer histologies and it is often lost during metastatic progression. In this review, we discuss the specific impact of transcriptional, post-transcriptional and post-translational regulation of expression and activation/inhibition of RKIP and focus on those tumours for which experimental data on all these factors are available. In this way, we could select how these processes cooperate with RKIP expression in (1) Lung cancer; (2) Colon cancer, (3) Breast cancer; (4) myeloid neoplasm and Multiple Myeloma, (5) Melanoma and (6) clear cell Renal Cell Carcinoma. Furthermore, since RKIP seems to be a key marker of the development of several tumours and it may be assessed easily in various biological fluids, here we discuss the potential role of RKIP dosing in more accessible biological matrices other than tissues. Moreover, this objective may intercept the still unmet need to identify new and more accurate markers for the early diagnosis and prognosis of many tumours.

Effect of Gene 33/Mig6/ERRFI1 on hexavalent chromium-induced transformation of human bronchial epithelial cells depends on the length of exposure

Hexavalent chromium (Cr(VI)) compounds are environmental and occupational lung carcinogens. The present study followed the chronic effect of Cr(VI) on the neoplastic transformation of BEAS-2B lung bronchial epithelial cells with or without deletion of Gene 33 (Mig6, EFFRI1), a multifunctional adaptor protein. We find that Gene 33-deleted cells exhibit increased anchorage-independent growth compared to control cells after transformed by 8-week but not 24-week Cr(VI) exposure. Gene 33-deleted cells show a higher level of cell proliferation and are more resistant to acute Cr(VI) toxicity compared to control cells after transformed by 8-week but not 24-week Cr(VI) exposure, despite that 24-week-transformed cells have increased resistance to acute Cr(VI) toxicity. However, Gene 33-deleted cells show increased migration after transformed by both 8-week and 24-week Cr(VI) exposures. Furthermore, only cells transformed by 24 weeks of Cr(VI) exposure can form subcutaneous tumors in nude mice. Although no significant difference in the size of tumors formed by the two cell types, there is a marked difference in the histological manifestation and more MMP3 expression in tumors from Gene 33-deleted cells. Our results demonstrate progressive neoplastic transformation of BEAS-2B cells and the adaptation of these cells to Gene 33 deletion during chronic exposure to Cr(VI).

Canine Idiopathic Arteriopathy, Appendicular Bone Infarcts, and Neoplastic Transformation of Bone Infarcts in 108 Dogs (Canis lupus familiaris).

Osteosarcoma (OSA) is the most common primary bone tumor in both dogs and humans. The dog is an important research model for OSA, yet dogs have much higher prevalence of bone tumors than do humans, a disparity that has yet to be explained. Neoplastic transformation of cells within or adjacent to bone infarcts into primary bone tumors has been described in humans but only sparsely characterized in the veterinary literature. In this study, 653 cases of canine bone infarcts were received through a referral veterinary osteopathology service over a 14-y period. We identified an idiopathic disorder affecting the nutrient artery, termed canine idiopathic arteriopathy (CIA), which to our knowledge has no direct counterpart in human medicine. This disorder was documented alongside ischemic necrosis of the medullary cavity in 114 bone infarcts in 108 dogs. We hypothesize that CIA precipitated an ischemic environment, resulting in development of a bone infarct down- stream of the abnormal artery. In 52% (59 of 114) of cases, bone infarcts demonstrated evidence of repair (termed reparative bone infarcts [RBI]), while in 48% (55 of 114) of infarcts, a bone tumor was also present, including pleomorphic sarcoma, OSA, fibrosarcoma, and chondrosarcoma. In some cases, a spectrum of tumors was present. We hypothesize that the ischemic infarct environment provoked bone marrow mesenchymal stem cells (MSCs) to attempt repair of the stroma, and in approximately half of cases, MSCs underwent neoplastic transformation (BINT) to produce tumors. The most common sites of bone infarcts were the distal femur, distal radius, proximal humerus, and distal tibia, coinciding with common sites of canine OSA. The authors propose that CIA leading to bone infarcts and infarct-derived tumors, in combination with possible underdiagnosis of canine bone infarcts and misdiagnosis of some RBI as neoplasia, may contribute to the higher reported proportion of bone tumors in dogs compared with humans.

Abstract IA22: Molecular classes and landscape of drivers of intrahepatic and extrahepatic cholangiocarcinoma

Abstract Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the neoplastic transformation of the epithelial cells of the bile ducts, both intrahepatic (iCCA) and extrahepatic (eCCA), and among the fastest growing cancers in the United states. Therapeutic options for CCA patients at advanced stages are limited and palliative chemotherapy remains the main treatment option. Over the past decade, the application of next-generation sequencing has significantly impacted the management of CCA where clinically-relevant subgroups have been identified based on the recurrence of specific structural aberrations (i.e. FGFR2 fusions, IDH1 mutations) with important differences according to the anatomical site. These efforts have increased the molecular understanding of this disease and ultimately suggested that iCCA and eCCA may represent distinct entities. Thereby, increasing efforts have tried to generate molecular classifications specific for each subtype, although initial studies analyzed CCA samples regardless of their anatomic site of origin. We will review current knowledge of the molecular landscape and immunogenomic classifications proposed to date for iCCA and eCCA. Citation Format: Daniela Sia. Molecular classes and landscape of drivers of intrahepatic and extrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA22.

Organochlorine pesticides induce epithelial as well as inflammatory mediators following exposure to human ovarian surface epithelial cells: An in vitro study.

Although studies have suggested organochlorine pesticides (OCPs) exposure increased the risk of epithelial ovarian cancer, the mechanisms underlying its potential tumorigenic effects in the human ovary are not well understood. In this study, we investigated the impact of dichlorodiphenyldichloroethylene (DDE), endosulfan, and heptachlor exposure on epithelial cadherin (E-cadherin) and proinflammatory mediators in human ovary surface epithelial (HOSE) cells. We found that DDE, endosulfan, and heptachlor exposure resulted in epithelial differentiation accompanied by upregulation of E-cadherin expression and overexpression of proinflammatory cytokines (TNFα,IL-1β, and IL-6) in HOSE cells. The epithelial differentiation may accelerate HOSE cells to inclusion body formation, a common site for ovarian cancer initiation and persistent exposure to OCPs creates a chronic inflammatory microenvironment that may promote the neoplastic transformation of HOSE cells within the inclusion cyst.

Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis.

Simple SummaryMembers of the interleukin (IL)-1 cytokine family exhibit dual functions in the regulation of inflammation and cancer. Recent studies have shown the critical role of IL-36γ, the newly identified IL-1 family member, in the regulation of cellular processes implicated in the progression of cancer. Therefore, the underlying mechanism of IL-36γ in tumor development is of considerable interest. Here, we identified the pivotal role of IL-36γ in the proliferation of breast cancer cells. Consistently, IL-36γ was found to promote epithelial cell transformation via the activation of c-Fos, c-Jun, and AP-1 transcription factors, followed by the IL36R-mediated MEK/ERK and JNK/c-Jun cascades. Furthermore, our findings demonstrate the critical role of PIN1 in the regulation of IL-36γ-induced mammary gland tumorigenesis. Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36γ increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36γ induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36γ-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36γ-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36γ-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout.

Chronic coexposure to arsenic and estrogen potentiates genotoxic estrogen metabolic pathway and hypermethylation of DNA glycosylase MBD4 in human prostate epithelial cells

AbstractBackgroundPreviously we reported that arsenic and estrogen cause synergistic effects in the neoplastic transformation of human prostate epithelial cells. In addition to receptor‐mediated pathways, DNA‐reactive estrogen metabolites have also been shown to play a critical role in mutagenicity and carcinogenicity. Both estrogen and arsenic are known prostate carcinogens, however, the effect of coexposure to these two chemicals on genes involved in estrogen metabolism is not known. Therefore, the objective of this study was to evaluate the role of arsenic and estrogen coexposure on the expression of estrogen receptors and estrogen metabolism‐associated genes. Earlier, we also reported the synergistic effect of arsenic and estrogen on decreased expression of MBD4 genes that play an important role in DNA repair through its DNA glycosylase activity. To further understand the mechanism, the promoter methylation of this gene was also analyzed.MethodsTotal RNA and protein were isolated from RWPE‐1 human prostate epithelial cells that were coexposed to arsenic and estrogen for a chronic duration (6 months). The expression of estrogen receptors, estrogen metabolism associated phase I genes (CYP 1A1, 1A2, 3A4, and 1B1) and phase II gene catechol‐O‐methyltransferase (COMT), as well as antioxidant MnSOD, were analyzed either at the RNA level by quantitative reverse transcriptase‐polymerase chain reaction or at the protein level by western blot. Promoter methylation of MBD4 was analyzed by pyrosequencing.ResultsExpression of MnSOD and phase I genes that convert E2 into genotoxic metabolites 2‐OH‐E2 and 4‐OH‐E2 were significantly increased, whereas the expression of phase II gene COMT that detoxifies estrogen metabolites was significantly decreased in arsenic and estrogen coexposed cells. MBD4 promoter was hypermethylated in arsenic and estrogen coexposed cells. Coexposure to arsenic and estrogen has synergistic effects on the expression of these genes as well as in MBD4 promoter hypermethylation.ConclusionsThese novel findings suggest that coexposure to arsenic and estrogen acts synergistically in the activation of not only the estrogen receptors but also the genes associated with genotoxic estrogen metabolism and epigenetic inactivation of DNA glycosylase MBD4. Together, these genetic and epigenetic aberrations provide the molecular basis for the potentiation of carcinogenicity of arsenic and estrogen coexposure in prostate epithelial cells.

Abstract 3750: Design and experimental validation of WG00446_MET_A methylation next generation sequencing panel using ion AmpliSeq technology

Abstract Background: DNA methylation is the most recognized epigenetic mark that leads to a massive distortion in cancer cells. It has been observed that a large number of DNA hypermethylation events co-occur in groups of genes, thus providing a growth advantage to the cell in promoting cell differentiation and neoplastic transformation. Here we designed and performed a first step of validation of a novel next-generation sequencing (NGS) targeted methylation panel that can simultaneously evaluate the methylation levels of multiple cancer-related genes. Methods: The WG00446_MET_A AmpliSeq™ Methylation Panel for Cancer Research was designed using the Ion AmpliSeq technology to amplify 152 regions with an amplicon size range of 125-175bp, that covers a total of 1107 promoter and intragenic CpGs of 18 cancer-related genes. The performance of the panel was assessed by running in duplicate commercially available fully methylated and unmethylated control human gDNA samples and a variable mixture of them to simulate 10%, 25%, 75%, and 90% of global methylation. The libraries (manual preparation using the Ion AmpliSeq Plus Library Kit) were loaded on 530 chips and run on the GeneStudio S5 Sequencer (Thermo Fisher Scientific). The sequencing output was analyzed using the methylation_analysis plugin, available on Ion Torrent Suite v5.16 (Thermo Fisher Scientific). Results: The WG00446_MET_A panel allowed to run 6 samples per 530 chips to reach an observed mean target depth >2,000X (observed reads on-targets: >80%; average number of mapped reads: >450,000/sample). The conversion efficiency, determined by spiking-in Unmethylated Lambda DNA into each sample before the bisulfite conversion process, was >97% for all samples. The observed % of global methylation for all CpGs were >98% and <2% for fully methylated and unmethylated gDNA samples, respectively. The observed results for the variable mixtures were in agreement with what expected. Conclusions: The methylation-specific NGS analysis using the WG00446_MET_A panel represents a feasible method for a fast and multiplexed screening of cancer patients by a high-throughput approach. It will offer the opportunity to design a more robust algorithm for disease prediction for those cancer patients with a low quantity of biological material available. The orthogonal testing on DNA extracted by FFPE and frozen samples is ongoing with a subset of amplicons from the WG00446_MET_A panel. Citation Format: Federico Pio Fabrizio, Stefano Castellana, Angelo Sparaneo, Tommaso Mazza, Flavia Centra, Domenico Trombetta, Vito Michele Fazio, Lucia Anna Muscarella. Design and experimental validation of WG00446_MET_A methylation next generation sequencing panel using ion AmpliSeq technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3750.

MP06-14 ROLE OF LATROPHILINS AS KEY DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR IN MODULATING UROTHELIAL TUMORIGENESIS

You have accessJournal of UrologyCME1 May 2022MP06-14 ROLE OF LATROPHILINS AS KEY DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR IN MODULATING UROTHELIAL TUMORIGENESIS Takuro Goto, Yuki Teramoto, Masato Yasui, Guiyang Jiang, Yujiro Nagata, George Netto, and Hiroshi Miyamoto Takuro GotoTakuro Goto More articles by this author , Yuki TeramotoYuki Teramoto More articles by this author , Masato YasuiMasato Yasui More articles by this author , Guiyang JiangGuiyang Jiang More articles by this author , Yujiro NagataYujiro Nagata More articles by this author , George NettoGeorge Netto More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002523.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We and others have indicated that androgen receptor (AR) signaling plays a critical role in urothelial cancer outgrowth. Meanwhile, our DNA microarray data suggest that latrophilin-3 (LPHN3), one of latrophilins (LPHNs) that are a group of the G-protein-coupled receptor where a spider venom latrotoxin (LTX) is known to bind, represents a downstream target of AR in bladder cancer cells. The present study aimed to determine the functional role of LPHNs, including LPHN1, LPHN2, and LPHN3, in the development of urothelial cancer. METHODS: We compared the levels of LPHN expression in 83 bladder tumors vs. paired normal bladder tissues (by immunohistochemistry) as well as in human normal urothelial SVHUC sublines stably expressing wild-type AR vs. vector only (by western blot). We then assessed the effects of ligand (e.g. LTX, FLRT3) treatment, as well as silencing of each LPHN via shRNA virus infection, on the neoplastic transformation of SVHUC-derived cells induced by a chemical carcinogen 3-methylcholanthrene (MCA). Bladder tumor development was also compared in C57BL/6 mice treated with a carcinogen BBN and LTX/FLRT3. RESULTS: The rates of immunoreactivity for LPHN1 (87% vs. 69%, P=0.012), LPHN2 (55% vs. 31%, P=0.002), and LPHN3 (51% vs. 37%, P=0.087) were significantly higher in bladder tumors than in non-neoplastic urothelial tissues. Moreover, LPHN3 positivity in non-muscle-invasive tumors was associated with the risk of disease recurrence after transurethral surgery (P=0.051). The expression levels of each LPHN were also higher in SVHUC-AR cells than in AR-negative SVHUC-vector cells, and androgen treatment in SVHUC-AR further increased them. Chromatin immunoprecipitation assay then revealed the binding of AR to the promoter region of each LPHN in SVHUC-derived cells. Meanwhile, induction in LPHN expression by LTX or FLRT3 treatment was seen in SVHUC cells. The in vitro transformation assay showed that LTX and FLRT3 induced the MCA-mediated oncogenic activity particularly in SVHUC-vector cells, while knockdown of LPHN1, LPHN2, or LPHN3 resulted in similar inhibition in that of MCA-SVHUC-AR cells. LTX (P=0.002) and FLRT3 (P=0.001) also accelerated the development of bladder tumors in BBN-treated female mice. CONCLUSIONS: These findings suggest that LPHNs, which are activated in bladder tumors as key downstream effectors of the AR, promote urothelial tumorigenesis. Accordingly, LPHN inhibition, along with AR inactivation, has the potential of being an effective chemopreventive approach for urothelial cancer. Source of Funding: Ferring Research Institute © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e82 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takuro Goto More articles by this author Yuki Teramoto More articles by this author Masato Yasui More articles by this author Guiyang Jiang More articles by this author Yujiro Nagata More articles by this author George Netto More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement PDF DownloadLoading ...

Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma

miR-10b is silenced in normal neuroglial cells of the brain but commonly activated in glioma, where it assumes an essential tumor-promoting role. We demonstrate that the entire miR-10b-hosting HOXD locus is activated in glioma via the cis-acting mechanism involving 3D chromatin reorganization and CTCF-cohesin-mediated looping. This mechanism requires two interacting lncRNAs, HOXD-AS2 and LINC01116, one associated with HOXD3/HOXD4/miR-10b promoter and another with the remote enhancer. Knockdown of either lncRNA in glioma cells alters CTCF and cohesin binding, abolishes chromatin looping, inhibits the expression of all genes within HOXD locus, and leads to glioma cell death. Conversely, in cortical astrocytes, enhancer activation is sufficient for HOXD/miR-10b locus reorganization, gene derepression, and neoplastic cell transformation. LINC01116 RNA is essential for this process. Our results demonstrate the interplay of two lncRNAs in the chromatin folding and concordant regulation of miR-10b and multiple HOXD genes normally silenced in astrocytes and triggering the neoplastic glial transformation.

In Vitro Anticancer and Cancer-Preventive Activity of New Triterpene Glycosides from the Far Eastern Starfish Solaster pacificus.

Sea stars or starfish (class Asteroidea) and holothurians or sea cucumbers (class Holothuroidea), belonging to the phylum Echinodermata (echinoderms), are characterized by different sets of glycosidic metabolites: the steroid type in starfish and the triterpene type in holothurians. However, herein we report the isolation of eight new triterpene glycosides, pacificusosides D–K (1–3, 5–9) along with the known cucumarioside D (4), from the alcoholic extract of the Far Eastern starfish Solaster pacificus. The isolated new compounds are closely related to the metabolites of sea cucumbers, and their structures of 1–3 and 5–9 were determined by extensive NMR and ESIMS techniques. Compounds 2, 5, and 8 have a new type of tetrasaccharide chain with a terminal non-methylated monosaccharide unit. Compounds 3, 6, and 9 contain another new type of tetrasaccharide chain, having 6-O-SO3-Glc as one of the sugar units. The cytotoxic activity of 1–9 against non-cancerous mouse epidermal cells JB6 Cl41 and human melanoma cell lines SK-MEL-2, SK-MEL-28, and RPMI-7951 was determined by MTS assay. Compounds 1, 3, 4, 6, and 9 showed potent cytotoxicity against these cell lines, but the cancer selectivity (SI > 9) was observed only against the SK-MEL-2 cell line. Compounds 1, 3, 4, 6, and 9 at the non-toxic concentration of 0.1 μM significantly inhibited neoplastic cell transformation of JB6 Cl41 cells induced by chemical carcinogens (EGF, TPA) or ionizing radiation (X-rays and UVB). Moreover, compounds 1 and 4 at the non-toxic concentration of 0.1 µM possessed the highest inhibiting activity on colony formation among the investigated compounds and decreased the colonies number of SK-MEL-2 cells by 64% and 70%, respectively. Thus, triterpene glycosides 1 and 4 can be considered as prospective cancer-preventive and anticancer-compound leaders.

Insights into the role of STAT3 in intrahepatic cholangiocarcinoma (Review).

Intrahepatic cholangiocarcinoma (ICC) is a primary malignant liver tumour whose incidence is second only to that of hepatocellular carcinoma. ICC is a highly heterogeneous disease arising from neoplastic transformation of intrahepatic biliary epithelial cells (cholangiocytes), and it is characterized by a very poor prognosis. Signal transducer and activator of transcription 3 (STAT3) is an important oncogene that is widely expressed in numerous cancers. STAT3 is a candidate target for the treatment of ICC. However, studies on STAT3 and the occurrence and development of ICC require improvements. Therefore, the present review summarized the mechanism of STAT3 in ICC and provided a theoretical basis for STAT3 to become an effective target for determining the prognosis and treatment of ICC.

Contribution of adrenergic mechanisms for the stress-induced breast cancer carcinogenesis.

Breast cancer is the most common and deadliest type of cancer in women. Stress exposure has been associated with carcinogenesis and the stress released neurotransmitters, noradrenaline and adrenaline, and their cognate receptors, can participate in the carcinogenesis process, either by regulating tumor microenvironment or by promoting systemic changes. This work intends to provide an overview of the research done in this area and try to unravel the role of adrenergic ligands in the context of breast carcinogenesis. In the initiation phase, adrenergic signaling may favor neoplastic transformation of breast epithelial cells whereas, during cancer progression, may favor the metastatic potential of breast cancer cells. Additionally, adrenergic signaling can alter the function and activity of other cells present in the tumor microenvironment towards a protumor phenotype, namely macrophages, fibroblasts, and by altering adipocyte's function. Adrenergic signaling also promotes angiogenesis and lymphangiogenesis and, systemically, may induce the formation of preneoplastic niches, cancer-associated cachexia and alterations in the immune system which contribute for the loss of quality of life of breast cancer patients and their capacity to fight cancer. Most studies points to a major contribution of β2 -adrenoceptor activated pathways on these effects. The current knowledge of the mechanistic pathways activated by β2 -adrenoceptors in physiology and pathophysiology, the availability of selective drugs approved for clinical use and a deeper knowledge of the basic cellular and molecular pathways by which adrenergic stimulation may influence cancer initiation and progression, opens the possibility to use new therapeutic alternatives to improve efficacy of breast cancer treatments.

Dietary Pterostilbene for MTA1-Targeted Interception in High-Risk Premalignant Prostate Cancer.

Prostate cancer remains one of the most prevalent cancers in aging men. Active surveillance subpopulation of patients with prostate cancer includes men with varying cancer risk categories of precancerous disease due to prostatic intraepithelial neoplasia (PIN) heterogeneity. Identifying molecular alterations associated with PIN can provide preventable measures through finding novel pharmacologic targets for cancer interception. Targeted nutritional interception may prove to be the most appropriate chemoprevention for intermediate- and high-risk active surveillance patients. Here, we have generated two prostate-specific transgenic mouse models, one overexpressing MTA1 (R26MTA1 ) and the other overexpressing MTA1 on the background of Pten heterozygosity (R26MTA1 ; Pten+/f ), in which we examined the potential chemopreventive efficacy of dietary pterostilbene. We show that MTA1 promotes neoplastic transformation of prostate epithelial cells by activating cell proliferation and survival, leading to PIN development. Moreover, MTA1 cooperates with PTEN deficiency to accelerate PIN development by increasing cell proliferation and MTA1-associated signaling. Further, we show that mice fed with a pterostilbene-supplemented diet exhibited more favorable histopathology with decreased severity and number of PIN foci accompanied by reduced proliferation, angiogenesis, and inflammation concomitant to reduction in MTA1 and MTA1-associated CyclinD1, Notch2, and oncogenic miR-34a and miR-22 levels. PREVENTION RELEVANCE: Developing novel interceptive strategies for prostate cancer chemoprevention is a paramount goal in clinical oncology. We offer preclinical evidence for the potential of pterostilbene as a promising natural agent for MTA1-targeted interceptive strategy in future cancer prevention trials towards protecting select patients with prostate cancer under active surveillance from developing cancer.

MicroRNA-96: A therapeutic and diagnostic tumor marker.

Cancer has been always considered as one of the main human health challenges worldwide. One of the main causes of cancer-related mortality is late diagnosis in the advanced stages of the disease, which reduces the therapeutic efficiency. Therefore, novel non-invasive diagnostic methods are required for the early detection of tumors and improving the quality of life and survival in cancer patients. MicroRNAs (miRNAs) have pivotal roles in various cellular processes such as cell proliferation, motility, and neoplastic transformation. Since circulating miRNAs have high stability in body fluids, they can be suggested as efficient noninvasive tumor markers. MiR-96 belongs to the miR-183-96-182 cluster that regulates cell migration and tumor progression as an oncogene or tumor suppressor by targeting various genes in solid tumors. In the present review, we have summarized all of the studies that assessed the role of miR-96 during tumor progression. This review clarifies the molecular mechanisms and target genes recruited by miR-96 to regulate tumor progression and metastasis. It was observed that miR-96 mainly affects tumorigenesis by targeting the structural proteins and FOXO transcription factors.

Herbal remedies through cactus nutrients

The main constituent of Opuntiaficus-indica cladodes is water (80-95%), followed by small amounts of carbohydrates (3-7%), fiber (1-2%), and protein (0. 5-1%); other compounds are only partly known and have not been quantitatively determined. The sugar moiety includes mucilaginous components containing polymers, such as chains of (1-4)-linked β-D-galacturonic acid and R (1-2)-linked L-rhamnose residues. Beneficial effects of herbal remedies can be obtained from active constituents present in the whole plant, parts of the plant (e. g., flowers, fruits, roots or leaves), or plant materials or combinations thereof, whether in crude or processed state. Cactus (Opuntiaficus-indica) commonly known as prickly pear belongs to the family Cactaceae. Opuntiaficus-indica produces sweet, nutritionally rich edible fruits; its tender cladodes are used as fresh green vegetable and salad. In South Africa, Mediterranean areas and South American this species is also cultivated for its edible fruit (prickly pear), although in some countries different parts of the plant are utilized in the food and cosmetic industry. Opuntiaficus-indica, fruits and stems, have been traditionally used in folk medicine in several countries for several medicinal purposes. Cactus dietary fiber is composed of several chemical components that are resistant to digestive enzymes such as cellulose, hemicelluloses, pectin, lignin, gums, etc. The benefits associated with fiber content are well known, especially for the prevention of illnesses such as diabetes, treatment of gastrointestinal disorders, illnesses associated with low dietary fiber intake, reduction of glucose values in the blood, anti-hyperlipidemic and anti-hypercholesterolemic effects. Throughout history, the benefits of consuming dietary fiber have been recognized. Soluble fibers, including pectins, gums, and mucilages, increase the viscosity of food in the gut, slowing or reducing sugar absorption. The effect of soluble fiber in reducing serum glucose concentrations is a proposed mechanism of action for the herbal hypoglycemic cactus. It has been reported that Opuntiaficus-indica contain phenolic compounds like ferulic acid, feruloyl-sucrose and sinapoyl-diglucoside, fatty acids like palmitic acid, stearic acid, oleic acid, vaccenic acid and linoleic acid (seeds, peel and juicy pulp). It has been observed that Opuntiaficus-indica oil extract with these components’ present antioxidant and anti-free radical activity, having a potential as anticancer, anti-inflammatory, hypoglycemic, hypolipidemic and hypocholesterolemic activities. Cactus fiber tablet contains 500 mg standardized cactus fiber; as well as common tableting excipients were used. Cactus fiber showed an increased fecal fat excretion compared with placebo. No adverse events were reported throughout the study period. The fruit peel contains large amounts of isorhamnetin. Isorhamnetin (3'-methoxy-3,4',5,7-tetrahydroxyflavone) exerts anticancer action by inhibition of epidermal growth factor (EGF)-induced neoplastic cell transformation through a direct lowering of MAP (mitogen-activated protein)/ERK (extracellular signal regulated kinase) kinase1 and phosphoinositol 3-kinase signaling pathways. Isorhamnetin exhibits cardio protective effects by improving viability of neonatal rat ventricular myocytes under invitro ischemia/reperfusion (I/R) via inhibition of lactate dehydrogenase (LDH) activity and prevention of apoptosis. Isorhamnetin improves skin barrier function through activation of Peroxisome Proliferator-Activated Receptor (PPAR)-αand suppression of inflammatory cytokines production. It also inhibits a dipocyte differentiation of murine 3T3 fibroblasts via a decrease of adiponectine expression and secretion, and down regulation of mRNAs of PPAR-γand C/EBP-α, the major adipogenic nuclear receptors. In contrast, isorhamnetin significantly increases the expression of PPAR-γin tumor tissues obtained from xenograft model of gastric cancer cells and, in combination with chemotherapeutic drugs, causes strong antiproliferative effects and cytotoxicity. The linoleic acid content in cactus cladode (34. 87%) is thus close to the percentage (29% to 40. 41%) found in argan oil. It is however lower than in extracts from barely (51. 26%) and soybean (53. 0%), respectively. Cactus pear (O. boldinghii) cladodes having high fiber content and potential health benefits bakery products have been produced and evaluated from composite flours of wheat (WF) and cactus pear stems (SF). Orange-yellow cactus pear fruit pulp has been used to produce a dehydrated cactus pulp sheet and pasteurized cactus pear fruit juices.