Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: PIK3CB (cancer-related)
Riyahi N, Safaroghli-Azar A, Sheikh-Zeineddini N, et al.Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.
Cancer Invest. 2019; 37(7):311-324 [PubMed
] Related Publications
Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.
Naghizadeh S, Mohammadi A, Baradaran B, Mansoori BOvercoming multiple drug resistance in lung cancer using siRNA targeted therapy.
Gene. 2019; 714:143972 [PubMed
] Related Publications
Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.
Wu TK, Chen CH, Pan YR, et al.Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed
] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.
Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear.
Recagni M, Greco ML, Milelli A, et al.Distinct biological responses of metastatic castration resistant prostate cancer cells upon exposure to G-quadruplex interacting naphthalenediimide derivatives.
Eur J Med Chem. 2019; 177:401-413 [PubMed
] Related Publications
Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.
Zhang P, Lu X, Shi Z, et al.miR-205-5p regulates epithelial-mesenchymal transition by targeting PTEN via PI3K/AKT signaling pathway in cisplatin-resistant nasopharyngeal carcinoma cells.
Gene. 2019; 710:103-113 [PubMed
] Related Publications
Epithelial-mesenchymal transition (EMT) symbolizes the predominant program of advanced-stage cancer, it is critical in cancer progression, metastasis, and chemotherapy resistance. In this study, the metastatic properties of nasopharyngeal carcinoma (NPC) cells were evaluated by morphological examination, wound healing assay, migration and invasion assay. Western blotting and qRT-PCR were used to ascertain the expression of markers which were associated with EMT. The effects of miR-205-5p on invasion, migration, EMT and proliferation of NPC cells were evaluated and the molecular mechanisms of their interaction were explored. In this study, we manifested firstly that the expression of miR-205-5p in cisplatin-resistant NPC cell line HNE1/DDP was obviously up-regulated than that in its parental cell line HNE1. Then we analyzed the specific role of miR-205-5p through functional assays by transfecting specific mimics and inhibitors. The results indicated that low expression of miR-205-5p restrained EMT progression of HNE1/DDP cells. Further studies on the mechanism of miR-205-5p manifested that PTEN was a downstream candidate gene of miR-205-5p, down-regulated PTEN expression could counteract the effect of miR-205-5p inhibitors, and the regulation of EMT by miR-205-5p on HNE1/DDP cells depended on the PI3K/AKT signaling pathway. Overall, our results indicated that miR-205-5p was targeting PTEN to regulate EMT through the PI3K/AKT pathway. This study will supply a new treatment target for advanced NPC.
The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen-induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non-small-cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN-transgenic (Tg-SPC-SFN
The tumor microenvironment is associated with various tumor progressions, including cancer metastasis, immunosuppression, and tumor sustained growth. Tumor-associated macrophages (TAMs) are considered an indispensable component of the tumor microenvironment, participating in the progression of tumor microenvironment remodeling and creating various compounds to regulate tumor activities. This study aims to observe enriched TAMs in tumor tissues during bladder cancer development, which markedly facilitated the proliferation of bladder cancer cells and promoted tumor growth in vivo. We determined that TAMs regulate tumor sustained growth by secreting type I collagen, which can activate the prosurvival integrin α2β1/PI3K/AKT signaling pathway. Furthermore, traditional chemotherapeutic drugs combined with integrin α2β1 inhibitor showed intensive anticancer effects, revealing an innovative approach in clinical bladder cancer treatment.
Liu JF, Gray KP, Wright AA, et al.Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer.
Gynecol Oncol. 2019; 154(1):95-101 [PubMed
] Related Publications
BACKGROUND: Improved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer.
METHODS: This was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes.
RESULTS: Planned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction.
CONCLUSIONS: The combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.
Chi G, Xu D, Zhang B, Yang FMatrine induces apoptosis and autophagy of glioma cell line U251 by regulation of circRNA-104075/BCL-9.
Chem Biol Interact. 2019; 308:198-205 [PubMed
] Related Publications
BACKGROUND: Matrine, a traditional Chinese medicine, has been reported to exert anti-tumor effects in several types of cancers. Here, we explored the anti-tumor effects of matrine on the glioma cells.
METHODS: Glioma cell line U251 cells were treated with matrine to assess viability and proliferation using CCK8 and EdU assays. PI/FITC staining was performed for apoptosis assay. Transfections were performed for circRNA-104075 or Bcl-9 overexpression. Western blot analysis was performed to evaluate changes of protein levels and changes of gene level were detected by qRT-PCR in U251 cells.
RESULTS: Matrine suppressed cell viability while induced apoptosis and autophagy in U251 cells. Matrine also decreased circRNA-104075 expression significantly. Overexpression of circRNA-104075 was found to counteract the inhibitory effects of matrine on cell proliferation and promoting effects on apoptosis and autophagy in U251 cells. Moreover, the suppressed Wnt/β-catenin and PI3K/AKT signaling pathways by matrine were activated by circRNA-104075 overexpression. Furthermore, Bcl-9 expression was also down-regulated by matrine treatment. Bcl-9 overexpression elevated the decreased cell proliferation while suppressed the increased apoptosis and autophagy induced by matrine in U251 cells.
CONCLUSION: Taken together, the present findings suggested that matrine induced apoptosis and autophagy through down-regulating circ-104075 and Bcl-9 expression via inhibition of PI3K/AKT and Wnt-β-catenin pathways in glioma cells. The present study provides a foundation for further preclinical and clinical evaluations of matrine as a glioma therapy.
Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.
Wang X, Wang Z, Zhang Y, et al.Golgi phosphoprotein 3 sensitizes the tumour suppression effect of gefitinib on gliomas.
Cell Prolif. 2019; 52(4):e12636 [PubMed
] Related Publications
OBJECTIVES: We previously reported that Golgi phosphoprotein 3 (GOLPH3) promotes glioma progression by inhibiting EGFR endocytosis and degradation, leading to EGFR accumulation and PI3K-AKT pathway over-activation. In the current study, we examine whether GOLPH3 affects the response of glioma cells to gefitinib, an EGFR selective inhibitor.
MATERIALS AND METHODS: The expression of GOLPH3 and EGFR in glioma cells was detected by immunofluorescence and immunoblotting. The cell viability or growth in vitro was determined by CCK-8, EdU incorporation and clonogenic assays. The primary glioma cells were cultured by trypsin and mechanical digestion. The transwell invasion assay was used to examine the primary glioma cell motility. Intracranial glioma model in nude mice were established to explore the sensitivity of gefitinib to GOLPH3 high cancer cells in vivo.
RESULTS: Both the immortalized and primary glioma cells with GOLPH3 over-expression hold higher EGFR protein levels on the cell membrane and exhibited higher sensitivity to gefitinib. In addition, primary glioma cells with higher GOLPH3 level exhibited stronger proliferation behaviour. Importantly, GOLPH3 enhanced the anti-tumour effect of gefitinib in vivo. Consistently, after gefitinib treatment, tumours derived from GOLPH3 over-expression cells exhibited lower Ki67-positive and higher cleaved caspase-3-positive cells than control tumours.
CONCLUSIONS: Our results demonstrate that GOLPH3 increases the sensitivity of glioma cells to gefitinib. Our study provides foundation for further exploring whether GOLPH3 high gliomas will be more sensitive to anti-EGFR therapy in clinic and give ideas for developing new possible treatments for individual glioma patients.
Pires LV, Yi Y, Cheng JC, et al.Lapatinib Inhibits Amphiregulin-induced BeWo Choriocarcinoma Cell Proliferation by Reducing ERK1/2 and AKT Signaling Pathways.
Anticancer Res. 2019; 39(5):2377-2383 [PubMed
] Related Publications
BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy.
AIM: To explore the role of AREG in human choriocarcinoma cell proliferation.
MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways.
RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib.
CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma and the incidence of this disease is increasing. The present study aimed to investigate the role of homeobox A6 (HOXA6) in the proliferation and apoptosis of ccRCC cells. Analysis of the GSE6344 dataset and immunohistochemistry revealed that the mRNA and protein expression levels of HOXA6 were suppressed in ccRCC tissues. To evaluate the roles of HOXA6 in cell proliferation and apoptosis, ccRCC cell lines (786‑O and 769‑P) were transfected with plasmids expressing HOXA6, empty vector, short hairpin (sh)HOXA6 and non‑targeting shRNA (NC). Cell Counting Kit‑8, colony formation and 5‑ethynyl‑2'‑deoxyuridine staining assays were performed to analyze cell proliferation. In addition, Caspase‑Glo and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to detect apoptosis. Furthermore, the cell cycle and apoptotic rates of 786‑O and 769‑P cells were analyzed by flow cytometry. The results demonstrated that, compared with the empty vector group, the proliferation of 786‑O and 769‑P cells decreased following HOXA6 overexpression; however, compared with the NC group, cell proliferation increased in the shHOXA6 group. The rate of apoptosis of HOXA6‑overexpressing cells was increased compared with the empty vector group, while the rate of apoptosis in the shHOXA6 group was reduced compared with the NC group. In addition, flow cytometry demonstrated that upregulated HOXA6 expression levels could inhibit the cell cycle at the G0/G1 phase. Western blotting revealed that the expression levels of phosphoinositide 3‑kinase (PI3K), phosphorylated (p)‑protein kinase B (Akt), mitogen‑activated protein kinase kinase, p‑extracellular signal‑regulated kinase (ERK) and B‑cell lymphoma 2 (Bcl‑2) were suppressed in cells overexpressing HOXA6; however, the protein expression levels of phosphatase and tensin homolog, Bcl‑2‑associated X protein, cleaved caspase‑3 and cleaved‑poly (ADP‑ribose) polymerase were increased compared with the empty vector group. Opposing results were reported for the shHOXA6 group compared with the NC group. In summary, the results demonstrated that HOXA6 suppresses cell proliferation and promotes apoptosis, which may occur via inhibition of the PI3K/Akt/ERK cascade. These findings indicate the role of HOXA6 in ccRCC; however, the underlying mechanism requires further investigation.
HER2 (human epidermal growth factor receptor 2) activation is critical in breast cancer development. HER2 promotes cell proliferation, angiogenesis, survival, and metastasis by activation of PI3K/Akt, Ras/MEK/ERK, and JAK/STAT pathways. However, beyond these signaling molecules, the key proteins underlining HER2-mediated metastasis remain elusive. ATF4 (Activating transcription factor 4), a critical regulator in unfolded protein response (UPR), is implicated in cell migration and tumor metastasis. In this study, we demonstrate that HER2 upregulated ATF4 expression at both mRNA and protein levels, resulting in cell migration increased. In addition, ATF4 upregulated ZEB1 (Zinc finger E-box-binding homeobox 1) and suppressed E-cadherin expression resulting in promoting cell migration. Restoration of E-cadherin expression effectively inhibited HER2- or ATF4-mediated cell migration. In addition, upregulated expression of ATF4 was found in HER2-positive breast cancer specimens. Together, this study demonstrates that ATF4-ZEB1 is important for HER2-mediated cell migration and suggests that ATF4-ZEB1 may be potential therapeutic targets for breast cancer metastasis.
Purpose: Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored.
Methods: A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-
Results: GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-
Conclusions: Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-
To better understand the molecular mechanism for the pathogenesis of follicular thyroid carcinoma (FTC), this study aimed at identifying key miRNAs and their target genes associated with FTC, as well as analyzing their interactions. Based on the gene microarray data GSE82208 and microRNA dataset GSE62054, the differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using R and SAM software. The common DEMs from R and SAM were fed to three different bioinformatic tools, TargetScan, miRDB, and miRTarBase, respectively, to predict their biological targets. With DEGs intersected with target genes of DEMs, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed through the DAVID database. Then a protein-protein interaction (PPI) network was constructed by STRING. Finally, the module analysis for PPI network was performed by MCODE and BiNGO. A total of nine DEMs were identified, and their function might work through regulating hub genes in the PPI network especially KIT and EGFR. KEGG analysis showed that intersection genes were enriched in the PI3K-Akt signaling pathway and microRNAs in cancer. In conclusion, the study of miRNA-mRNA network would offer molecular support for differential diagnosis between malignant FTC and benign FTA, providing new insights into the potential targets for follicular thyroid carcinoma diagnosis and treatment.
Hung CY, Lee CH, Chiou HL, et al.Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.
Cell Physiol Biochem. 2019; 52(6):1255-1266 [PubMed
] Related Publications
BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.
METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.
RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.
CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.
Ahmed ESA, Ahmed NH, Medhat AM, et al.Mesenchymal stem cells targeting PI3K/AKT pathway in leukemic model.
Tumour Biol. 2019; 41(4):1010428319846803 [PubMed
] Related Publications
Mesenchymal stem cells have therapeutic properties that are related to their potentials for trans-differentiation, immunomodulation, anti-inflammatory, inhibitory effect on tumor proliferation, and induction of apoptosis. This study was performed to analyze the role of mesenchymal stem cells as an alternative for cellular signaling growth factors involved in the pathogenesis of leukemogenesis in rats. Treatment of rats with 7,12-dimethyl benz [a] anthracene induced leukemogenesis appeared as a significant decrease in hematological parameters with concomitant significant increase in bone marrow oxidative and inflammatory indices (transforming growth factor beta and interleukin-6) in comparison with normal groups. On the contrary, Western immunoblotting showed a significant increase in the signaling growth factors: PI3K, AKT, mTOR proteins and a significant decrease in PTEN in 7,12-dimethyl benz [a] anthracene-treated group. In addition, a significant increase in the transcript levels of B cell lymphoma-2 protein gene in the 7,12-dimethyl benz [a] anthracene group, while that of C-X-C motif chemokine receptor-4 and B cell lymphoma-2 protein associated x-protein were significantly downregulated compared to controls. Meanwhile, therapeutic mesenchymal stem cells treatment predict a significant improvement versus 7,12-dimethyl benz [a] anthracene group through the modulation of growth factors that confront bone marrow dysplasia. In the same direction treatment of 7,12-dimethyl benz [a] anthracene group with mesenchymal stem cells, it induced apoptosis and increased the homing efficacy to bone marrow. In conclusion, mesenchymal stem cells improve hematopoiesis and alleviate inflammation, and modulated PI3K/AKT signaling pathway contributed to experimental leukemogenesis.
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a well-characterized tumour-suppressor gene that is lost or mutated in about half of metastatic castration-resistant prostate cancers and in many other human cancers. The restoration of functional PTEN as a treatment for prostate cancer has, however, proven difficult. Here, we show that PTEN messenger RNA (mRNA) can be reintroduced into PTEN-null prostate cancer cells in vitro and in vivo via its encapsulation in polymer-lipid hybrid nanoparticles coated with a polyethylene glycol shell. The nanoparticles are stable in serum, elicit low toxicity and enable high PTEN mRNA transfection in prostate cancer cells. Moreover, significant inhibition of tumour growth is achieved when delivered systemically in multiple mouse models of prostate cancer. We also show that the restoration of PTEN function in PTEN-null prostate cancer cells inhibits the phosphatidylinositol 3-kinase (PI3K)-AKT pathway and enhances apoptosis. Our findings provide proof-of-principle evidence of the restoration of mRNA-based tumour suppression in vivo.
The epithelial-mesenchymal transition (EMT) is a phenomenon that facilitates epithelial cells to acquire invasive potential to induce the initiation the metastatic spread of tumor cells. Here, we determined if brassinin (BSN) can affect the EMT process and deciphered its anti-cancer effects. BSN attenuated the levels of EMT linked genes and suppressed transforming growth factor beta (TGF-β)-mediated regulation of diverse mesenchymal markers. Additionally, BSN did increase the expression of various epithelial marker proteins in lung cancer cells. TGF-β-induced morphological changes and induction of invasive ability of tumor cells was also found to be abrogated by BSN treatment. Finally, BSN not only suppressed constitutive, but also inducible phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation in tumor cells.
Background: Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported.
Methods: Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis and report gene, pathway, and drug set-based overlaps between them.
Results: Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD.
Conclusions: Comparisons of ASD and cancer differential gene expression meta-analysis results suggest that brain, kidney, thyroid, and pancreatic cancers are candidates for direct comorbid associations with ASD. On the other hand, lung and prostate cancers are candidates for inverse comorbid associations with ASD. Joint perturbations in a set of specific biological processes underlie these associations which include several pathways previously implicated in both cancer and ASD encompassing immune system alterations, impairments of energy metabolism, cell cycle, and signaling through PI3K and G protein-coupled receptors among others. These findings could help to explain epidemiological observations pointing towards direct and inverse comorbid associations between ASD and specific cancer types and depict a complex scenario regarding the molecular patterns of association between ASD and cancer.
Wang Y, Huang H, Li YKnocking down miR-384 promotes growth and metastasis of osteosarcoma MG63 cells by targeting SLBP.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1458-1465 [PubMed
] Related Publications
Osteosarcoma is a common malignant bone tumour in adolescents and old people, with highly invasive and metastatic features and poor prognosis. This study aimed to explore the role of miR-384 in osteosarcoma MG63 cells by targeting SLBP. Cell viability, migration and invasion, apoptosis, as well as apoptosis-related factors were evaluated by CCK-8 assay, Transwell assay, flow cytometer and Western blotting, respectively. Dual-luciferase reporter assay was used to determine the target of miR-384. SLBP level was analyzed using qRT-PCR and Western blotting. Important factors of MEK/ERK and PI3K/AKT signalling pathways were analyzed using Western blotting. We found that miR-384 was down-regulated in osteosarcoma tissue samples and cell lines (MG63, U2OS and OS732). miR-384 overexpression inhibited viability, migration and invasion, but promoted apoptosis of MG63 cells; whereas, miR-384 silence exhibited the contrary effects on MG63 cells. SLBP was a target of miR-384. Knockdown of SLBP reversed the promoting effect of miR-384 silence on cells, indicating that miR-384 silence promoted growth and metastasis of MG63 cells by up-regulating SLBP. In conclusion, knocking down miR-384 promoted the growth and metastasis of osteosarcoma MG63 cells by up-regulating SLBP. To conclude, miR-384-SLBP may be a potential therapeutic target for osteosarcoma therapy.
Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.
Bhuvaneshwar K, Harris M, Gusev Y, et al.Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients.
BMC Cancer. 2019; 19(1):357 [PubMed
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BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients.
METHODS: We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival.
RESULTS: We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance.
CONCLUSION: We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.
Yao SS, Han L, Tian ZB, et al.Celastrol inhibits growth and metastasis of human gastric cancer cell MKN45 by down-regulating microRNA-21.
Phytother Res. 2019; 33(6):1706-1716 [PubMed
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Celastrol could inhibit cancer cell growth in vitro. However, effect(s) of celastrol on gastric cancer is not well studied. Therefore, we investigated the effects of celastrol on human gastric cancer cell line MKN45 and the underlying mechanisms. We found that celastrol inhibited cell proliferation, migration, and invasion and induced cell apoptosis and G2/M cell cycle arrest (p < .05, p < .01, or p < .001). Under celastrol treatment, overexpression of microRNA-21 (miR-21) increased cell viability, migration, and invasion and inhibited cell apoptosis compared with negative control (p < .05, p < .01, or p < .001). In addition, the phosphorylation of PTEN was significantly up-regulated, whereas PI3K, AKT, p65, and IκBα phosphorylation was statistically decreased by celastrol (p < .05 or p < .01) and then further reversed by miR-21 overexpression (p < .05 or p < .01). On the other side, miR-21 silence showed contrary results (p < .05) as relative to miR-21 overexpression. In conclusion, celastrol inhibits proliferation, migration, and invasion and inactivates PTEN/PI3K/AKT and nuclear factor κB signaling pathways in MKN45 cells by down-regulating miR-21.
BACKGROUND: Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance.
METHODS: Radioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses.
RESULTS: Proliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity.
CONCLUSIONS: This is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.
OBJECTIVE: Colorectal cancer (CRC) is an extremely common gastrointestinal malignancy. The present study aimed to identify microRNAs (miRNAs) and transcription factors (TFs) associated with tumor development.
METHODS: Three miRNA profile datasets were integrated and analyzed to elucidate the potential key candidate miRNAs in CRC. The starBase database was used to identify the potential targets of common differentially expressed miRNAs (DEMs). Transcriptional Regulatory Element Database and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text databases were used to identify cancer-related TFs and the TF-regulated target genes. Functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integration Discovery (DAVID) database, and the miRNA-TF-gene networks were constructed by Cytoscape. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of genes and miRNAs.
RESULTS: In total, 14 DEMs were found in CRC. By bioinformatics analysis, 5 DEMs (miR-145, miR-497, miR-30a, miR-31, and miR-20a) and 8 TFs (ELK4 (ETS-family transcription factor), myeloblastosis proto-oncogene like (MYBL)1, MYBL2, CEBPA, PPARA, PPARD, PPARG, and endothelial PAS domain protein (EPAS1)) appeared to be associated with CRC and were therefore used to construct miRNA-TF-gene networks. From the networks, we found that miR-20a might play the most important role as an miRNA in the networks. By qRT-PCR, we demonstrated that miR-20a was significantly upregulated in CRC tissues. We also performed qRT-PCR to identify the expression of miR-20a-related TFs (PPARA, PPARD, PPARG, EPAS1). Three of them, PPARA, PPARG, and EPAS1, were downregulated in CRC tissues, with statistically significant differences, while the downregulation of PPARD in CRC tissues was not significantly different. Pathway enrichment analyses indicated that the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway was the most significantly enriched pathway. Two main elements of the PI3K-Akt signaling pathway, phosphatase and tensin homolog deleted on chromosome 10 and B-cell lymphoma 2-associated agonist of cell death, were demonstrated to be downregulated in CRC.
CONCLUSION: The present study identified hub miRNAs and miRNA-related TF regulatory networks in CRC, which might be potential targets for the diagnosis and treatment of CRC.
Background: The specific functional roles of long noncoding RNAs (lncRNAs) as ceRNAs in colon cancer and their potential implications for colon cancer prognosis remain unclear. In the present study, a genome-wide analysis was performed to investigate the potential lncRNA-mediated ceRNA interplay in colon cancer based on the "ceRNA hypothesis." The prognostic value of the lncRNAs was evaluated.
Methods: A dysregulated lncRNA-associated ceRNA network was constructed based on the miRNA, lncRNA, and mRNA expression profiles in combination with the miRNA regulatory network by using an integrative computational method. Molecular biological techniques, including qPCR and gene knockdown techniques, were used to verify candidate targets in colon cancer. Survival analysis was performed to identify the candidate lncRNAs with prognostic value.
Results: Our network analysis uncovered several novel lncRNAs as functional ceRNAs through crosstalk with miRNAs. The QRT-PCR assays of patient tissues as well as gene knockdown colon cancer cells confirmed the expression of top lncRNAs and their correlation with target genes in the ceRNA network. Functional enrichment analysis predicted that differentially expressed lncRNAs might participate in broad biological functions associated with tumor progression. Moreover, these lncRNAs may be involved in a range of cellular pathways, including the apoptosis, PI3K-AKT, and EGFR signaling pathways. The survival analysis showed that the expression level of several lncRNAs in the network was correlated with the prognosis of patients with colon cancer.
Conclusions: This study uncovered a dysregulated lncRNA-associated ceRNA network in colon cancer. The function of the identified lncRNAs in colon cancer was preliminarily explored, and their potential prognostic value was evaluated. Our study demonstrated that lncRNAs could potentially serve as important regulators in the development and progression of colon cancer. Candidate prognostic lncRNA biomarkers in colon cancer were identified.
Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies.