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 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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: FYN (cancer-related)
Huang E, Huang H, Guan T, et al.Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.
Toxicol Lett. 2019; 312:11-21 [PubMed
] Related Publications
Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.
Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.
6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6-phosphogluconate into ribulose-5-phosphate with NADP
Li G, Cai L, Zhou LMicroarray gene expression profiling and bioinformatics analysis reveal key differentially expressed genes in clival and sacral chordoma cell lines.
Neurol Res. 2019; 41(6):554-561 [PubMed
] Related Publications
OBJECTIVE: Chordoma is a rare tumor with a certain rate of distant metastasis. Skull base and sacrum are the two most common origin sites. This study tends to identify key differentially expressed genes (DEGs) between classical clival and sacral chordomas, provide new targets for future treatment options of chordomas.
METHODS: The gene expression profiles of GSE95084 and GSE68497 were downloaded from Gene Expression Omnibus database and were analyzed using the limma R package. Function and enrichment analyses of DEGs were performed based on DAVID Database. Protein-protein interaction (PPI) network was constructed using the Cytoscape based on the data collected from STRING online datasets. Hub genes selection and modules analyses of the PPI network were conducted by plugin cytoHubba and MCODE of Cytoscape software, respectively.
RESULT: In total, 728 genes, including 363 up-regulated genes and 365 down-regulated genes were selected as DEGs. Notably, GO analysis showed that both up-regulated and down-regulated DEGs were mainly involved in cell component such as an integral component of the membrane, plasma membrane and extracellular exosome. DEGs were mainly enriched in pathways like Pathways in cancer, PI3K-Akt signaling pathway, Cytokine-cytokine receptor interaction. FYN, ITGB3, ACTN2 and IGF1 were identified as hub genes and they were all involved in focal adhesion signaling pathway. Furthermore, five significant network modules were obtained from the PPI network.
CONCLUSION: This study helps to further understand the molecular characteristics of classic chordomas of two distinct sites. Hub genes FYN, ITGB3, ACTN2, and IGF1, as well as focal adhesion signaling pathway, would be new targets for future treatment options of chordomas.
Zhang G, Bi M, Li S, et al.Determination of core pathways for oral squamous cell carcinoma via the method of attract.
J Cancer Res Ther. 2018; 14(Supplement):S1029-S1034 [PubMed
] Related Publications
Objective: We expected to demonstrate a practical framework for oral squamous cell carcinoma (OSCC) candidate biomarker analysis at the pathway level based on the attract method, so as to give great insights to reveal the pathological mechanism underlying this disease at its early stage.
Methods: First, gene expression profile of OSCC was recruited and preprocessed. Then, Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was conducted. Next, attract method, an approach that begins its analysis from the "foundation knowledge sets" to discriminate the cell-phenotypes by those well-annotated gene-sets, then expands the syn-expression groups via decomposing each significant pathway into correlated subsets and extends the analysis to the entire expression was applied to identify core pathways. Finally, gene ontology (GO) functional enrichment analysis was performed on each of the correlated set groups to discover any potentially shared biological themes.
Results: A total of 226 pathways were obtained. Then, 39 core KEGG pathways was identified via attract. After removing the uninformative genes, a total of 1, 2, and 3 clusters were separately identified for the three discriminative pathways extracellular matrix (ECM)-receptor interaction, neuroactive ligand-receptor interaction, and cell adhesion molecules (CAMs) pathway based on the correlation coefficient < 0.85. GO functional enrichment analysis for the correlated partners groups indicated that there were 40, 11, 78 significant GO terms for ECM-receptor interaction, neuroactive ligand-receptor interaction, and CAMs pathway, respectively.
Conclusions: We predict that pathways such as ECM-receptor interaction, neuroactive ligand-receptor interaction, and CAMs may play significant roles in OSCC and targeting these pathways may provide an effective avenue to combat the complicated illness.
Lu G, Wu X, Zhao Z, et al.MicroRNA-126 regulates the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway in SLK cells in vitro and the expression of its pathway members in Kaposi's sarcoma tissue.
Medicine (Baltimore). 2018; 97(35):e11855 [PubMed
] Free Access to Full Article Related Publications
In vitro, microRNA-126 (miR-126) inhibits SLK cell proliferation, inhibits the cell cycle, induces cell apoptosis, and reduces cell invasiveness. Double luciferase assays have shown that phosphatidylinositol-3 kinase (PI3K) is the miR-126 target in SLK cells. We aimed to investigate the influence of miR-126 on the phosphate and tension homology deleted on chromosome ten (PTEN)/PI3K/protein kinase B (AKT) pathway members in SLK cells and to determine the expression of these pathway members in Kaposi's sarcoma (KS). The mimic and inhibitor of miR-126 were transfected into SLK cells and PTEN and AKT1 expression was assayed in SLK cells by real-time quantitative PCR and western blotting. PTEN, AKT1, phosphorylated (P)-PTEN, and phosphorylated (P)-AKT expression in KS and paraneoplastic skin were assayed by immunohistochemistry. AKT1 expression was downregulated in SLK cells that overexpressed miR-126, while there was no significant difference in PTEN expression between SLK cells overexpressing miR-126 and those in which its expression was knocked down. PTEN and AKT1 were expressed in KS and paraneoplastic skin but P-AKT was not. Interestingly, P-PTEN was not expressed in paraneoplastic skin but it was expressed in 90% of KS biopsies (P < .05). P-PTEN expression was also significantly higher in visceral than in cutaneous KS (P = .01) and was higher in indoor than in outdoor workers (P = .018). In vitro, miR-126 negatively regulated AKT1 expression but no regulation of PTEN expression was evident. Results indicated that in KS, PTEN is activated and may therefore be a potential therapeutic target for KS. In addition, these results also indicate that sunlight may not be the cause of KS.
Gene fusion structure is a class of common somatic mutational events in cancer genomes, which are often formed by chromosomal mutations. Identifying the driver gene(s) in a fusion structure is important for many downstream analyses and it contributes to clinical practices. Existing computational approaches have prioritized the importance of oncogenes by incorporating prior knowledge from gene networks. However, different methods sometimes suffer different weaknesses when handling gene fusion data due to multiple issues such as fusion gene representation, network integration, and the effectiveness of the evaluation algorithms. In this paper, Synstable Fusion (SYN), an algorithm for computationally evaluating the fusion genes, is proposed. This algorithm uses network-based strategy by incorporating gene networks as prior information, but estimates the driver genes according to the destructiveness hypothesis. This hypothesis balances the two popular evaluation strategies in the existing studies, thereby providing more comprehensive results. A machine learning framework is introduced to integrate multiple networks and further solve the conflicting results from different networks. In addition, a synchronous stability model is established to reduce the computational complexity of the evaluation algorithm. To evaluate the proposed algorithm, we conduct a series of experiments on both artificial and real datasets. The results demonstrate that the proposed algorithm performs well on different configurations and is robust when altering the internal parameter settings.
Donner I, Katainen R, Kaasinen E, et al.Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma.
Fam Cancer. 2019; 18(1):113-119 [PubMed
] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.
One of the most challenging issues in oncology research and treatment is identifying oncogenic drivers within an individual patient's tumor which can be directly targeted by a clinically available therapeutic drug. In this context, gene fusions as one important example of genetic aberrations leading to carcinogenesis follow the widely accepted concept that cell growth and proliferation are driven by the accomplished fusion (usually involving former proto-oncogenes) and may therefore be successfully inhibited by substances directed against the fusion. This concept has already been established with oncogenic gene fusions like BCR-ABL in chronic myelogenous leukemia (CML) or anaplastic lymphoma kinase (ALK) in lung cancer, including special tyrosine kinase inhibitors (TKIs) which are able to block the activation of the depending downstream proliferation pathways and, consequently, tumor growth. During the last decade, the NTRK1, 2, and 3 genes, encoding the TRKA, B, and C proteins, have attracted increasing attention as another significant and targetable gene fusion in a variety of cancers. Several TRK inhibitors have been developed, and one of them, Larotrectinib (formerly known as LOXO-101), represents an orally available, selective inhibitor of the TRK receptor family that has already shown substantial clinical benefit in both pediatric and adult patients harboring an NTRK gene fusion over the last few years.
Liu G, Ji L, Ke M, et al.miR-125a-3p is responsible for chemosensitivity in PDAC by inhibiting epithelial-mesenchymal transition via Fyn.
Biomed Pharmacother. 2018; 106:523-531 [PubMed
] Related Publications
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and resistance to cytotoxic chemotherapy is the major cause of mortality in PDAC patients. miR-125a-3p was found to be down-regulated in PDAC cells; however, the function of miR-125a-3p in PDAC has been elusive. Here, we explored the role of miR-125a-3p in chemosensitivity in PDAC cells.
METHODS: We used qRT-PCR to detect miR-125a-3p expression in two PDAC cell lines. And we measured cell viability and apoptosis by MTT assay and flow cytometry, respectively. Scratch wound healing assay and transwell invasion assay were used to test the effects of miR-125a-3p and Fyn on cell EMT process. In addition, we validated the interaction of miR-125a-3p and Fyn by dual luciferase reporter assay. qRT-PCR and western blot were used to detect the mRNA and protein expressions of E-cadhrein, N-cadhrein, Snail and Fyn.
RESULTS: We found that miR-125a-3p was down-regulated in a time-dependent manner following treatment with gemcitabine in PDAC cells. Meanwhile, we found that overexpression of miR-125a-3p significantly increased chemosensitivity to gemcitabine and suppressed epithelial-mesenchymal transition (EMT) of PDAC cells. Mechanistically, miR-125a-3p directly targeted Fyn and decreased the expression of Fyn that functions to promote EMT process in PDAC. Furthermore, overexpression of Fyn could partially reverse the effects of miR-125a-3p on chemosensitivity to gemcitabine.
CONCLUSION: Our study is the first to show that miR-125a-3p is responsible for chemosensitivity in PDAC and could inhibit epithelial-mesenchymal transition by directly targeting Fyn. This provides a novel potential therapeutic strategy to overcome chemoresistance in PDAC.
Mehra S, Ghosh D, Kumar R, et al.Glycosaminoglycans have variable effects on α-synuclein aggregation and differentially affect the activities of the resulting amyloid fibrils.
J Biol Chem. 2018; 293(34):12975-12991 [PubMed
] Free Access to Full Article Related Publications
Parkinson's disease is mainly a sporadic disorder in which both environmental and cellular factors play a major role in the initiation of this disease. Glycosaminoglycans (GAG) are integral components of the extracellular matrix and are known to influence amyloid aggregation of several proteins, including α-synuclein (α-Syn). However, the mechanism by which different GAGs and related biological polymers influence protein aggregation and the structure and intercellular spread of these aggregates remains elusive. In this study, we used three different GAGs and related charged polymers to establish their role in α-Syn aggregation and associated biological activities of these aggregates. Heparin, a representative GAG, affected α-Syn aggregation in a concentration-dependent manner, whereas biphasic α-Syn aggregation kinetics was observed in the presence of chondroitin sulfate B. Of note, as indicated by 2D NMR analysis, different GAGs uniquely modulated α-Syn aggregation because of the diversity of their interactions with soluble α-Syn. Moreover, subtle differences in the GAG backbone structure and charge density significantly altered the properties of the resulting amyloid fibrils. Each GAG/polymer facilitated the formation of morphologically and structurally distinct α-Syn amyloids, which not only displayed variable levels of cytotoxicity but also exhibited an altered ability to internalize into cells. Our study supports the role of GAGs as key modulators in α-Syn amyloid formation, and their distinct activities may regulate amyloidogenesis depending on the type of GAG being up- or down-regulated
Inflammatory genes serve a crucial role in the pathogenesis of inﬂammation‑associated tumors. However, as recent studies have mainly focused on the effects of single inflammatory genes on colorectal cancer (CRC), but not on the global interactions between genes, the underlying mechanisms between inflammatory genes and CRC remain unclear. In the current study, two inflammation‑associated networks were constructed based on inflammatory genes, differentially expressed genes (DEGs) in CRC vs. normal samples, and protein‑protein interactions (PPIs). These networks included an inflammation‑related neighbor network (IRNN) and an inflammation‑related DEG network (IRDN). Notably, the results indicated that the inflammatory genes served as important CRC‑associated genes in the IRNN. Certain inflammatory genes were more likely to be network hubs and exhibited higher betweenness centralities, indicating that these inflammatory hub genes had central roles in the communication between genes in the IRNN. By contrast, in the IRDN, functional enrichment analysis revealed that genes were enriched in numerous cancer‑associated functions and pathways. Subsequently, 14 genes in a module were identified in the IRDN as the potential biomarkers associated with disease‑free survival (DFS) in CRC patients in the GSE24550 dataset, the prognosis of which was further validated using three independent datasets (GSE24549, GSE34551 and GSE103479). All 14 genes (including BCAR1, CRK, FYN, GRB2, LCP2, PIK3R1, PLCG1, PTK2, PTPN11, PTPN6, SHC1, SOS1, SRC and SYK) in this module were inflammatory genes, emphasizing the critical role of inflammation in CRC. In conclusion, these findings based on integrated inflammation‑associated networks provided a novel insight that may help elucidate the inflammation‑mediated mechanisms involved in CRC.
The concept that abnormal protein aggregates show prion-like propagation between cells has been considered to explain the onset and progression of many neurodegenerative diseases. Indeed, both synthetic amyloid-like fibrils and pathogenic proteins extracted from patients' brains induce self-templated amplification and cell-to-cell transmission in vitro and in vivo. However, it is unclear whether exposure to exogenous prion-like proteins can potentially cause these diseases in humans. Here, we investigated in detail the prion-like seeding activities of several kinds of pathogenic α-synuclein (α-syn), including synthetic fibrils and detergent-insoluble fractions extracted from brains of patients with α-synucleinopathies. Exposure to synthetic α-syn fibrils at concentrations above 100 pg/mL caused seeded aggregation of α-syn in SH-SY5Y cells, and seeded aggregation was also observed in C57BL/6 J mice after intracerebral inoculation of at least 0.1 μg/animal. α-Syn aggregates extracted from brains of multiple system atrophy (MSA) patients showed higher seeding activity than those extracted from patients with dementia with Lewy bodies (DLB), and their potency was similar to that of synthetic α-syn fibrils. We also examined the effects of various methods that have been reported to inactivate abnormal prion proteins (PrP
Fathi Z, Syn NL, Zhou JG, Roudi RMolecular epidemiology of lung cancer in Iran: implications for drug development and cancer prevention.
J Hum Genet. 2018; 63(7):783-794 [PubMed
] Related Publications
Epidemiological studies undertaken over the past decades reveal a gradual but progressive increase in the incidence and mortality attributable to lung cancer in the Islamic Republic of Iran, a sovereign state geographically situated at the crossroads of Central Eurasia and Western Asia. We identified references published in English and Persian through searches of PubMed, EMBASE, Web of Science, Scopus, and the Scientific Information Database (SID)-a specialized Iranian database, which indexes Iranian scientific journals-between inception and 15 September 2017. Of 1475 references identified through electronic searches, we reviewed the full text of 88 studies, and included 38 studies in the review. Potentially druggable NSCLC targets, which have been studied in Iran include EGFR, ALK, ERBB2, and KIT; but no studies were found, which examined the impact of MET, ROS1, BRAF, PIK3CA, and FGFR1 aberrations. We were able to identify some literature on DNA repair genes and xenobiotic metabolism, including TP53, TP63, ERCC2, XRCC2, SIRT1, PTEN, CYP1A1, CYP1B1, GSTT1, and GSTM1. We also found an increasing amount of research performed in relation to the tumor microenvironment and immune contexture, including CTLA4, MAGE, FOXP3, IFN-γ, and various interleukins, chemokines, and transcription factors; but did not identify any publication concerning the expression of PD-1/PD-L1 in lung cancer. Our survey of research performed in Iran has revealed a dearth of studies in topics, which are otherwise highly pursued in developed countries, but nevertheless, has begun to hint at a distinct biology of lung cancer in this part of the world.
Tumor angiogenesis is mainly regulated by vascular endothelial growth factor (VEGF) produced by cancer cells. It is active on the endothelium via VEGF receptor 2 (VEGFR-2). G-quadruplexes are DNA secondary structures formed by guanine-rich sequences, for example, within gene promoters where they may contribute to transcriptional activity. The proximal promoter of
Objective: The objective of the study was to summarize the role of DNA methylation in the development and metastasis of uveal melanoma (UM).
Data Sources: The relevant studies in MEDLINE were searched.
Study Selection: In this review, we performed a comprehensive literature search in MEDLINE using "uveal melanoma" AND ("DNA methylation" OR "epigenetics") for original research/review articles published before February 2018 on the relationship between DNA methylation and UM. References of the retrieved studies were also examined to search for potentially relevant papers.
Results: Previous studies on the relationship between DNA methylation and UM covered many genes including tumor suppressor genes (TSGs), cyclin-dependent kinase genes, and other genes. Among them, the TSG genes such as RASSF1A and p16INK4a, which encodes a cyclin-dependent kinase inhibitor, are relatively well-studied genes. Specifically, a high percentage of promoter methylation of RASSF1A was observed in UM cell lines and/or patients with UM. Promoter methylation of RASSF1A was also associated with the development of metastasis. Similarly, a high percentage of promoter hypermethylation of p16INK4a was found in UM cell lines. DNA promoter methylation can control the expression of p16INK4a, which affect cell growth, migration, and invasion in UM. Many other genes might also be involved in the pathogenesis of UM such as the Ras and EF-hand domain containing (RASEF) gene, RAB31, hTERT, embryonal fyn-associated substrate, and deleted in split-hand/split-foot 1.
Conclusions: Our review reveals the complex mechanisms underlying the tumorigenesis of UM and highlights the great needs of future studies to discover more genes/5'-C-phosphate-G-3' sites contributing to the development/metastasis of UM and explore the mechanisms through which epigenetic changes exert their function in UM.
In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.
Yuan H, Zhou W, Yang Y, et al.ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway.
Exp Cell Res. 2018; 367(1):47-55 [PubMed
] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in China with a poor prognosis. Most ESCC patients were diagnosed at advanced stages, losing the opportunity for surgical excision. Hence, it remains a pressing work to identify biomarkers for early detection, prognosis prediction and targeting therapies in ESCC. Interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, and is involved in the post-translational modification (PTMs) of multiple proteins. However, the molecular functions of ISG15 in ESCC remain unclear. In this work, we found that ISG15 was aberrantly expressed in ESCC tissues and cell lines. Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation, migration, invasion and tumor formation in vivo. Consistently, reduction of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines. Furthermore, gene-expression profiles suggested that the differentially expressed ISG15 affected the expression of a panel of genes enriched in the cell adherens junction, such as c-MET. Notably, as a secreted protein, the concentration of ISG15 was elevated in ESCC plasma than healthy individuals, acting as a potential diagnostic marker. Taken together, our results suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway.
Wang K, Hong RL, Lu JB, Wang DLSte20-like kinase is upregulated in glioma and induces glioma invasion.
Neoplasma. 2018; 65(2):185-191 [PubMed
] Related Publications
The malignant development and poor prognosis of gliomas are associated with a high degree of invasion and a high recurrence rate. However, the molecular mechanism underlying the invasiveness of glioma remains to be elucidated. Ste20- like kinase (SLK) is one of the members of the Ste20 family, which has been implicated in cellular migration and invasion. In this study, we intended to explore the expression of SLK significantly related to clinicopathologic stages of gliomas. Immunohistochemical staining and western blot analysis demonstrated that SLK was highly expressed in human glioma tissues and cell lines. Kaplan-Meier analysis revealed that poor survival was associated with high SLK expression. The inhibition of SLK by RNA interference significantly suppressed the invasion ability of glioma, and on protein level, knock- down of SLK leaded to an up-regulation of E-cadherin and a down-regulation of Vimentin in glioma cells. Collectively, this research shed light on mechanisms of invasion and progression of malignant gliomas and suggested that SLK may be a potential therapeutic strategy for glioma.
Lim SM, Syn NL, Cho BC, Soo RAAcquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies.
Cancer Treat Rev. 2018; 65:1-10 [PubMed
] Related Publications
The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research.
Manka P, Coombes JD, Boosman R, et al.Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment.
Cancer Lett. 2018; 419:175-186 [PubMed
] Related Publications
Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.
He XR, Liu Z, Wei J, et al.Primary desmoplastic small round cell tumor in the left orbit: a case report and literature review.
Int Ophthalmol. 2019; 39(2):471-475 [PubMed
] Related Publications
PURPOSE: Desmoplastic small round cell tumor is a rare malignant neoplasm that most often occurs in the abdomen or pelvis of young men. We herein describe a rare case of desmoplastic small round cell tumor arising from the left orbit in a 16-year-old male.
METHODS AND RESULTS: A biopsy was performed and the histology showed the nests of tumor cells with small round cell morphology. The tumor cells showed immunopositivity for desmin, CD99, CD56, SMA, NSE, CgA, SYN, Ki67 and vimentin. Fluorescence in situ hybridization study using EWSR1 break-apart probe was positive for EWSR1 gene rearrangement. After complete surgical resection of the tumor, we did not find tumor recurrence or metastasis with one-year follow-up. Furthermore, a review of the relevant English literature has been discussed.
CONCLUSIONS: In the present study, for the first time, we report a case of desmoplastic small round cell tumor which is located in the orbital region.
Martens MC, Seebode C, Lehmann J, Emmert SPhotocarcinogenesis and Skin Cancer Prevention Strategies: An Update.
Anticancer Res. 2018; 38(2):1153-1158 [PubMed
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UV radiation is acknowledged as the primary cause of photocarcinogenesis and therefore contributes to the development of skin cancer entities such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. Typical DNA photoproducts and indirect DNA damage caused by reactive oxygen species are the result of UV radiation. UV-induced DNA damage is repaired by nucleotide excision repair, which consequently counteracts the development of mutations and skin carcinogenesis. Tumour-suppressor genes are inactivated by mutation and growth-promoting pathways are activated leading to disruption of cell-cycle progression. Depending on the skin cancer entity, some genes are more frequently affected than others. In BCC mutations in Patched or Smoothened are common and affect the Sonic hedgehog pathway. In SCC, cell regulator protein p53 (TP53) mutations are prevalent, as well as mutations of the epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2A (CDKN2A), Rat sarcoma (RAS), or the tyrosine kinase Fyn (FYN). UV-induced mutations in TP53 and CDKN2A are frequent in melanoma. UV-induced inflammatory processes also facilitate photocarcinogenesis. Recent studies showed a connection between photocarcinogenesis and citrus consumption, phytochemicals, alcohol consumption, hormone replacement therapy, as well as oral contraceptive use. Preventative measures include adequate use of sun protection and skin cancer screening at regular intervals, as well as the use of chemopreventative agents.
The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non-small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB-resistant (VR) lung cancer cells (NCI-H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP-binding Cassette Sub-family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB-resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.
Non-alcoholic steatohepatitis (NASH) is commonly associated with obesity, type 2 diabetes, and/or hypertriglyceridemia, while alcoholic steatohepatitis (ASH) is associated with alcohol abuse. Both NASH and ASH patients can develop cirrhosis and hepatocellular carcinoma (HCC) if left untreated. However, the rate of tumorigenesis in NASH and ASH appears to be different. Individuals with NASH progress to HCC at a rate of 0.5% annually (Lindenmeyer and McCullough, 2018), when individuals with ASH progress to HCC at a rate of 3-10% annually (Schwartz and Reinus, 2012). Thus, the objective of our study is to determine if there are differences in NASH versus ASH in the levels of different proteins expressed involved in cancer development. The method used was measuring the proteins expressed in liver biopsied sections from NASH and ASH patients using immunohistochemical staining with fluorescent antibodies and then quantitating the fluorescence intensity morphometrically. The 20 proteins tested are parts of the Ingenuity Canonical Pathway of Molecular Mechanisms of Cancer and include: RAP2B, NAIP, FYN, PAK6, SUV39H1, GNAI1, BAX, E2F3, CKDN2B, BAK1, BCL2, DIABLO, RASGRF2, GNA15, PIK3CB, BRCA1, MAP2K1, BIRC3, CDK2, and ATM. In ASH, the proteins that showed upregulated levels of expression were SUV39H1, E2F3, BCL2, BAK1, BIRC3, and GNAI1. In NASH, the proteins that showed upregulated levels of expression were BAK1 and GNAI1 and the protein that showed downregulated level of expression was BCL2. Additionally, levels of expression for SUV39H1, E2F3, BCL2, BAK1, BIRC3, and GNAI1 were significant upregulated in ASH compared to NASH. These results showed significant differences in ASH compared to normal liver, and significant differences in ASH compared to NASH. Thus, we conclude that there are more proteins involved in tumorigenesis in ASH compared to NASH and in ASH compared to normal liver, which is consistent with the known tumor development rate in ASH and NASH.
de Moura NA, Caetano BFR, de Moraes LN, et al.Enhancement of colon carcinogenesis by the combination of indole-3 carbinol and synbiotics in hemin-fed rats.
Food Chem Toxicol. 2018; 112:11-18 [PubMed
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The risk of developing colorectal cancer (CRC) could be associated with red and processed meat intake. Experimental data supports that hemin iron, found abundantly in red meat, promotes CRC in mice and rats, while indole-3 carbinol (I3C) and synbiotics (syn) exert anti-carcinogenic activities in most studies of colon carcinogenesis. This study aimed to investigate the modifying effects of I3C and syn (inulin + Bifidobacterium lactis), given separately or together, on dimethylhidrazine (DMH)-induced colon carcinogenesis in hemin-fed rats. All animals were given four subcutaneous DMH injections and then, two weeks after carcinogen exposure, they began a basal diet containing hemin, hemin + I3C, hemin + syn, or hemin + I3C + syn for 23 weeks. The combination of I3C + syn significantly increased fecal water genotoxicity, tumor volume and invasiveness when compared to the hemin-fed control group. The groups fed I3C or syn alone had a significant reduction in the number of preneoplastic aberrant crypt foci (ACF) lesions compared to the hemin-fed group. Dietary I3C also reduced fecal water genotoxicity. Gene expression analysis of colorectal tumors demonstrated that the combination of dietary I3C + syn increased transcript levels for Raf1 and decreased tumor progression and invasiveness related to the genes Cdh1 and Appl1. This analysis also revealed that the Tnf and Cdh1 genes were significantly up- and down-regulated, respectively, in tumors of rats that received I3C, in comparison with the hemin-fed group. These findings reveal that the joint administration of I3C and syn enhanced the development of colon tumors induced by DMH in hemin-fed rats, while they potentially reduced ACF development when given alone.
BACKGROUND: The diagnosis of early phase lung adenocarcinoma (LADC) is associated with therapeutic strategy, effect, and survival time. However, the sensitive biomarkers of early phase LADC are still unclear. This study aimed to identify protein-coding genes that can be used as biomarkers of early stage LADC.
METHODS: Gene microarray analysis was performed to identify key hub genes that show different expression in lung adenocarcinoma compared to normal tissues. The microarray data of lung adenocarcinoma in stages IA, IB, IIA, IIB, and normal tissues (GSE10072) were downloaded from a free online database, Gene Expression Omnibus (GEO).
RESULTS: A total of 572 differentially expressed genes (DEGs) were identified between early phase lung adenocarcinoma and normal tissues using R software. Database for Annotation, Visualization and Integrated Discovery online tools were used to obtain Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes was used to analyze DEGs. Cytoscape software was used to express the protein-protein interaction network. We found that some cancer-related Gene Ontology terms and pathways (e.g. cell adhesion, cell surface receptor signaling pathway, PI3K-Akt signaling pathway) were significantly enriched in DEGs.
CONCLUSION: Protein-coding genes JUN, FYN, CAV1, and SFN may play vital roles in the progress of early-stage lung adenocarcinoma. Consequently, through bioinformatics analysis, the key genes could be established to provide more potential references for the therapeutic targets of lung adenocarcinoma.
Sharif S, Ghahremani MH, Soleimani MInduction of morphological and functional differentiation of human neuroblastoma cells by miR-124.
J Biosci. 2017; 42(4):555-563 [PubMed
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Neuroblastoma is the most common extracranial solid tumour in children, and differentiation is considered its most appropriate therapy. In this work, we studied effects of miR-124 overexpression on differentiation in M17 cell line as a model of neuroblastoma cancer. Influence of miR-124 overexpression on differentiation in M17 cells was studied. M17 cells were infected with lentivirus that contained miR-124 precursor sequence and followed for 2 weeks to differentiate. Ectopic expression of miR-124 in M17 cells changed the shape of spherical undifferentiated cells to cells with extended neurites that formed neuronal networks. Overexpression of MiR-124 respectively increased the expression level of markers of β-Tubulin III, MAP2, SYN, NF-M and Nestin by 16-, 5-, 4-, 2.3- and 2-folds at the messenger RNA level. MiR-124 overexpression also increased the protein levels of β-Tubulin III and MAP2. Moreover, exogenous expression of miR-124 significantly increased the intracellular calcium in differentiated M17 cells. Since miR-124 is naturally expressed in neuronal cells and is downregulated in neuroblastoma cancer cells, differentiation with this type of microRNA can be a novel treatment for neuroblastoma cancer.
Zheng J, Li H, Xu D, Zhu HUpregulation of Tyrosine Kinase FYN in Human Thyroid Carcinoma: Role in Modulating Tumor Cell Proliferation, Invasion, and Migration.
Cancer Biother Radiopharm. 2017; 32(9):320-326 [PubMed
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Tyrosine kinase FYN-a member of the SRC family of kinases-is associated with mediating mitogenic signals and regulating cell cycle entry, growth, and proliferation. It was hypothesized that FYN is upregulated in thyroid carcinoma, which plays a critical role in tumorigenesis. FYN expression level in thyroid carcinoma tissue and tumor cell lines was determined. Also, the effects of FYN on thyroid cancer (TC) growth, signaling, cell cycle, and apoptosis were evaluated in vitro. FYN was knocked down in thyroid cancer cells (TPC-1) by siRNA to investigate the effects on cell proliferation, invasion, and migration. First, FYN was upregulated both in thyroid carcinoma tissue and in tumor cell lines. Loss of FYN by siRNA weakened proliferation, invasion, and migration of PTC-1 cells. Furthermore, it was demonstrated that knockdown of FYN can inhibit the G0/G1 phase of cell cycle. It was also observed that reduced expression of FYN could increase the level of NF-κB/P65 and IκBα. This study was the first to demonstrate critical positive regulation of thyroid tumorigenesis by FYN, which could be a potential target gene for thyroid carcinoma treatment. In addition, findings from this study highlighted the potential role of FYN inhibitors in TC therapy.