Gene Summary

Gene:CRK; CRK proto-oncogene, adaptor protein
Aliases: p38, CRKII
Summary:This gene encodes a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. The product of this gene has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of this protein functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:adapter molecule crk
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
Show (20)
Pathways:What pathways are this gene/protein implicaed in?
Show (6)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Proto-Oncogene Proteins c-crk
  • Breast Cancer
  • Tetradecanoylphorbol Acetate
  • Protein Structure, Tertiary
  • Up-Regulation
  • Amino Acid Sequence
  • Mutation
  • Neoplasm Proteins
  • Phosphoproteins
  • Antineoplastic Agents
  • Protein-Tyrosine Kinases
  • Retinoblastoma-Like Protein p130
  • Cell Proliferation
  • MicroRNAs
  • Messenger RNA
  • Drug Resistance
  • Immunohistochemistry
  • BCAR1
  • Lung Cancer
  • Chromosome 17
  • Molecular Sequence Data
  • Nuclear Proteins
  • Cell Adhesion
  • Phosphorylation
  • RNA Interference
  • Gene Expression Profiling
  • Down-Regulation
  • Protein Binding
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Proto-Oncogene Proteins
  • Fusion Proteins, bcr-abl
  • Proteins
  • Signal Transducing Adaptor Proteins
  • Cell Movement
  • Transfection
  • Apoptosis
  • Neoplasm Invasiveness
  • Tamoxifen
  • Non-Small Cell Lung Cancer
Tag cloud generated 11 March, 2017 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).

Latest Publications: CRK (cancer-related)

Nass N, Streit S, Wybranski C, et al.
Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro.
Anticancer Res. 2017; 37(1):87-93 [PubMed] Related Publications
As there is currently no superior hepatocellular carcinoma (HCC) model with percutaneous vascular access for transarterial treatments available, the VX2 rabbit model is frequently used for in vivo investigations on liver carcinoma. However, the VX2 cell line was derived from a virus-induced skin papilloma that can form carcinosarcoma in liver of rabbits and the transferability of obtained results to HCC treatment remains open. Here we compared the most frequently investigated human HCC model cell line, HepG2, with VX2 cells in vitro in terms of sensitivity towards the broad specificity kinase inhibitor sorafenib and responsiveness to the addition of platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF), as well as insulin and interleukin-1β (IL1β). Phosphorylation of protein kinase B (AKT) the mitogen-activated protein kinases (MAPKs) p38 and p42/44 (extracellular signal-regulated kinase, ERK1/2) and inhibitor of kappa light chain gene enhancer alpha (IĸBα) was determined by western blotting as these events are associated with early signaling cascades. Additionally, the inhibition of phosphorylation under sorafenib treatment was investigated. Sorafenib was equally toxic to both cell lines, but only in HepG2 was activation of caspase 3/7 activity, as a sign of apoptosis, observed. VX2 cells exhibited generally more intense phosphorylation signals in response to the growth factors and also serum. In contrast to VX2, HepG2 cells showed no response to PDGF-AB or VEGF as determined by kinase phosphorylation. In both cell lines, sorafenib inhibited growth factor-induced phosphorylation of ERK and p38-MAPK. AKT phosphorylation was only inhibited in VX2 cells and IĸBα phosphorylation was not influenced by this kinase inhibitor in either cell type. Taken together, the two cellular models for HCC share several features related to sorafenib application, but differed in their responsiveness towards growth factors. Therefore, results obtained with the VX2 model cannot be extended to human HCC without appropriate caution.

Lu E, Su J, Zhou Y, et al.
CCL20/CCR6 promotes cell proliferation and metastasis in laryngeal cancer by activating p38 pathway.
Biomed Pharmacother. 2017; 85:486-492 [PubMed] Related Publications
Chemokine and its receptors play important roles in laryngeal cancer development and progression. CCR6 is the receptor of CCL20 chemokine, but its function in laryngeal cancer is not known. The aim of this study is to explore the roles of CCR6 and its regulation mechanism in laryngeal cancer. We found CCR6 expression was higher in laryngeal cancer tissues compared with their normal controls, so did in laryngeal cancer cells. Cellular function indicated that down-regulation of CCR6 in laryngeal cancer cells could suppress cell proliferation and metastasis. Further research showed that CCR6 could activate p38, which was related with the changes of microRNA (miRNA) profile in laryngeal cancer cells. We also found that CCR6 was positively associated with miR-20a-5p, miR-489 and negatively related to miR-29-3p, miR-632 and miR-1276 in laryngeal cancer tissues.

Hsu CC, Chang WC, Hsu TI, et al.
Suberoylanilide hydroxamic acid represses glioma stem-like cells.
J Biomed Sci. 2016; 23(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.
METHODS: Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.
RESULTS: We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.
CONCLUSION: SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.

Demiroglu-Zergeroglu A, Candemir G, Turhanlar E, et al.
EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.
Biomed Pharmacother. 2016; 84:2000-2007 [PubMed] Related Publications
The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals.

Liu L, Xu Y, Reiter RJ, et al.
Inhibition of ERK1/2 Signaling Pathway is Involved in Melatonin's Antiproliferative Effect on Human MG-63 Osteosarcoma Cells.
Cell Physiol Biochem. 2016; 39(6):2297-2307 [PubMed] Related Publications
BACKGROUND: In a previous study, we found that melatonin inhibits MG-63 osteosarcoma cell proliferation; however, the underlying mechanisms remain elusive. Mitogen-activated protein kinase (MAPK) and Akt signaling pathways play key roles in the anticancer effects of melatonin.
AIMS: The present study investigated whether MAPK and Akt signaling pathways are involved in melatonin's antiproliferative actions on the human MG-63 osteosarcoma cells.
METHODS/RESULTS: Western blot analysis confirmed that melatonin significantly inhibited phosphorylation of ERK1/2 but not p38, JNK, or Akt. The expression of ERK1/2, p38, JNK, and Akt was not altered by melatonin. PD98059 and melatonin alone, and especially in combination, significantly inhibited cell proliferation. The changes included G1 and G2/M phase arrest of the cell cycle, and a downregulation of the expression at both the protein and mRNA levels of cyclin D1 and CDK4 (related to the G1 phase) and of cyclin B1 and CDK1 (related to the G2/M phase) as measured by flow cytometry after propidium iodide staining, and both western blot and real-time PCR, respectively. Furthermore, the combination of PD98059 and melatonin synergistically and markedly augmented the action of either agent alone. Co-immunoprecipitation further confirmed that there was an interaction between p-ERK1/2 and cyclin D1, CDK4, cyclin B1, or CDK1, which was blunted in the presence of melatonin or PD98059.
CONCLUSION: These findings suggest that melatonin's antiproliferative action is mediated by inhibition of the ERK1/2 signaling pathway rather than the p38, JNK, or Akt pathways.

Hsia TC, Yu CC, Hsiao YT, et al.
Cantharidin Impairs Cell Migration and Invasion of Human Lung Cancer NCI-H460 Cells via UPA and MAPK Signaling Pathways.
Anticancer Res. 2016; 36(11):5989-5997 [PubMed] Related Publications
Cantharidin (CTD), a component of natural mylabris (Mylabris phalerata Pallas), has been shown to have biological activities and induce cell death in many human cancer cells. In the present study, we investigated the effect of CTD on cell migration and invasion of NCI-H460 human lung cancer cells. Cell viability was examined and results indicated that CTD decreased the percentage of viable cells in dose-dependent manners. CTD inhibited cell migration and invasion in dose-dependent manners. Gelatin zymography analysis was used to measure the activities of matrix metalloproteinases (MMP-2/-9) and the results indicated that CTD inhibited the enzymatic activities of MMP-2/-9 of NCI-H460 cells. Western blotting was used to examine the protein expression of NCI-H460 cells after incubation with CTD and the results showed that CTD decreased the expression of MMP-2/-9, focal adhesion kinase (FAK), Ras homolog gene family, member A (Rho A), phospho-protein kinase B (AKT) (Thr308)(p-AKT(308)), phospho-extracellular signal-regulated kinase1/2 (p-ERK1/2), phospho-p38 mitogen-activated protein (MAP) kinase (p-p38), phospho c-Jun N-terminal kinase 1/2 (p-JNK1/2), nuclear factor-κB (NF-κB) and urokinase plasminogen activator (UPA). Furthermore, confocal laser microscopy was used to confirm that CTD suppressed the expression of NF-κB p65, but did not significantly affect protein kinase C (PKC) translocation in NCI-H460 cells. Based on those observations, we suggest that CTD may be used as a novel anticancer metastasis agent for lung cancer in the future.

Roh T, Kim SW, Moon SH, Nam MJ
Genistein induces apoptosis by down-regulating thioredoxin-1 in human hepatocellular carcinoma SNU-449 cells.
Food Chem Toxicol. 2016; 97:127-134 [PubMed] Related Publications
Genistein (GEN), a natural isoflavonoid phytoestrogen, has anti-cancer activity against various types of cancers. However, GEN has not been thoroughly investigated in human hepatocellular carcinoma cells. In this study, we evaluated the anti-cancer effects of GEN on SNU-449 cells. GEN inhibited the proliferation of SNU-449 cells in a concentration-dependent manner. We observed the typical characteristics of apoptosis, such as DNA fragmentation and caspase-3 activation. To identify proteins related to GEN-induced apoptosis, we performed two-dimensional electrophoresis and identified differentially expressed proteins. Proteomic analysis showed that the antioxidant protein thioredoxin-1 was associated with GEN-induced apoptosis. GEN treatment decreased thioredoxin-1 levels and increased intracellular accumulation of reactive oxygen species. In addition, GEN activated apoptosis signal-regulating kinase 1, c-Jun N-terminal kinases (JNK) and p38. We also observed that pretreatment with the JNK and p38 inhibitors (SP600125 and SB203580) decreased GEN-induced cell death. These results indicate that GEN has potential antitumor effects against SNU-449 cells through the down-regulation of thioredoxin-1.

Li A, Zhang W, Xia H, et al.
Overexpression of CASS4 promotes invasion in non-small cell lung cancer by activating the AKT signaling pathway and inhibiting E-cadherin expression.
Tumour Biol. 2016; 37(11):15157-15164 [PubMed] Related Publications
The role of Crk-associated substrate (CAS) family members in regulating invasion and metastasis has been described in several cancers. As the fourth member of the CAS family, CASS4 is also related with positive lymph node metastasis and poor prognosis in lung cancer. However, the underlying mechanisms and downstream effectors of CASS4 in the development and progression of non-small cell lung cancer (NSCLC) remain unclear. In this study, CASS4 overexpression inhibited E-cadherin expression and enhanced invasion in NSCLC cell line transfected with CASS4 plasmid, while CASS4 depletion upregulated E-cadherin expression and inhibited invasion in NSCLC cell line transfected with CASS4 siRNA. The effect of CASS4 overexpression in facilitating invasion of NSCLC cells was reversed by restoring E-cadherin expression, which indicates that CASS4 may promote invasion by inhibiting E-cadherin expression. Subsequent immunohistochemistry results confirmed that CASS4 overexpression correlated with loss of E-cadherin expression. We next investigated the phosphorylation levels of focal adhesion kinase (FAK), p38, extracellular signal-related kinase (ERK), and AKT after CASS4 plasmid or CASS4 siRNA transfection. CASS4 facilitated AKT (Ser473) phosphorylation. Treatment with an AKT phosphorylation inhibitor reversed the increased invasive capacity and downregulation of E-cadherin protein induced by CASS4 overexpression. Taken together, the present results indicate that CASS4 may promote NSCLC invasion by activating the AKT signaling pathway, thereby inhibiting E-cadherin expression.

Liu R, Wang G, Liu C, et al.
Gene expression profile analysis of dbpA knockdown in colorectal cancer cells.
Cell Biol Int. 2016; 40(12):1280-1293 [PubMed] Related Publications
DNA-binding protein A (dbpA) has been reported associated with the pathogenesis and development of various cancers. However, no evidence showed the gene expression profiling alternation involved in dbpA knockdown in colorectal cancer (CRC) cells. Small interference RNA (siRNA) method was used to knock down dbpA expression in SW620 cells. The changes of gene expression profiles in dbpA knockdown SW620 cells were determined by microarray analysis and Western blot. A total of 578 genes expressed differentially (twofold change), 181 genes were up-regulated, and 397 down-regulated in the dbpA knockdown group in comparison with the control group. The discrimination reliability was further verified by principal component analysis and Pearson correlation. Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to MAPK signaling pathway. Furthermore, Western blot verified that dbpA knockdown directly inhibited the activations of TAK1, p38, and JNK in CRC cells. In conclusion, dbpA knockdown in SW620 cells altered the expression of carcinogenesis-associated genes in CRC and the involvement of dbpA on CRC might through MAPK signaling pathway, which might provide valuable evidence to further investigate the correlation between dbpA expression and CRC development.

Li Y, Huang S, Li Y, et al.
Decreased expression of LncRNA SLC25A25-AS1 promotes proliferation, chemoresistance, and EMT in colorectal cancer cells.
Tumour Biol. 2016; 37(10):14205-14215 [PubMed] Related Publications
Increasing evidence suggests that long non-coding RNAs (lncRNAs) are aberrantly expressed in colorectal cancer (CRC); however, only few CRC-related lncRNAs have been characterized. In this study, we aimed to dig out potential dysregulated lncRNAs that are highly involved in CRC development. Using a lncRNA-mining approach, we performed lncRNA expression profiling in a large CRC cohort from Gene Expression Ominus (GEO), GSE39582 test series (N = 585). We identified 31 downregulated lncRNAs and 16 upregulated lncRNAs from the GSE39582 test series patients (566 tumor patients and 19 normal controls). The reliability of lncRNA expression profiles was further confirmed by RT-qPCR in carcinoma tissues and paired adjacent normal tissues from 30 CRC patients, also in the serum from 109 CRC patients, and 99 normal individuals. We demonstrated that the expression of SLC25A25-AS1, which has not been reported previously, was significantly decreased in both the tumor tissues (27 out of 30) and serum of CRC patients. SLC25A25-AS1 overexpression significantly inhibited proliferation and colony formation in colorectal cancer cell lines, and downregulation of SLC25A25-AS1 obviously enhanced chemoresistance and promoted EMT process in vitro associated with Erk and p38 signaling pathway activation. Therefore, SLC25A25-AS1 was determined to play a tumor suppressive role in CRC. Our results might provide a lncRNA-based target for CRC treatment.

Luo F, Shi J, Shi Q, et al.
Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy.
Cell Physiol Biochem. 2016; 39(3):1051-67 [PubMed] Related Publications
Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma.

Osama A, Sabry D, Hassany SM, et al.
SIRT-1expression is associated with expression of NANOG in patients with colorectal adenocarcinoma.
Cancer Biomark. 2016; 17(2):155-63 [PubMed] Related Publications
AIMS: The study aimed to investigate the quantitative expression of NANOG, p38 α , NCF2, ELF and TGF-β genes in patients with colorectal adenocarcinoma, adenoma and normal colonic tissue and their correlation with SIRT-1 protein level expression.
METHOD: This study enrolled one hundred sixty seven patients; group A: 87 patients with colonoscopic findings of no adenoma or adenocarcinoma and group B: 80 patients with colorectal mass. Consecutive colonoscopic examinations were conducted, and tissue samples were taken from the colonic lesions/masses. Total RNA was isolated and mRNA expression level of NANOG, mitogen activated p38α , Neutrophil Cytosol Factor 2 (NCF2), Embryonic Liver Fodrin (ELF) and Transforming Growth Factor Beta (TGF-β) genes were quantified by qRT-PCR. Sirt-1 protein expression level was assessed by quantitative western blot.
RESULTS: There were significantly high level of mRNA transcripts expression of the genes studied in patients with adenocarcinoma and adenoma compared with normal tissue (P value < 0.01), NANOG, NCF2, ELF and TGF-β at a cut of > 0.314, > 0.392, 0.349 and 0.333 respectively showed sensitivity (96.5%, 98.8%, 95.3%, 98.8%) and specificity of (95.3%, 92.6%, 89.5%, 93.8%) respectively in diagnosing colonic adenocarcinoma. Sirt-1 protein level was significantly highly expressed in colorectal adenocarcinoma compared to normal and adenoma colonic tissue and positively correlated with NANOG.
CONCLUSION: Over expression of NANOG, p38α , NCF2, ELF and TGF-β genes in both cases of adenocarcinoma and adenoma could have a diagnostic value. SIRT-1 and NANOG are high correlated biological markers for diagnosis and prognosis follow up in patients with adenocarcinoma.

Lee SI, Bae JA, Ko YS, et al.
Geijigajakyak decoction inhibits the motility and tumorigenesis of colorectal cancer cells.
BMC Complement Altern Med. 2016; 16(1):288 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies report that inflammatory diseases of the large intestine are associated with colorectal cancer. Geijigajakyak Decoction (GJD) has antispasmodic and anti-inflammatory effects on the gastrointestinal tract. Thus, in light of the connection between chronic bowel inflammation and colorectal cancer (CRC), we asked whether GJD inhibits colorectal tumorigenesis.
METHODS: The effects of GJD on the viability and proliferation of CRC cells were evaluated using MTT and BrdU assays, respectively. The motility of CRC cells was examined by a Transwell migration/invasion assay and immunoblot analysis was used to examine the signaling pathways associated with migration. A syngeneic Balb/c mice allograft model, in which CT26 cells were injected into the dorsum, was used to evaluate the anti-tumor effects of GJD in vivo.
RESULTS: GJD had no cytotoxic effects against HCT116 CRC cells, although it did inhibit their proliferation. GJD inhibited the migration of HCT116 cells, and suppressed the invasion of HCT116, Caco2, and CSC221 CRC cells. In addition, GJD downregulated the expression of p-JNK and p-p38 MAPK, which are downstream signaling molecules associated with invasiveness. Furthermore, oral administration of GJD (333 mg/kg, twice a day) inhibited tumor growth in a mouse xenograft model.
CONCLUSIONS: GJD inhibited the motility of human CRC cells and suppressed tumorigenesis in a mouse model. These results suggest that GJD warrants further study as a potential adjuvant anti-cancer therapy.

Demiroglu-Zergeroglu A, Ergene E, Ayvali N, et al.
Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells.
BMC Complement Altern Med. 2016; 16(1):281 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Malignant mesothelioma is a locally aggressive and highly lethal neoplasm of pleural, peritoneal and pericardial mesothelial cells without successful therapy. Previously, we reported that Quercetin in combination with Cisplatin inhibits cell proliferation and activates caspase-9 and -3 enzymes in different malignant mesothelioma cell lines. Moreover, Quercetin + Cisplatin lead to accumulation of both SPC111 and SPC212 cell lines in S phase.
METHODS: In present work, 84 genes involved in cell growth and proliferation have analysed by using RT(2)-PCR array system and protein profile of mitogen activated protein kinase (MAPK) family proteins investigated by western blots.
RESULTS: Our results showed that Quercetin and Quercetin + Cisplatin modulated gene expression of cyclins, cyclin dependent kinases and cyclin dependent kinases inhibitors. In addition genes involved in JNK, p38 and MAPK/ERK pathways were up regulated. Moreover, while p38 and JNK phosphorylations were increased, ERK phosphorylations were decreased after using Quercetin + Cisplatin.
CONCLUSION: This research has clarified our previous results and detailed mechanism of anti-carcinogenic potential of Quercetin alone and incombination with Cisplatin on malignant mesothelioma cells.

Shin SS, Park SS, Hwang B, et al.
MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression.
Oncol Rep. 2016; 36(4):2421-9 [PubMed] Related Publications
Despite the clinical significance of tumorigenesis, little is known about the cellular signaling networks of microRNAs (miRs). Here we report a new finding that mir‑106a regulates the proliferation, migration, and invasion of bladder cancer cells. Basal expression levels of mir‑106a were significantly lower in bladder cancer cells than in normal urothelial cells. Overexpression of mir‑106a suppressed the proliferation of bladder cancer cell line EJ. Transient transfection of mir‑106a into EJ cells led to downregulation of ERK phosphorylation and upregulation of p38 and JNK phosphorylation over their levels in the control. Flow cytometry analysis revealed that mir‑106a-transfected cells accumulated in the G1-phase of the cell cycle, and cyclin D1 and CDK6 were significantly downregulated. This G1-phase cell cycle arrest was due in part to the upregulation of p21CIP1/WAF1. In addition, mir‑106a overexpression blocked the wound-healing migration and invasion of EJ cells. Furthermore, mir‑106a transfection resulted in decreased expression of MMP-2 and diminished binding activity of transcription factor Ets-1 in EJ cells. Collectively, we report the novel mir‑106a-mediated molecular signaling networks that regulate the proliferation, migration, and invasion of bladder cancer cells, suggesting that mir‑106a may be a therapeutic target for treating advanced bladder tumors.

Xiao YF, Li JM, Wang SM, et al.
Cerium oxide nanoparticles inhibit the migration and proliferation of gastric cancer by increasing DHX15 expression.
Int J Nanomedicine. 2016; 11:3023-34 [PubMed] Free Access to Full Article Related Publications
Gastric cancer is one of the leading causes of tumor-related deaths in the world. Current treatment options do not satisfy doctors and patients, and new therapies are therefore needed. Cerium oxide nanoparticles (CNPs) have been studied as a potential therapeutic approach for treating many diseases. However, their effects on human gastric cancer are currently unknown. Therefore, in this study, we aimed to characterize the effects of CNPs on human gastric cancer cell lines (MKN28 and BGC823). Gastric cancer cells were cocultured with different concentrations of CNPs, and proliferation and migration were measured both in vitro and in vivo. We found that CNPs inhibited the migration of gastric cancer cells when applied at different concentrations, but only a relatively high concentration (10 µg/mL) of CNPs suppressed proliferation. Furthermore, we found that CNPs increased the expression of DHX15 and its downstream signaling pathways. We therefore provide evidence showing that CNPs may be a promising approach to suppress malignant activity of gastric cancer by increasing the expression of DHX15.

Li J, Liu C, Sato T
Novel Antitumor Invasive Actions of p-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells.
Biol Pharm Bull. 2016; 39(8):1247-53 [PubMed] Related Publications
p-Cymene (4-isopropyltoluene) has been reported to have beneficial actions such as anti-inflammatory and antinociceptive activities. To evaluate whether p-cymene exhibits antitumor invasive actions, we examined the effects of p-cymene on the production of matrix metalloproteinase 9 (MMP-9)/gelatinase B and tissue inhibitor of metalloproteinases-1 (TIMP-1) in human fibrosarcoma HT-1080 cells. p-Cymene was found to dose-dependently inhibit the 12-O-tetradecanoylphorbol 13-acetate (TPA)-augmented production and gene expression of MMP-9 in HT-1080 cells. In contrast, p-cymene enhanced the TPA-augmented production and gene expression of TIMP-1 in HT-1080 cells. However, there was no change in the constitutive level of MMP-9 and TIMP-1 mRNAs and TIMP-1 protein in p-cymene-treated cells. In addition, we found that the in-vitro TPA-augmented invasiveness of HT-1080 cells was inhibited by p-cymene in a dose-dependent manner. Furthermore, p-cymene was found to suppress the constitutive and/or TPA-augmented phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) in HT-1080 cells. Thus, these results provide novel evidence that p-cymene is an effective candidate for the prevention of tumor invasion and metastasis through mechanisms that include the inhibition of MMP-9 expression and the augmentation of TIMP-1 production along with the suppression of ERK1/2 and p38 MAPK signal pathways in tumor cells.

Guzmán-Rodríguez JJ, López-Gómez R, Salgado-Garciglia R, et al.
The defensin from avocado (Persea americana var. drymifolia) PaDef induces apoptosis in the human breast cancer cell line MCF-7.
Biomed Pharmacother. 2016; 82:620-7 [PubMed] Related Publications
Antimicrobial peptides (AMPs) are cytotoxic to cancer cells; however, mainly the effects of AMPs from animals have been evaluated. In this work, we assessed the cytotoxicity of PaDef defensin from avocado (Persea americana var. drymifolia) on the MCF-7 cancer cell line (a breast cancer cell line) and evaluated its mechanism of action. PaDef inhibited the viability of MCF-7 cells in a concentration-dependent manner, with an IC50=141.62μg/ml. The viability of normal peripheral blood mononuclear cells was unaffected by this AMP. Additionally, PaDef induced apoptosis in MCF-7 cells in a time-dependent manner, but did not affect the membrane potential or calcium flow. In addition, PaDef IC50 induced the expression of cytochrome c, Apaf-1, and the caspase 7 and 9 genes. Likewise, this defensin induced the loss of mitochondrial Δψm and increased the phosphorylation of MAPK p38, which may lead to MCF-7 apoptosis by the intrinsic pathway. This is the first report of an avocado defensin inducing intrinsic apoptosis in cancer cells, which suggests that it could be a potential therapeutic molecule in the treatment of cancer.

Chai R, Yu X, Tu S, Zheng B
Depletion of UBA protein 2-like protein inhibits growth and induces apoptosis of human colorectal carcinoma cells.
Tumour Biol. 2016; 37(10):13225-13235 [PubMed] Related Publications
Ubiquitin-proteasome system regulates cell proliferation, apoptosis, angiogenesis, and motility, which are processes with particular importance for carcinogenesis. UBA protein 2-like protein (UBAP2L) was found to be associated with proteasome; however, its biological function is largely unknown. In this study, the mRNA levels of UBAP2L in human normal and colorectal carcinoma tissues were analyzed using the datasets from the publicly available Oncomine database ( ) and found UBAP2L was overexpressed in colorectal carcinoma tissues. Furthermore, we elucidated the role of UBAP2L in human colorectal cancer via an RNA interference lentivirus system in three colorectal carcinoma cell lines HCT116, SW1116, and RKO. Knockdown of UBAP2L led to suppressed cell proliferation and impaired colony formation. UBAP2L depletion in HCT116 and RKO cells also induced cell cycle arrest as well as apoptosis. Moreover, the phosphorylation of PRAS40, Bad, and the cleavage of PARP were remarkably increased after UBAP2L knockdown by Intracellular signaling array and also the activation of P38 was obviously decreased and the cleavage of Caspase 3 and Bax were increased after UBAP2L silencing by western blot assay, indicated that UBAP2L might be involved in the cell growth by the regulation of apoptosis-related proteins. Our findings indicated that UBAP2L may be essential for colorectal carcinoma growth and survival. Lentivirus-mediated small interfering RNA against UBAP2L might serve as a potential therapeutic approach for the treatment of colorectal cancer.

Liu C, Wu HT, Zhu N, et al.
Steroid receptor RNA activator: Biologic function and role in disease.
Clin Chim Acta. 2016; 459:137-46 [PubMed] Related Publications
Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.

Yang GY, Zhang AQ, Wang J, et al.
Hepatoma-derived growth factor promotes growth and metastasis of hepatocellular carcinoma cells.
Cell Biochem Funct. 2016; 34(4):274-85 [PubMed] Related Publications
We aimed to elucidate the effects of hepatoma-derived growth factor (HDGF) on growth and metastasis of hepatocellular carcinoma (HCC) cells. Tissue microarrays with 236 HCC specimens and 18 extrahepatic metastases were utilized to detect the HDGF expression by immunohistochemistry. Meanwhile, HDGF expressions in HCC cell lines with different metastatic potentials were examined using immunofluorescence staining, real-time PCR and western blotting. After HDGF silencing, the growth and metastatic potentials of HCC cells were evaluated by soft agar assay, invasion assay, together with tumorigenicity assay in nude mice. The gelatin zymography was performed by detecting MMP-2 and MMP-9 levels. Additionally, western blotting was conducted to determine the levels of total and phosphorylated ERK1/2, JNK, p38 and Akt. The results showed that HDGF was overexpressed in HCC metastasis tumour, and the expression increased with the differentiation degree of tumours (Grade I 44.0%, Grade II 48.4% and Grade III 65.6%). Consistently, HDGF levels were positively associated with the metastatic capability of HCC cells (MHCC97L < MHCC97H < HCCLM3). The growth and metastasis were suppressed by HDGF-siRNA. Gelatinolytic activities were enhanced in the three metastatic HCC cell lines, but had no significant difference among them. The tumourigenicity and metastatic capability of HCCLM3 cells in nude mice were inhibited after silencing HDGF. Meanwhile, HDGF-siRNA specifically suppressed the total and phosphorylated protein levels of ERK1/2, while not JNK, p38 and Akt. In conclusion, HDGF was overexpressed in HCC patients and cells, and HDGF might be closely correlated with HCC metastasis via regulating ERK signalling pathway. Copyright © 2016 John Wiley & Sons, Ltd.

Castro Aceituno V, Ahn S, Simu SY, et al.
Silver nanoparticles from Dendropanax morbifera Léveille inhibit cell migration, induce apoptosis, and increase generation of reactive oxygen species in A549 lung cancer cells.
In Vitro Cell Dev Biol Anim. 2016; 52(10):1012-1019 [PubMed] Related Publications
Green synthesized silver nanoparticles have significant potential in the pharmaceutical field because of their biological functions such as antioxidant and anticancer activities. Novel silver nanoparticles synthesized from Dendropanax morbifera Léveille leaves (D-AgNPs) exhibit antimicrobial activity and reduce the viability of cancer cells without affecting the viability of RAW 264.7 macrophage-like cells. In this study, we evaluated the anticancer effect of D-AgNPs by measuring the levels of reactive oxygen species (ROS) production and toxicity against A549 and HepG2 cell lines. The effect of D-AgNPs on cell migration, induction of apoptosis, and modification of gene and/or protein expression of cancer-related markers was determined using A549 cells. D-AgNPs exhibited cytotoxicity in A549 and HepG2 cell at different concentrations and enhanced the production of ROS in both cell lines. An increase in cell apoptosis and a reduction in cell migration in A549 cells were also observed after D-AgNP treatment. Furthermore, the effect of D-AgNPs in A549 cells was shown to be related to modification of the EGFR/p38 MAPK pathway. Our data provide the first evidence supporting the potential of D-AgNPs as a possible anticancer agent, particularly for the treatment of non-small cell lung carcinoma.

Wu CF, Bohnert S, Thines E, Efferth T
Cytotoxicity of Salvia miltiorrhiza Against Multidrug-Resistant Cancer Cells.
Am J Chin Med. 2016; 44(4):871-94 [PubMed] Related Publications
Salvia miltiorrhiza Bunge (Lamiaceae) is a well-known Chinese herb that possesses numerous therapeutic activities, including anticancer effects. In this study, the cytotoxicity and the biological mechanisms of S. miltiorrhiza (SM) root extract on diverse resistant and sensitive cancer cell lines were investigated. CEM/ADR5000 cells were 1.68-fold resistant to CCRF-CEM cells, while HCT116 (p53[Formula: see text] and U87.MG[Formula: see text]EGFR cells were hypersensitive (collateral sensitive) compared to their parental cells. SM root extract stimulated ROS generation, cell cycle S phase arrest and apoptosis. The induction of the intrinsic apoptotic pathway was validated by increased cleavage of caspase 3, 7, 9 and poly ADP-ribose polymerase (PARP). MAP kinases including JNK, ERK1/2 and p38 were obviously phosphorylated and nuclear P65 was downregulated upon SM treatment. Transcriptome-wide COMPARE analysis revealed that the expression of encoding genes with diverse functions were associated with the cellular response to cryptotanshinone, one of the main constituents of SM root extract. In conclusion, SM root extract exerted profound cytotoxicity towards various sensitive and resistant cancer cells and induced the intrinsic apoptotic pathway.

Ribeiro JR, Schorl C, Yano N, et al.
HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells.
J Ovarian Res. 2016; 9(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemotherapy resistance presents a difficult challenge in treating epithelial ovarian cancer patients, particularly when tumors exhibit resistance to multiple chemotherapeutic agents. A few studies have shown that elevated serum levels of the ovarian cancer biomarker HE4 correlate with tumor chemoresistance, response to treatment, and survival. Here, we sought to confirm our previous results that HE4 contributes to collateral resistance to cisplatin and paclitaxel in vitro and uncover factors that may contribute to HE4-mediated chemoresistance.
METHODS: MTS assays and western blots for cleaved PARP were used to assess resistance of HE4-overexpressing SKOV3 and OVCAR8 clones to cisplatin and paclitaxel. CRISPR/Cas technology was used to knockdown HE4 in HE4-overexpressing SKOV3 cells. A microarray was conducted to determine differential gene expression between SKOV3 null vector-transfected and HE4-overexpressing clones upon cisplatin exposure, and results were validated by quantitative RT-PCR. Regulation of mitogen activated protein kinases (MAPKs) and tubulins were assessed by western blot.
RESULTS: HE4-overexpressing SKOV3 and OVCAR8 clones displayed increased resistance to cisplatin and paclitaxel. Knockdown of HE4 in HE4-overexpressing SKOV3 cells partially reversed chemoresistance. Microarray analysis revealed that HE4 overexpression resulted in suppression of cisplatin-mediated upregulation of EGR1, a MAPK-regulated gene involved in promoting apoptosis. Upregulation of p38, a MAPK activated in response to cisplatin, was suppressed in HE4-overexpressing clones. No differences in extracellular signal-regulated kinase (ERK) activation were noted in HE4-overexpressing clones treated with 25 μM cisplatin, but ERK activation was partially suppressed in HE4-overexpressing clones treated with 80 μM cisplatin. Furthermore, treatment of cells with recombinant HE4 dramatically affected ERK activation in SKOV3 and OVCAR8 wild type cells. Recombinant HE4 also upregulated α-tubulin and β-tubulin levels in SKOV3 and OVCAR8 cells, and microtubule associated protein tau (MAPT) gene expression was increased in SKOV3 HE4-overexpressing clones.
CONCLUSIONS: Overexpression of HE4 promotes collateral resistance to cisplatin and paclitaxel, and downregulation of HE4 partially reverses this chemoresistance. Multiple factors could be involved in HE4-mediated chemoresistance, including deregulation of MAPK signaling, as well as alterations in tubulin levels or stability.

Thanee M, Loilome W, Techasen A, et al.
CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment.
Cancer Sci. 2016; 107(7):991-1000 [PubMed] Free Access to Full Article Related Publications
Expression of CD44, especially the variant isoforms (CD44v) of this major cancer stem cell marker, contributes to reactive oxygen species (ROS) defense through stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38(MAPK) (a major ROS target) expression in Opisthorchis viverrini-induced hamster CCA tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho-p38(MAPK) signal, whereas the CD44v signal was increased during bile duct transformation. Patients with CCA showed CD44v overexpression and negative-phospho-p38(MAPK) patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38(MAPK) patients (P = 0.030). Knockdown of CD44 showed that xCT and glutathione levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v cancer stem cell therapy using sulfasalazine. Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38(MAPK) in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug (e.g. gemcitabine) by blocking the mechanism of the cell's ROS defensive system.

Wang Y, Dong X, Hu B, et al.
The effects of Micro-429 on inhibition of cervical cancer cells through targeting ZEB1 and CRKL.
Biomed Pharmacother. 2016; 80:311-21 [PubMed] Related Publications
MicroRNA-429 (miR-429) has been suggested to inhibit epithelial-mesenchymal transition (EMT), mainly due to targeting of ZEB1 and ZEB2, which are repressors of the cell to cell contact protein, E-cadherin. In this study, we indicated that regulation of miR-429 in cervical cancer cells modulates cell migration, elongation, as well as transforming growth factor β (TGF-β)-induced stress fiber formation through regulating the cytoskeleton reorganization which is likely independent of the zinc finger E-box binding homeobox (ZEB)/E-cadherin axis. ZEB1 and Crk-like adapter protein (CRKL), as novel targets of miR-429 and direct regulators of the actin cytoskeleton were identified. Remarkably, expression levels of ZEB1 and CRKL were inversely associated with the level of miR-429 in cervical cancer cell lines. In addition, individual knockdown and over-expression of these targeting genes phenocopied the roles of miR-429 over-expression and inhibition on cell elongation, migration, stress fiber formation, and invasion. Targeting of ZEB1 by miR-429 led to a decreased expression and transcriptional activity of CRB3, regulated by interference with the translocation of the CRB3. This finally led to decreasing of the expression of Crumbs 3 (CRB3), which is needed for the formation of stress fiber and contractility. Therefore, miR-429 affects cervical cancer by modulating some EMT-related processes. And in this study, evidences were provided to support a role for miR-429 as a novel target suppressing invasion and migration of human cervical cancer cells through modulation of its targeting genes ZEB1 and CRKL. Taken together, our data indicate that miR-429 plays a pivotal role in cervical cancer progression, which is a potential therapeutic target for patients.

Wang Y, Ren T, Zheng L, et al.
Astragalus saponins Inhibits Lipopolysaccharide-Induced Inflammation in Mouse Macrophages.
Am J Chin Med. 2016; 44(3):579-93 [PubMed] Related Publications
Excessive nitric oxide (NO) and pro-inflammatory cytokines are produced during the pathogenesis of inflammatory diseases and cancer. It has been demonstrated that anti-inflammation contributes Astragalus membranaceus saponins (AST)'s beneficial effects in combination of conventional anticancer drugs. However, the immunomodulating property of AST has not been well characterized. In this study, we found that AST suppressed lipopolysaccharide (LPS)-induced generation of NO without causing cytotoxicity in the mouse macrophage RAW264.7. The gene and protein overexpression of inducible NO synthase (iNOS) as well as the production of tumor necrosis factor-[Formula: see text], evoked by LPS, was consistently down-regulated by AST. AST also inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and suppressed nuclear factor (NF)-[Formula: see text]B activation and the associated I[Formula: see text]B[Formula: see text] degradation during LPS insult. Furthermore, AST induced growth inhibition in promyelocytic leukemic HL-60 cells and T-lymphocyte leukemic Jurkat cells, but exerted no cytotoxic effects in normal human peripheral blood mononuclear cells (PBMC). It is known that the chemotherapeutic drug 5-FU can suppress the immune system, which can be identified by a reduced white blood cell count and decreased hematocrit, while the combination of AST and 5-FU can reverse the above hematologic toxicities. To summarize, non-cytotoxic concentrations of AST suppress LPS-induced inflammatory responses via the modulation of p38 MAPK signaling and the inhibition of NO and cytokine release. Importantly, AST can alleviate the hematologic side effects of current chemotherapeutic agents. These findings can facilitate the establishment of AST in the treatment of inflammatory diseases and inflammation-mediated tumor development.

Pekarčíková L, Knopfová L, Beneš P, Šmarda J
c-Myb regulates NOX1/p38 to control survival of colorectal carcinoma cells.
Cell Signal. 2016; 28(8):924-36 [PubMed] Related Publications
The c-Myb transcription factor is important for maintenance of immature cells of many tissues including colon epithelium. Overexpression of c-Myb occurring in colorectal carcinomas (CRC) as well as in other cancers often marks poor prognosis. However, the molecular mechanism explaining how c-Myb contributes to progression of CRC has not been fully elucidated. To address this point, we investigated the way how c-Myb affects sensitivity of CRC cells to anticancer drugs. Using CRC cell lines expressing exogenous c-myb we show that c-Myb protects CRC cells from the cisplatin-, oxaliplatin-, and doxorubicin-induced apoptosis, elevates reactive oxygen species via up-regulation of NOX1, and sustains the pro-survival p38 MAPK pathway. Using pharmacological inhibitors and gene silencing of p38 and NOX1 we found that these proteins are essential for the protective effect of c-Myb and that NOX1 acts upstream of p38 activation. In addition, our result suggests that transcription of NOX1 is directly controlled by c-Myb and these genes are strongly co-expressed in human tumor tissue of CRC patients. The novel c-Myb/NOX1/p38 signaling axis that protects CRC cells from chemotherapy described in this study could provide a new base for design of future therapies of CRC.

Perez-Escuredo J, Lopez-Hernandez A, Costales M, et al.
Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma.
Rhinology. 2016; 54(3):278-86 [PubMed] Related Publications
BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC.
MATERIAL AND METHODS: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome.
RESULTS: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome.
CONCLUSION: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

Chuang WL, Lin PY, Lin HC, Chen YL
The Apoptotic Effect of Ursolic Acid on SK-Hep-1 Cells is Regulated by the PI3K/Akt, p38 and JNK MAPK Signaling Pathways.
Molecules. 2016; 21(4):460 [PubMed] Related Publications
Ursolic acid (UA) is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.

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