Research IndicatorsGraph generated 27 August 2015 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 27 August, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
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
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: KRT18 (cancer-related)
Cancers exhibit abnormal molecular signatures associated with disease initiation and progression. Molecular signatures could improve cancer screening, detection, drug development and selection of appropriate drug therapies for individual patients. Typically only very small amounts of tissue are available from patients for analysis and biopsy samples exhibit broad heterogeneity that cannot be captured using a single marker. This report details application of an in-house custom designed GenomeLab System multiplex gene expression assay, the hCellMarkerPlex, to assess predictive gene signatures of normal, adenomatous polyp and carcinoma colon tissue using archived tissue bank material. The hCellMarkerPlex incorporates twenty-one gene markers: epithelial (EZR, KRT18, NOX1, SLC9A2), proliferation (PCNA, CCND1, MS4A12), differentiation (B4GANLT2, CDX1, CDX2), apoptotic (CASP3, NOX1, NTN1), fibroblast (FSP1, COL1A1), structural (ACTG2, CNN1, DES), gene transcription (HDAC1), stem cell (LGR5), endothelial (VWF) and mucin production (MUC2). Gene signatures distinguished normal, adenomatous polyp and carcinoma. Individual gene targets significantly contributing to molecular tissue types, classifier genes, were further characterised using real-time PCR, in-situ hybridisation and immunohistochemistry revealing aberrant epithelial expression of MS4A12, LGR5 CDX2, NOX1 and SLC9A2 prior to development of carcinoma. Identified gene signatures identify aberrant epithelial expression of genes prior to cancer development using in-house custom designed gene expression multiplex assays. This approach may be used to assist in objective classification of disease initiation, staging, progression and therapeutic responses using biopsy material.
The eukaryotic cell cycle is controlled by a complex regulatory network, which is still poorly understood. Here we demonstrate that TRPS1, an atypical GATA factor, modulates cell proliferation and controls cell cycle progression. Silencing TRPS1 had a differential effect on the expression of nine key cell cycle-related genes. Eight of these genes are known to be involved in the regulation of the G2 phase and the G2/M transition of the cell cycle. Using cell synchronization studies, we confirmed that TRPS1 plays an important role in the control of cells in these phases of the cell cycle. We also show that silencing TRPS1 controls the expression of 53BP1, but not TP53. TRPS1 silencing also decreases the expression of two histone deacetylases, HDAC2 and HDAC4, as well as the overall HDAC activity in the cells, and leads to the subsequent increase in the acetylation of histone4 K16 but not of histone3 K9 or K18. Finally, we demonstrate that TRPS1 expression is elevated in luminal breast cancer cells and luminal breast cancer tissues as compared with other breast cancer subtypes. Overall, our study proposes that TRPS1 acts as a central hub in the control of cell cycle and proliferation during cancer development.
Early growth response 1 (EGR1) is a multifunctional transcription factor; Positive and negative functions of EGR1 in various tumors rely on the integrated functions of various genes it regulates. In this study, we observed the role of EGR1 in non-small-cell lung carcinoma (NSCLC) and identified genes that influence cell fate and tumor development. Various assays showed that EGR1 arrested cell mobility, inhibited migration, and induced apoptosis. Microarray analysis revealed that 100 genes, including CDKN1C, CDC27 and PRKDC, changed their mRNA expressions with the increase of EGR1 and contributed to intervention of tumor progression. Bioinformatics analysis and promoter analysis indicated that an EGR1 binding site was situated in the promoter of KRT18 (also named CK18) and KRT18 could assist in inhibition of NSCLC development. The expression level of EGR1 and KRT18 in NSCLC clinical cases was investigated by immunohistochemistry, in which the protein expression of KRT18 was found to be significantly associated with EGR1 and lymph node metastasis. The results collectively confirm that EGR1 functions as a tumor suppressor in NSCLC. This study is the first to report KRT18 expression is directly regulated by EGR1, and contributes to decrease malignancy of NSCLC.
Liao Y, Guo S, Chen Y, et al.VSIG4 expression on macrophages facilitates lung cancer development.
Lab Invest. 2014; 94(7):706-15 [PubMed
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Tumor-associated macrophages are a prominent component of lung cancer stroma and contribute to tumor progression. The protein V-set and Ig domain-containing 4 (VSIG4), a novel B7 family-related macrophage protein that has the capacity to inhibit T-cell activation, has a potential role in the development of lung cancer. In this study, 10 human non-small-cell lung cancer specimens were collected and immunohistochemically analyzed for VSIG4 expression. Results showed massive VSIG4(+) cell infiltration throughout the samples. Immunofluorescent double staining showed that VSIG4 was present on CD68(+) macrophages, but absent from CD3(+) T cells, CD31(+) endothelial cells, and CK-18(+) epithelial cells. Moreover, VSIG4 was coexpressed on B7-H1(+) and B7-H3(+) cells in these tumor specimens. Transfection of the VSIG4 gene into 293FT cells demonstrated that the VSIG4 signal could inhibit cocultured CD4(+) and CD8(+) T-cell proliferation and cytokine (IL-2 and IFN-γ) production in vitro. Interestingly, in a murine tumor model induced by Lewis lung carcinoma cell line, we found that tumors grown in VSIG4-deficient (VSIG4(-/-)) mice were significantly smaller than those found in wild-type littermates. All of these results demonstrate that macrophage-associated VSIG4 is an activator that facilitates lung carcinoma development. Specific targeting of VSIG4 may prove to be a novel, efficacious strategy for the treatment of this carcinoma.
To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.
Zhou X, Hu Y, Dai L, et al.MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer.
PLoS One. 2014; 9(5):e96718 [PubMed
] Free Access to Full Article Related Publications
Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention.
Liao XH, Wang Y, Wang N, et al.Human chorionic gonadotropin decreases human breast cancer cell proliferation and promotes differentiation.
IUBMB Life. 2014; 66(5):352-60 [PubMed
] Related Publications
Human chorionic gonadotropin (hCG) is a glycoprotein produced by placental trophoblasts. Previous studies indicated that hCG could be responsible for the pregnancy-induced protection against breast cancer in women. It is reported that hCG decreases proliferation and invasion of breast cancer MCF-7 cells. Our research also demonstrates that hCG can reduce the proliferation of MCF-7 cells by downregulating the expression of proliferation markers, proliferating cell nuclear antigen (PCNA), and proliferation-related Ki-67 antigen (Ki-67). Interestingly, we find here that hCG elevates the state of cellular differentiation, as characterized by the upregulation of differentiation markers, β-casein, cytokeratin-18 (CK-18), and E-cadherin. Inhibition of hCG secretion or luteinizing hormone/hCG receptors (LH/hCGRs) synthesis can weaken the effect of hCG on the induction of cell differentiation. Furthermore, hCG can suppress the expression of estrogen receptor alpha. hCG activated receptor-mediated cyclic adenosine monophosphate/protein kinase A signaling pathway. These findings indicated that a protective effect of hCG against breast cancer may be associated with its growth inhibitory and differentiation induction function in breast cancer cells.
BACKGROUND: Oestrogen receptor (ER) positive (luminal) tumours account for the largest proportion of females with breast cancer. Theirs is a heterogeneous disease presenting clinical challenges in managing their treatment. Three main biological luminal groups have been identified but clinically these can be distilled into two prognostic groups in which Luminal A are accorded good prognosis and Luminal B correlate with poor prognosis. Further biomarkers are needed to attain classification consensus. Machine learning approaches like Artificial Neural Networks (ANNs) have been used for classification and identification of biomarkers in breast cancer using high throughput data. In this study, we have used an artificial neural network (ANN) approach to identify DACH1 as a candidate luminal marker and its role in predicting clinical outcome in breast cancer is assessed.
MATERIALS AND METHODS: A reiterative ANN approach incorporating a network inferencing algorithm was used to identify ER-associated biomarkers in a publically available cDNA microarray dataset. DACH1 was identified in having a strong influence on ER associated markers and a positive association with ER. Its clinical relevance in predicting breast cancer specific survival was investigated by statistically assessing protein expression levels after immunohistochemistry in a series of unselected breast cancers, formatted as a tissue microarray.
RESULTS: Strong nuclear DACH1 staining is more prevalent in tubular and lobular breast cancer. Its expression correlated with ER-alpha positive tumours expressing PgR, epithelial cytokeratins (CK)18/19 and 'luminal-like' markers of good prognosis including FOXA1 and RERG (p<0.05). DACH1 is increased in patients showing longer cancer specific survival and disease free interval and reduced metastasis formation (p<0.001). Nuclear DACH1 showed a negative association with markers of aggressive growth and poor prognosis.
CONCLUSION: Nuclear DACH1 expression appears to be a Luminal A biomarker predictive of good prognosis, but is not independent of clinical stage, tumour size, NPI status or systemic therapy.
Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin β-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.
Fortier AM, Asselin E, Cadrin MKeratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation.
J Biol Chem. 2013; 288(16):11555-71 [PubMed
] Free Access to Full Article Related Publications
Keratins 8 and 18 (K8/18) are simple epithelial cell-specific intermediate filament proteins. Keratins are essential for tissue integrity and are involved in intracellular signaling pathways that regulate cell response to injuries, cell growth, and death. K8/18 expression is maintained during tumorigenesis; hence, they are used as a diagnostic marker in tumor pathology. In recent years, studies have provided evidence that keratins should be considered not only as markers but also as regulators of cancer cell signaling. The loss of K8/18 expression during epithelial-mesenchymal transition (EMT) is associated with metastasis and chemoresistance. In the present study, we investigated whether K8/18 expression plays an active role in EMT. We show that K8/18 stable knockdown using shRNA increased collective migration and invasiveness of epithelial cancer cells without modulating EMT markers. K8/18-depleted cells showed PI3K/Akt/NF-κB hyperactivation and increased MMP2 and MMP9 expression. K8/18 deletion also increased cisplatin-induced apoptosis. Increased Fas receptor membrane targeting suggests that apoptosis is enhanced via the extrinsic pathway. Interestingly, we identified the tight junction protein claudin1 as a regulator of these processes. This is the first indication that modulation of K8/18 expression can influence the phenotype of epithelial cancer cells at a transcriptional level and supports the hypothesis that keratins play an active role in cancer progression.
Liu Y, Xing ZB, Zhang JH, Fang YAkt kinase targets the association of CBP with histone H3 to regulate the acetylation of lysine K18.
FEBS Lett. 2013; 587(7):847-53 [PubMed
] Related Publications
CREB binding protein (CBP) is an acetyltransferase that plays an important role in many biological processes. Here, we show that Akt phosphorylates CBP at threonine 1871 and suppresses its acetyltransferase activity by impeding the binding of CBP to histone H3, which results in a decrease in lysine K18 acetylation and dysregulation of target genes. Our results demonstrate that Akt regulates acetyltransferase activity through CBP phosphorylation, which may contribute to tumorigenesis.
Li J, Cao D, Guo G, et al.Expression and anatomical distribution of TIM-containing molecules in Langerhans cell sarcoma.
J Mol Histol. 2013; 44(2):213-20 [PubMed
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Signals from the T cell immunoglobulin and mucin-domain (TIM)-containing molecules have been demonstrated to be involved in regulating the progress of carcinoma. However, the expression and anatomical distribution of TIMs in Langerhans cell sarcoma (LCS), which is a rare malignancy derived from dendritic cells of the epidermis, has yet to be determined. In this study, the expression of TIM-1, TIM-3 and TIM-4 in LCS samples were detected by immunohistochemistry. Our results showed that these three molecules were found in LCS sections. At the cellular level, these molecules were found on the cell membrane and in the cytoplasm. Immunofluorescence double-staining demonstrated that these TIMs were co-expressed with Langerin, a potential biomarker for detecting LCS. In addition, TIM-1 was also expressed on CD68(+) macrophages and CK-18(+) epithelial cells, while TIM-3 and TIM-4 were expressed on all cell types investigated, including CD3(+)T cells, CD68(+) macrophages, CD11c(+) dendritic cells, CD16(+) NK Cells, CD31(+) endothelial cells and CK-18(+) epithelial cells. Interestingly, TIMs were also co-expressed with some members of the B7 superfamily, including B7-H1, B7-H3 and B7-H4 on sarcoma cells. Our results clearly showed the characteristic expression and anatomical distribution of TIMs in LCS, and a clear understanding of their functional roles may further elucidate the pathogenesis of this carcinoma and potentially contribute to the development of novel immunotherapeutic strategies.
Increasing evidence indicates that invasive properties of breast cancers rely on gain of mesenchymal and stem features, which has suggested that the dual targeting of these phenotypes may represent an appealing therapeutic strategy. It is known that the fraction of stem cells can be enriched by culturing breast cancer cells as mammospheres (MS), but whether these pro-stem conditions favor also the expansion of cells provided of mesenchymal features is still undefined. In the attempt to shed light on this issue, we compared the phenotypes of a panel of 10 breast cancer cell lines representative of distinct subtypes (luminal, HER2-positive, basal-like and claudin-low), grown in adherent conditions and as mammospheres. Under MS-proficient conditions, the increment in the fraction of stem-like cells was associated to upregulation of the mesenchymal marker Vimentin and downregulation of the epithelial markers expressed by luminal cells (E-cadherin, KRT18, KRT19, ESR1). Luminal cells tended also to upregulate the myoepithelial marker CD10. Taken together, our data indicate that MS-proficient conditions do favor mesenchymal/myoepithelial features, and indicate that the use of mammospheres as an in vitro tumor model may efficiently allow the exploitation of therapeutic approaches aimed at targeting aggressive tumors that have undergone epithelial-to-mesenchymal transition
Usachov V, Nahon P, Lunova M, et al.Keratin 8 variants are infrequent in patients with alcohol-related liver cirrhosis and do not associate with development of hepatocellular carcinoma.
BMC Gastroenterol. 2012; 12:147 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Keratins 8/18 (K8/K18) are established hepatoprotective proteins and K8/K18 variants predispose to development and adverse outcome of multiple liver disorders. The importance of K8/K18 in alcoholic liver disease as well as in established cirrhosis remains unknown.
METHODS: We analyzed the K8 mutational hot-spots in 261 prospectively followed-up patients with alcoholic cirrhosis (mean follow-up 65 months). PCR-amplified samples were pre-screened by denaturing high-performance liquid chromatography and conspicuous samples were sequenced.
RESULTS: 67 patients developed hepatocellular carcinoma (HCC) and 133 died. Fourteen patients harbored amino-acid-altering K8 variants (5xG62C, 8xR341H). The presence of K8 variants did not associate with development of HCC (log-rank=0.5) or death (log-rank=0.7) and no significant associations were obtained for the single K8 variants after a correction for multiple testing was performed.
CONCLUSIONS: Keratin variants are expressed in a low percentage of patients with alcoholic cirrhosis and do not influence HCC development. Further studies conducted in larger prospective cohorts are needed to find out whether presence of K8 R341H variant predispose to non-HCC-related liver mortality.
Deng M, Zhang W, Tang H, et al.Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms.
Oncogene. 2013; 32(36):4273-83 [PubMed
] Related Publications
LTF (lactotransferrin, also known as lactoferrin) is a key component of innate immune defense. It has recently been found to have anti-tumor and anti-metastatic activity in different cancers. We previously reported LTF to be the most significantly downregulated gene in nasopharyngeal carcinoma (NPC) specimens relative to normal nasopharyngeal epithelial tissues, and it was also negatively associated with the progression and metastasis of NPC. However, the mechanism underlying this remains unclear. In the current study, we revealed that LTF can suppress 3-phosphoinositide-dependent protein kinase 1 expression via the mitogen-activated protein kinase/c-Jun pathway and thus repress AKT signaling. We also showed that LTF interacts with keratin 18 (K18) and so blocks the formation of the K18-14-3-3 complex, leading to downregulation of K18-mediated AKT activation. Thus, LTF suppresses AKT signaling by two separate mechanisms, leading to inhibition of NPC tumorigenesis. This is the first report on the tumor suppressive effects of LTF through repression of AKT signaling in NPC. It suggests that both LTF and AKT signaling merit further study in the field of NPC research.
Kumar JM, Kombairaju P, Nagarajan P, et al.Tamoxifen-resistant, ER-positive MAC 51 cell line with a high metastatic potential developed from a spontaneous breast cancer mouse model.
Cell Tissue Res. 2012; 350(2):347-60 [PubMed
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We developed and characterized an estrogen-responsive and ER-positive murine breast cancer cell line (MAC51) from a spontaneous breast cancer animal model. These cells are overexpressed with K8, K18 and K19 proteins in an immunofluoresence assay. Upregulation of ER alpha was observed in the immunofluoresence assay, real-time PCR analysis and western blot assay. A colocalization experiment in MAC 51 showed cytoplasmic colocalization of K18 and K19 proteins with ER α. Real-time analysis of tumor samples from engrafted animals, MAC 51, metastatic liver and metastatic ovary revealed overexpression of K8 and K18 compared to the respective controls. A hormone responsive experiment in immunodeficient mice showed highly significant decreases in estrogen and tumor volume after 14 days ovariectomization. The tumorogenicity assay showed higher (3 × 10 (5)) and lower (3 × 10(4)) concentrations of MAC 51 cells that developed tumors within 2 weeks post-transplantation. Tumor morphology and histology resembled a sarcoma pattern but our spontaneous model appeared in an adenocarcinoma pattern. Metastasis to different organs occurred through hematogenous and lymphatic routes. We assessed the potency of the anticancer effect in MAC 51 cells by treating various anticancer drugs with E2, followed by studying apoptotic gene expression profiles. E2 and E2+ tamoxifen-treated cells showed upregulation of apoptotic genes caspase 1, 3, 9, P53 and Bcl-xl but the tamoxifen- and paclitaxel-treated cells did not upregulate the apoptotic genes. Tamoxifen-resistant, ER-positive and high metastatic potential cell lines from murine origin are very rare. Also, estrogen greatly induced apoptosis in this cell line, hence MAC 51 has a greater application potential to evaluate low doses of estrogen with other targeted therapeutic drugs to treat breast cancer.
Singleminded-2s (SIM2s) is a member of the bHLH/PAS family of transcription factors and a key regulator of mammary epithelial cell differentiation. SIM2s is highly expressed in mammary epithelial cells and downregulated in human breast cancer. Loss of Sim2s causes aberrant mouse mammary ductal development, with features suggestive of malignant transformation, whereas overexpression of SIM2s promotes precocious alveolar differentiation in nulliparous mouse mammary glands, suggesting that SIM2s is required for establishing and enhancing mammary gland differentiation. To test the hypothesis that SIM2s regulates tumor cell differentiation, we analyzed SIM2s expression in human primary breast ductal carcinoma in situ (DCIS) samples and found that SIM2s is lost with progression from DCIS to invasive ductal cancer (IDC). Using a MCF10DCIS.COM progression model, we have shown that SIM2s expression is decreased in MCF10DCIS.COM cells compared with MCF10A cells, and reestablishment of SIM2s in MCF10DCIS.COM cells significantly inhibits growth and invasion both in vitro and in vivo. Analysis of SIM2s-MCF10DCIS.com tumors showed that SIM2s promoted a more differentiated tumor phenotype including the expression of a broad range of luminal markers (CSN2 (β-casein), CDH1 (E-cadherin), and KER18 (keratin-18)) and suppressed genes associated with stem cell maintenance and a basal phenotype (SMO (smoothened), p63, SLUG (snail-2), KER14 (keratin-14) and VIM (vimentin)). Furthermore, loss of SIM2s expression in MCF10DCIS.COM xenografts resulted in a more invasive phenotype and increased lung metastasis likely due to an increase in Hedgehog signaling and matrix metalloproteinase expression. Together, these exciting new data support a role for SIM2s in promoting human breast tumor differentiation and maintaining epithelial integrity.
Primary small cell carcinoma of the nose and paranasal sinuses is very rare; only a few reports are present in the English literature. The author herein reports a very rare case of primary small cell carcinoma of the maxillary sinus with an emphasis on immunohistochemistry and on KIT and PDGFRA. A 64-year-old man was admitted to our hospital because of left nasal obstruction. Endoscopy revealed three nasal polyps, and imaging modalities revealed an infiltrative tumor (45 x 45 mm) in the left maxillary sinus with invasion into nasal cavity. Multiple biopsies are taken from the nasal lesions. Histologically, the tumor consists of proliferation of malignant small epithelioid cells with hyperchromatic nuclei, fine chromatin, scant cytoplasm, molded nuclei, and absent nucleoli. Immunohistochemically, the malignant cells were positive for cytokeratin (CK) 18, synaptophysin, CD56, p53, Ki-67 (labeling=95%), bcl-2, KIT, and PDGFRA. However, they were negative for pancytokeratins, high molecular weight CK, CK5/6, CK7, CK 14, CK 19, CK20, vimentin, neuron-specific enolase, chromogranin, CD15, CD45, S100 protein, CEA, CA19-9, glial fibrillary acidic protein, neurofilaments, neuroblastoma, CD99, surfactant apoprotein A, melanosome, and TTF-1. The pathologic diagnosis was small cell carcinoma. A molecular genetic analysis using PCR-direct sequencing was performed using paraffin sections, and it showed no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. Imaging modalities including CT, MRI and PET did not reveal any tumors, including the lung, other than the maxillary sinus tumor. The present case is the first of small cell carcinoma of the maxillary sinus with a comprehensive immunohistochemical examination and a gene analysis of KIT and PDGFRA.
Szponar A, Kovacs GExpression of KRT7 and WT1 differentiates precursor lesions of Wilms' tumours from those of papillary renal cell tumours and mucinous tubular and spindle cell carcinomas.
Virchows Arch. 2012; 460(4):423-7 [PubMed
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Wilms' tumours (WT) and adult papillary renal cell tumours (pRCT) are associated with precursor lesions of embryonic origin. The aim of this study was to analyse the expression of WT1, KRT7, KRT8, KRT18 and KRT19 genes by immunohistochemistry in 74 precursor lesions associated with WTs, pRCTs and mucinous tubular and spindle cell carcinomas (MTSCC). All precursor lesions associated with Wilms' tumours were positive for WT1, whereas all precursor lesions in pRCT and MTSCC-bearing kidneys were negative. None of the WT-associated lesions were positive for KRT7, but 69-80% of lesions associated with pRCTs and MTSCCs were positive for KRT7. KRT8, KRT18 and KRT19 were found to be expressed in 80-100% of all types of precursor lesions. Our findings indicate that the precursor lesions analysed in this study are committed in an early stage of cellular differentiation to the development of either Wilms' tumours or papillary RCTs and MTSCCs.
BACKGROUND: Since the end of last century, RNAs from the 3'untranslated region (3'UTR) of several eukaryotic mRNAs have been found to exert tumor suppression activity when introduced into malignant cells independent of their whole mRNAs. In this study, we sought to determine the molecular mechanism of the tumor suppression activity of a short RNA from 3'UTR of C/EBPβ mRΝΑ (C/EBPβ 3'UTR RNA) in human hepatocarcinoma cells SMMC-7721.
METHODOLOGY/PRINCIPAL FINDINGS: By using Western blotting, immunocytochemistry, molecular beacon, confocal microscopy, protein kinase inhibitors and in vitro kinase assays, we found that, in the C/EBPβ 3'UTR-transfectant cells of SMMC-7721, the overexpressed C/EBPβ 3'UTR RNA induced reorganization of keratin 18 by binding to this keratin; that the C/EBPβ 3'UTR RNA also reduced phosphorylation and expression of keratin 18; and that the enzyme responsible for phosphorylating keratin 18 is protein kinase Cε. We then found that the C/EBPβ 3'UTR RNA directly inhibited the phosphorylating activity of protein kinase Cε; and that C/EBPβ 3'UTR RNA specifically bound with the protein kinase Cε-keratin 18 conjugate.
CONCLUSION/SIGNIFICANCE: Together, these facts suggest that the tumor suppression in SMMC-7721 by C/EBPβ 3'UTR RNA is due to the inhibition of protein kinase Cε activity through direct physical interaction between C/EBPβ 3'UTR RNA and protein kinase Cε. These facts indicate that the 3'UTR of some eukaryotic mRNAs may function as regulators for genes other than their own.
The acquisition of invasiveness in ovarian cancer (OC) is accompanied by the process of epithelial-to-mesenchymal transition (EMT). The MUC4 mucin is overexpressed in ovarian tumors and has a role in the invasiveness of OC cells. The present study was aimed at evaluating the potential involvement of MUC4 in the metastasis of OC cells by inducing EMT. Ectopic overexpression of MUC4 in OC cells (SKOV3-MUC4) resulted in morphological alterations along with a decreased expression of epithelial markers (E-cadherin and cytokeratin (CK)-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) compared with the control cells (SKOV3-vector). Also, pro-EMT transcription factors TWIST1, TWIST2 and SNAIL showed an upregulation in SKOV3-MUC4 cells. We further investigated the pathways upstream of N-cadherin, such as focal adhesion kinase (FAK), MKK7, JNK1/2 and c-Jun, which were also activated in the SKOV3-MUC4 cells compared with SKOV3-vector cells. Inhibition of phospho-FAK (pFAK) and pJNK1/2 decreased N-cadherin expression in the MUC4-overexpressing cells, which further led to a significant decrease in cellular motility. Knockdown of N-cadherin decreased the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), AKT and matrix metalloproteinase 9 (MMP9), and inhibited the motility in the SKOV3-MUC4 cells. Upon in vivo tumorigenesis and metastasis analysis, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distance organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm). Taken together, our study reveals a novel role for MUC4 in inducing EMT through the upregulation of N-cadherin and promoting metastasis of OC cells.
Aleskandarany MA, Rakha EA, Ahmed MA, et al.Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer.
Breast Cancer Res Treat. 2011; 127(2):407-16 [PubMed
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Akt/PKB serine/threonine kinase is a leading signalling modulator for several cellular processes including metabolism, growth, proliferation and survival. However, complexity and diversity in the upstream/downstream arms of Akt pathway, as recent genetic studies reported, challenge considerably the evolvement of effective targeted therapies. The aim was to study the expression of phospho-Akt1 (pAkt) in breast cancer (BC), with respect to different component proteins upstream/downstream of Akt pathway activation, clinicopathologic parameters and patients' outcome. pAkt (Ser473) was evaluated by immunohistochemistry, on tissue microarrays containing 1,202 early invasive BC with long-term clinical follow-up. Seventy-six percent of the studied tumours overexpressed pAkt, where it was associated with expression of oestrogen and androgen receptors, PIK3CA, cytokeratin (CK)18, CK19 and PTEN. Loss of pAkt was correlated with high grade, CK5/6, p53 and high Ki67 labelling index. Higher proportions of luminal tumours were pAkt positive relative to triple negative/basal subtypes. However, pAkt overexpression was not associated with breast cancer specific (BCSS) or metastasis-free survival (MFS). Four tumour phenotypes were identified based on PIK3CA and pAkt expression, with substantial proportions being PIK3CA⁻/pAkt⁺ or PIK3CA⁺/pAkt⁻. These four combinatorial phenotypes were significantly associated with BCSS (p = 0.001) and MFS (p = 0.002). Although pAKT is an oncogene correlated with poor prognostic variables, it was not a prognostic marker. Combinatorial phenotypic groups of PIK3CA/pAkt denoted functional complexity, at translational level, within the upstream and downstream arms of Akt activation with significant impact on patients' outcome. These findings may help development more adequate therapeutic regimens for specific subgroups of this key cancer pathway.
PURPOSE: The epithelial lining of the anorectum still raises discussions concerning the levels of transition between the various zones and leads to an incomplete understanding of the immmunoprofile of rectal carcinoma. Since the expression of cytokeratins depends on the epithelial cell-type and the parahox-gene CDX2 is important for the development of the colorectal epithelium, we investigated different cytokeratins and CDX2 in the anorectum of human prenatal stages and in adult normal and neoplastic anorecta.
MATERIALS AND METHODS: The differentiation and spatiotemporal distribution of the epithelial zones were examined in 33 human embryos and fetuses, in a 2-year-old child and four adults. In comparison, 17 specimens of ultralow rectal adenocarcinoma and 4 specimens of anal carcinoma were investigated. Monoclonal antibodies were directed against cytokeratin (CK) 18, 20, 7 and 14 and CDX2.
RESULTS: Due to the cytokeratin profile and to CDX2 expression, the different anorectal zones could already be differentiated in human prenatal life. We showed that anorectal epithelial differentiation including the squamous epithelia ran in a craniocaudal direction, and that the anorectal zone was a transitional zone between rectal zone and anal transitional zone where CK 7, 18, 20 and CDX2 are simultaneously expressed. All cases of rectal adenocarcinoma showed positivity for CK 18, 20 and CDX2, and three also labelled for CK 7, whereas CK 14 was only expressed in the cases of anal carcinoma.
CONCLUSIONS: Our results elucidate the connection between the prenatal pattern and the origin of the different types of anorectal carcinoma.
Hoenerhoff MJ, Shibata MA, Bode A, Green JEPathologic progression of mammary carcinomas in a C3(1)/SV40 T/t-antigen transgenic rat model of human triple-negative and Her2-positive breast cancer.
Transgenic Res. 2011; 20(2):247-59 [PubMed
] Free Access to Full Article Related Publications
The C3(1) component of the rat prostate steroid binding protein has been used to target expression of the SV40 T/t-antigen to the mammary epithelium of mice resulting in pre-neoplastic lesions that progress to invasive and metastatic cancer with molecular features of human basal-type breast cancer. However, there are major differences in the histologic architecture of the stromal and epithelial elements between the mouse and human mammary glands. The rat mammary gland is more enriched with epithelial and stromal components than the mouse and more closely resembles the cellular composition of the human gland. Additionally, existing rat models of mammary cancer are typically estrogen receptor positive and hormone responsive, unlike most genetically engineered mouse mammary cancer models. In an attempt to develop a mammary cancer model that might more closely resemble the pathology of human breast cancer, we generated a novel C3(1)/SV40 T/t-antigen transgenic rat model that developed progressive mammary lesions leading to highly invasive adenocarcinomas. However, aggressive tumor development prevented the establishment of transgenic lines. Characterization of the tumors revealed that they were primarily estrogen receptor and progesterone receptor negative, and either her2/neu positive or negative, resembling human triple-negative or Her2 positive breast cancer. Tumors expressed the basal marker K14, as well as the luminal marker K18, and were negative for smooth muscle actin. The triple negative phenotype has not been previously reported in a rat mammary cancer model. Further development of a C3(1)SV40 T/t-antigen based model could establish valuable transgenic rat lines that develop basal-type mammary tumors.
Catto JW, Abbod MF, Wild PJ, et al.The application of artificial intelligence to microarray data: identification of a novel gene signature to identify bladder cancer progression.
Eur Urol. 2010; 57(3):398-406 [PubMed
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BACKGROUND: New methods for identifying bladder cancer (BCa) progression are required. Gene expression microarrays can reveal insights into disease biology and identify novel biomarkers. However, these experiments produce large datasets that are difficult to interpret.
OBJECTIVE: To develop a novel method of microarray analysis combining two forms of artificial intelligence (AI): neurofuzzy modelling (NFM) and artificial neural networks (ANN) and validate it in a BCa cohort.
DESIGN, SETTING, AND PARTICIPANTS: We used AI and statistical analyses to identify progression-related genes in a microarray dataset (n=66 tumours, n=2800 genes). The AI-selected genes were then investigated in a second cohort (n=262 tumours) using immunohistochemistry.
MEASUREMENTS: We compared the accuracy of AI and statistical approaches to identify tumour progression.
RESULTS AND LIMITATIONS: AI identified 11 progression-associated genes (odds ratio [OR]: 0.70; 95% confidence interval [CI], 0.56-0.87; p=0.0004), and these were more discriminate than genes chosen using statistical analyses (OR: 1.24; 95% CI, 0.96-1.60; p=0.09). The expression of six AI-selected genes (LIG3, FAS, KRT18, ICAM1, DSG2, and BRCA2) was determined using commercial antibodies and successfully identified tumour progression (concordance index: 0.66; log-rank test: p=0.01). AI-selected genes were more discriminate than pathologic criteria at determining progression (Cox multivariate analysis: p=0.01). Limitations include the use of statistical correlation to identify 200 genes for AI analysis and that we did not compare regression identified genes with immunohistochemistry.
CONCLUSIONS: AI and statistical analyses use different techniques of inference to determine gene-phenotype associations and identify distinct prognostic gene signatures that are equally valid. We have identified a prognostic gene signature whose members reflect a variety of carcinogenic pathways that could identify progression in non-muscle-invasive BCa.
Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.
Min W, Wen-li M, Zhao-hui S, et al.Microarray analysis identifies differentially expressed genes induced by human papillomavirus type 18 E6 silencing RNA.
Int J Gynecol Cancer. 2009; 19(4):547-63 [PubMed
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The oncoprotein E6 of high-risk human papillomavirus (HPV) types promotes cell proliferation and contributes to carcinogenesis of HPV-positive cervical cancer cells. In this study, we used small interfering RNA (siRNA) technology to silence the E6 gene in HPV-18-transformed human cervical cell line HeLa and determined the effects of E6 gene knockdown on the cell by using microarray-based gene expression profiling coupled with gene functional classification with bioinformatics methods. Silencing RNA prepared by siRNA expression cassettes against HPV-18 E6 gene could significantly inhibit E6 gene expression and induce HeLa cells to apoptosis. The microarray analysis identified 359 differentially expressed genes containing 307 up-regulated and 52 down-regulated genes. We analyzed the gene functions and cellular pathways in detail, including cell cycle-related genes, CCNG1 and p21; apoptosis-related genes, CASP4, CASP6, IGFBP3, and DFFA; ubiquitin proteolysis pathway-related genes, UBE3A and UBE2C; keratinocyte differentiation-related genes, KRT4, KRT6E, and KRT18; and antioncogenes, RECK and VEL. In addition, it can be concluded that cellular apoptosis induced by HPV-18 E6 siRNA mainly depends on the P53 and ubiquitin proteolysis pathway to regulate gene expression, consequently inhibiting cell proliferation and promoting cell apoptosis. Meanwhile, activation of antioncogene and upper regulation of immunization-related genes signified the degression of the malignant extent of tumor cells after E6 inhibition. Our approach, which combines the use of siRNA-mediated gene silencing, microarray screening, and functional classification of differential genes, can be used in functional genomics study to elucidate the role of E6 oncogene in the carcinogenesis of HPV-18 and provide some possible targets for clinical treatment and drug development of cervical cancer.
Kieback DGAdenovirus-mediated thymidine kinase gene therapy induces apoptosis in human epithelial ovarian cancer cells and damages PARP-1.
In Vivo. 2009 Jan-Feb; 23(1):77-80 [PubMed
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Adenoviral (ADV) gene therapy with the thymidine kinase gene (TK) under control of the Rous sarcoma virus (RSV) promotor followed by the administration of acyclovir leads to replication errors in transcription and to cell death. This concept of ADV-RSV-TK has been established for the treatment of ovarian cancer cells. The purpose of this investigation was to clarify whether cell death after ADV-RSV-TK gene therapy and acyclovir administration is indeed due to apoptosis induction, whether the synergistic effect of ADV-RSV-TK gene therapy with chemotherapy was limited to the primary mechanism of action or whether the vector transduction itself exerted any pro-apoptotic effect was examined using the epithelial cell lines OVCAR-3 and MDAH-2774, established from human poorly differentiated serous ovarian cancer. Fluorimetric assay of caspase-3 activity was performed, as well as ELISA of the CK 18 split product M30. PARP cleavage was analysed by Western blotting. Apoptosis induction was established in this investigation as the mechanism of the ADV-RSV-TK gene therapy effect of acyclovir administration by caspase activity and subsequent CK 18 cleavage. Neither acyclovir nor vector administration alone showed any apoptotic activity. The synergistic effect of TK gene therapy and chemotherapeutic agents was shown to be TK induced. Significant anti-PARP 1 activity was found to be an ADV-RSV-TK treatment effect after acyclovir addition.
Landriscina M, Bagalà C, Piscazzi A, et al.Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo.
Prostate. 2009; 69(7):744-54 [PubMed
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BACKGROUND: Prostate carcinomas are androgen-dependent neoplasms which progress toward a hormone-independent phenotype during hormone-deprivation therapy. We evaluated nevirapine, a reverse transcriptase inhibitor, as a new treatment in hormone-refractory prostate carcinoma cells with the aim of restoring the androgen-dependency of tumor cells, the rationale being that endogenous reverse transcriptase is up-regulated in transformed cells and reverse transcriptase inhibitors exert a differentiating activity in human tumors.
METHODS AND RESULTS: Nevirapine induced extensive reprogramming of gene expression in vitro with up-regulation of genes that might be silenced during prostate tumor progression (i.e., K18, PSA and androgen receptor) and down-regulation of genes involved in the progression toward an androgen-independent phenotype (i.e., K5, EGFR1, EGF and VEGF-A). Furthermore, nevirapine down-regulated the growth of prostate carcinoma xenografts in athymic mice and induced a differentiated phenotype in vivo with increased K18 expression. Interestingly, the drug restored androgen signaling by enhancing the ability of tumor cells to respond to dihydrotestosterone stimulation and to the antiproliferative activity of the androgen receptor blocker bicalutamide. Finally, nevirapine pretreatment increased the susceptibility of tumor cells to docetaxel, by enhancing their ability to undergo apoptosis.
CONCLUSIONS: These data suggest that nevirapine may be clinically tested in human hormone-refractory prostate carcinoma to restore the susceptibility to androgen deprivation therapy or to docetaxel.
AIM: To identify the genes related to lymph node metastasis in human hepatocellular carcinoma (HCC), 32 HCC patients with or without lymph node metastasis were investigated by high-throughput microarray comprising 886 genes.
METHODS: The samples of cancerous and non-cancerous paired tissue were taken from 32 patients with HCC who underwent hepatectomy with lymph node dissection. Total RNA was extracted from the cells obtained by means of laser microdissection (LCM) and was amplified by the T7-based amplification system. Then, the amplified samples were applied in the cDNA microarray comprising of 886 genes.
RESULTS: The results demonstrated that 25 up-regulated genes such as cell membrane receptor, intracellular signaling and cell adhesion related genes, and 48 down-regulated genes such as intracellular signaling and cell cycle regulator-related genes, were correlated with lymph node metastasis in HCC. Amongst them were included some interesting genes, such as MET, EPHA2, CCND1, MMP2, MMP13, CASP3, CDH1, and PTPN2. Expression of 16 genes (MET, CCND1, CCND2, VEGF, KRT18, RFC4, BIRC5, CDC6, MMP2, BCL2A1, CDH1, VIM, PDGFRA, PTPN2, SLC25A5 and DSP) were further confirmed by real-time quantitative reverse transcriptional polymerase chain reaction (RT-PCR).
CONCLUSION: Tumor metastasis is an important biological characteristic, which involves multiple genetic changes and cumulation. This genome-wide information contributes to an improved understanding of molecular alterations during lymph node metastasis in HCC. It may help clinicians to predict metastasis of lymph nodes and assist researchers in identifying novel therapeutic targets for metastatic HCC patients.