|Gene:||TACSTD2; tumor-associated calcium signal transducer 2|
|Aliases: || EGP1, GP50, M1S1, EGP-1, TROP2, GA7331, GA733-1 |
|Summary:||This intronless gene encodes a carcinoma-associated antigen. This antigen is a cell surface receptor that transduces calcium signals. Mutations of this gene have been associated with gelatinous drop-like corneal dystrophy.[provided by RefSeq, Dec 2009]|
|Databases:||OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene|
|Protein:||tumor-associated calcium signal transducer 2|
|Updated:||14 December, 2014|
What does this gene/protein do?
Graph generated 14 December 2014 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 14 December, 2014 using data from PubMed, MeSH and CancerIndex
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: TACSTD2 (cancer-related)
Liu X, Li S, Yi FTrop2 gene: a novel target for cervical cancer treatment.
J Cancer Res Clin Oncol. 2014; 140(8):1331-41 [PubMed
] Related Publications
Trop2 plays an important role in proliferation and invasion of tumors. Extensive research has shown that the expression level of Trop2 is closely related to the progress of cervical diseases. This study was to explore the effects of Trop2 on cell proliferation and apoptosis in cervical cancer.METHODS:
Trop2 was knocked down by shRNA in CaSki cells. The expression level of mRNA and protein was detected by real-time PCR and western blot, respectively. Cell proliferation was determined by CCK-8 and clone formation assay; apoptosis was measured by flow cytometry; cell cycle and apoptosis-related proteins cyclinD1, P53, bcl-2, bax, caspase 3, 8 and 9 were analyzed as well to investigate possible mechanism.RESULTS:
Trop2 expression was effectively repressed in CaSki cells by Trop2 shRNA, which resulted in inhibition of proliferation and colony formation, whereas apoptosis rate was significantly increased. Furthermore, in Trop2 knockdown CaSki cells, the expression of cyclinD1 and bcl-2 was significantly down-regulated, while that of P53 and bax was up-regulated accompanied by increased activities of caspase 9 and 3 but not caspase 8.CONCLUSIONS:
Trop2 is important in proliferation and apoptosis regulation in CaSki cells, which may become a novel target for cervical cancer treatment.Related: Apoptosis Cervical Cancer
Tumor-associated calcium signal transducer 2 (TACSTD2), a calcium signal transducer, is universally expressed in stratified squamous epithelia of many organs, including skin, esophagus and cervix. Although TACSTD2, was reported to be overexpressed in many epithelial tumors, which has increased interest in using it as a molecular target for cancer therapy, the role of TACSTD2 in carcinogenesis of squamous cell carcinoma (SCC) is largely unclear and controversial. To explore the role of TACSTD2, temporal-spatial expression of TACSTD2 was analyzed in both normal and SCC tissues. Our data demonstrate that Tacstd2 expression and membrane localization are tightly associated with stratified epithelial homeostasis, while loss of TACSTD2 was identified in poorly differentiated SCC tissues collected from cervix, esophagus, head and neck. Gradual loss of TACSTD2 was correlated with stepwise progression of SCC. Consistent with these in vivo observations, our data show that inhibition of Tacstd2 expression significantly inhibited chemotherapeutic reagent-induced apoptosis, and TACSTD2 regulated apoptotic gene expression through P63 containing the transactivation domain (TAp63). These findings indicated that loss of TACSTD2 could promote SCC progression and treatment resistance through attenuating chemotherapeutic reagent-induced apoptosis through TAp63, and TACSTD2 could be used as a marker for pathological grading of SCC.Related: Apoptosis Cancer of the Esophagus Esophageal Cancer Head and Neck Cancers Head and Neck Cancers - Molecular Biology Signal Transduction Cervical Cancer
Behnke MK, Reimers M, Fisher RAStem cell and hepatocyte proliferation in hepatitis C cirrhosis and hepatocellular carcinoma: transplant implications.
Ann Hepatol. 2013 Jan-2014 Feb; 13(1):45-53 [PubMed
] Related Publications
Liu T, Liu Y, Bao X, et al.Overexpression of TROP2 predicts poor prognosis of patients with cervical cancer and promotes the proliferation and invasion of cervical cancer cells by regulating ERK signaling pathway.
PLoS One. 2013; 8(9):e75864 [PubMed
] Free Access to Full Article Related Publications
Overwhelming evidence has demonstrated that the aberrant expression of the human trophoblast cell-surface antigen (TROP2) was associated with tumor aggressiveness and poor prognosis in a variety of human cancers, however the roles of TROP2 in cervical cancer have not been investigated. The purpose of our study was to elucidate the prognostic significance of TROP2 expression in patients with cervical cancer and determine its effect on tumor progression. Immunohistochemistry assay showed that 88.7% (94/106 cases) of cervical cancer specimens were positively stained with TROP2, and the overexpression of TROP2 was closely related with FIGO stage, histological grades, lymphatic metastasis, invasive interstitial depth and high expression of Ki-67. Patients with TROP2-positive staining exhibited a significantly decreased overall survival and progression free survival; it was also an independent predictor for prognosis according to multivariate analysis. Moreover, down-regulation of TROP2 mediated by siRNA in Siha and CaSki cells resulted in a strong inhibition of proliferation and invasion, TROP2 abrogation also elevated the apoptotic ratio and caused G1 arrest. Conversely, enforced expression of TROP2 in HeLa and C33A cells remarkably promoted cell growth, migration and invasion. In addition, the tumorigenic function of TROP2 was associated with the increased expressions of cyclin D1, cyclin E, CDK2 and CDK4 but reduced expression of p27 and E-cadherin via the activation of Erk1/2 signaling pathway. Furthermore, the inhibition of TROP2 expression in cervical cancer cell lines enhances sensitivity to cisplatin. The present study suggest that overexpression of TROP2 may play crucial roles in the development and pathogenesis of human cervical cancer, therefore, TROP2 may represent a prospective prognostic indicator and a potential therapeutic target of cervical cancer.Related: Cisplatin MKI67 Cervical Cancer
Le Magnen C, Bubendorf L, Rentsch CA, et al.Characterization and clinical relevance of ALDHbright populations in prostate cancer.
Clin Cancer Res. 2013; 19(19):5361-71 [PubMed
] Related Publications
High aldehyde dehydrogenase (ALDH) has been suggested to selectively mark cells with high tumorigenic potential in established prostate cancer cell lines. However, the existence of cells with high ALDH activity (ALDH(bright)) in primary prostate cancer specimens has not been shown so far. We investigated the presence, phenotype, and clinical significance of ALDH(bright) populations in clinical prostate cancer specimens.EXPERIMENTAL DESIGN:
We used ALDEFLUOR technology and fluorescence-activated cell-sorting (FACS) staining to identify and characterize ALDH(bright) populations in cells freshly isolated from clinical prostate cancer specimens. Expression of genes encoding ALDH-specific isoforms was evaluated by quantitative real-time PCR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer tissues. ALDH1A1-specific expression and prognostic significance were assessed by staining two tissue microarrays that included more than 500 samples of BPH, prostatic intraepithelial neoplasia (PIN), and multistage prostate cancer.RESULTS:
ALDH(bright) cells were detectable in freshly excised prostate cancer specimens (n = 39) and were mainly included within the EpCAM((+)) and Trop2((+)) cell populations. Although several ALDH isoforms were expressed to high extents in prostate cancer, only ALDH1A1 gene expression significantly correlated with ALDH activity (P < 0.01) and was increased in cancers with high Gleason scores (P = 0.03). Most importantly, ALDH1A1 protein was expressed significantly more frequently and at higher levels in advanced-stage than in low-stage prostate cancer and BPH. Notably, ALDH1A1 positivity was associated with poor survival (P = 0.02) in hormone-naïve patients.CONCLUSIONS:
Our data indicate that ALDH contributes to the identification of subsets of prostate cancer cells of potentially high clinical relevance.Related: Prostate Cancer ALDH1A1
Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive.DESIGN:
Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays.RESULTS:
In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib.CONCLUSIONS:
Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.Related: Liver Cancer EPCAM
An important topic in systems biology is the reverse engineering of regulatory mechanisms through reconstruction of context-dependent gene networks. A major challenge is to identify the genes and the regulations specific to a condition or phenotype, given that regulatory processes are highly connected such that a specific response is typically accompanied by numerous collateral effects. In this study, we design a multi-layer approach that is able to reconstruct condition-specific genes and their regulation through an integrative analysis of large-scale information of gene expression, protein interaction and transcriptional regulation (transcription factor-target gene relationships). We establish the accuracy of our methodology against synthetic datasets, as well as a yeast dataset. We then extend the framework to the application of higher eukaryotic systems, including human breast cancer and Arabidopsis thaliana cold acclimation. Our study identified TACSTD2 (TROP2) as a target gene for human breast cancer and discovered its regulation by transcription factors CREB, as well as NFkB. We also predict KIF2C is a target gene for ER-/HER2- breast cancer and is positively regulated by E2F1. The predictions were further confirmed through experimental studies.AVAILABILITY:
The implementation and detailed protocol of the layer approach is available at http://www.egr.msu.edu/changroup/Protocols/Three-layer%20approach%20 to % 20reconstruct%20condition.html.Related: Breast Cancer
Chordomas are rare mesenchymal tumors occurring exclusively in the midline from clivus to sacrum. Early tumor detection is extremely important as these tumors are resistant to chemotherapy and irradiation. Despite continuous research efforts surgical excision remains the main treatment option. Because of the often challenging anatomic location early detection is important to enable complete tumor resection and to reduce the high incidence of local recurrences. The aim of this study was to explore whether DNA methylation, a well known epigenetic marker, may play a role in chordoma development and if hypermethylation of specific CpG islands may serve as potential biomarkers correlated with SNP analyses in chordoma. The study was performed on tumor samples from ten chordoma patients. We found significant genomic instability by Affymetrix 6.0. It was interesting to see that all chordomas showed a loss of 3q26.32 (PIK 3CA) and 3q27.3 (BCL6) thus underlining the potential importance of the PI3K pathway in chordoma development. By using the AITCpG360 methylation assay we elucidated 20 genes which were hyper/hypomethylated compared to normal blood. The most promising candidates were nine hyper/hypomethylated genes C3, XIST, TACSTD2, FMR1, HIC1, RARB, DLEC1, KL, and RASSF1. In summary, we have shown that chordomas are characterized by a significant genomic instability and furthermore we demonstrated a characteristic DNA methylation pattern. These findings add new insights into chordoma development, diagnosis and potential new treatment options.Related: DLEC1 RASSF1 RARB
Govindan SV, Cardillo TM, Sharkey RM, et al.Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers.
Mol Cancer Ther. 2013; 12(6):968-78 [PubMed
] Related Publications
CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic tumors but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy of CD74-expressing solid tumors. Milatuzumab-doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, whereas in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, whereas doxorubicin ADC was better in lymphoma tested.Related: Monoclonal Antibodies Doxorubicin Cancer Prevention and Risk Reduction CD74 gene Irinotecan
Nakanishi H, Taccioli C, Palatini J, et al.Loss of miR-125b-1 contributes to head and neck cancer development by dysregulating TACSTD2 and MAPK pathway.
Oncogene. 2014; 33(6):702-12 [PubMed
] Related Publications
MicroRNAs (miRNAs) have important roles in the initiation and progression of human cancer, but their role in head and neck cancer development and progression is not well defined. We aimed to determine whether specific miRNAs and their target mRNAs contribute to head and neck cancer pathogenesis and progression. To identify miRNAs associated with head and neck squamous cell carcinomas (HNSCCs), we analyzed HNSCC cell lines, normal head and neck tissues and normal keratinocytes by miRNA profiling; a group of differentially expressed miRNAs was identified, which includes miR-125b. Decreased expression of miR-125b is known to occur in epithelial cancers and many target mRNAs for this miR have been reported. We found decreased expression of miR-125b-1 and hypermethylation of its promoter in HNSCC compared with its non-malignant counterpart. The TACSTD2 (also known as TROP2) gene was identified and validated as a direct target of miR-125b-1. Abnormal expression of TACSTD2 cell-surface glycoprotein has been reported in most epithelial tumors, and the overexpressions of this mRNA and protein product has been considered a useful tumor marker. We report that miR-125b-1 causes mitogen-activated protein kinase pathway dysfunction through regulation of TACSTD2 expression. Thus, loss of miR-125b-1 may have a key role in the pathogenesis and progression of squamous cell carcinomas of head and neck and possibly of other tumors.Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology
Ning S, Liang N, Liu B, et al.TROP2 expression and its correlation with tumor proliferation and angiogenesis in human gliomas.
Neurol Sci. 2013; 34(10):1745-50 [PubMed
] Related Publications
Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein which is associated with tumor development and progression in a variety of epithelial carcinomas, while its expression and role in gliomas have not been considered. The aim of the study was to investigate TROP2 expression in malignant gliomas with different World Health Organization (WHO) classification and its correlation with tumor proliferation and angiogenesis. Immuohistochemistry was used to determine TROP2 and Ki-67 expression and microvessel density (MVD) in tumor specimens and normal brain tissues from 69 glioma patients and the relationship between TROP2 and Ki-67 and MVD was investigated. Immunohistochemistry results showed that the TROP2 expression was found in 59 (85.5 %) of the 69 tumor specimens, but no expression in normal brain tissues. Furthermore, TROP2 expression is significantly higher in WHO grade III (P = 0.025) and WHO grade IV (P = 0.011) gliomas than in WHO grade II gliomas. TROP2 expression correlates with Ki-67 (r = 0.676, P = 0.012) and MVD (r = 0.365, P = 0.035), but not with gender or age in human gliomas. These results suggested that the TROP2 correlated with malignancy, proliferation and angiogenesis in human gliomas. This is the first study describing TROP2 expression in gliomas and its proliferation and angiogenesis-related characteristic may serve as a potential therapeutic target for glioma treatment.Related: MKI67 Angiogenesis and Cancer
Citterio C, Menacho-Márquez M, García-Escudero R, et al.The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells.
Sci Signal. 2012; 5(244):ra71 [PubMed
] Related Publications
The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav-regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played nonredundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor-β family ligand inhibin βA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use.Related: Apoptosis Breast Cancer COX2 (PTGS2) VAV1 Signal Transduction
Lin H, Huang JF, Qiu JR, et al.Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer.
Exp Mol Pathol. 2013; 94(1):73-8 [PubMed
] Related Publications
The tumor-associated calcium signal transducer 2 (TACSTD2) gene has been reported to be highly expressed in many types of human epithelial cancers, and is associated with tumor metastasis and poor prognosis. The aims of the present investigation were to analyze the TACSTD2 and Cyclin D1 expression at the mRNA and protein levels and to assess its prognostic significance in invasive ductal breast cancer (IDC). The expressions of TACSTD2 and Cyclin D1 in IDC tissues were consistently higher than those in the tumor-adjacent non-malignant tissues by a one-step real-time polymerase chain reaction and immunohistochemistry (P<0.001 and P=0.023, respectively). The statistical analysis of clinicopathologic characteristics and immunohistochemistry by the χ(2) test showed that the high expression of TACSTD2 in IDC was correlated to histological grade (P=0.023), P53 status (P=0.042), Cyclin D1 status (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P=0.004) and TNM staging (P<0.001). Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of IDC. These analyses also showed that a high TACSTD2 expression (P=0.003), a high Cyclin D1 expression (P=0.041), and lymph node metastasis (P=0.006) were independent prognosis factors. Collectively, our studies demonstrated that the high expression of TACSTD2 correlates with a poor prognosis in IDC.Related: Breast Cancer
Wu H, Xu H, Zhang S, et al.Potential therapeutic target and independent prognostic marker of TROP2 in laryngeal squamous cell carcinoma.
Head Neck. 2013; 35(10):1373-8 [PubMed
] Related Publications
The human trophoblastic cell surface antigen 2 (TROP2) gene is associated with the development of malignancies, but its expression in laryngeal squamous cell carcinoma (SCC) and its relationship with clinical characteristics of the disease remain undetermined.METHODS:
Expression of TROP2 protein was detected by immunohistochemistry with a self-made anti-TROP2 antibody in laryngeal SCC tissue microarrays.RESULTS:
Elevated expression of TROP2 was detected in laryngeal SCC tissues compared with adjacent noncancerous tissues. TROP2 expression in laryngeal SCC was related to tumor differentiation (p = .0001) and lymph node metastasis (p = .0352). Cox regression analyses confirmed that TROP2 expression (p = .015), lymph node metastasis (p = .001), degree of differentiation (p = .002), tumor site (p = .021), and T classification (p = .003) were independent prognostic factors.CONCLUSIONS:
TROP2 can be used as an independent prognostic indicator for laryngeal SCC.Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Cancer of the Larynx Laryngeal Cancer - Molecular Biology
Sharkey RM, van Rij CM, Karacay H, et al.A new Tri-Fab bispecific antibody for pretargeting Trop-2-expressing epithelial cancers.
J Nucl Med. 2012; 53(10):1625-32 [PubMed
] Related Publications
UNLABELLED: RS7 is an internalizing anti-Trop-2 pancarcinoma antibody capable of targeting most epithelial cancers. Because pretargeting strategies could improve the tumor localization of radionuclides, a new anti-Trop-2 × antihapten bispecific antibody for pretargeting, based on humanized RS7, was prepared and evaluated with a radiolabeled hapten-peptide in vitro and in vivo to determine whether its internalization properties would interfere with pretargeting.
METHODS: The anti-Trop-2 × antihapten bispecific antibody, TF12, was prepared using the modular dock-and-lock method. TF12 and humanized RS7 binding was assessed by cell binding assays and fluorescence-activated cell sorting analysis in a variety of human carcinoma cell lines. The internalization of TF12 was evaluated in vitro using a fluorescent TF12 conjugate or hapten-peptide and (111)In-labeled TF12 and RS7. The biodistribution of TF12 and its use as a pretargeting agent with an (111)In-labeled hapten-peptide were assessed in several human epithelial cancer xenografts. Dose optimization was examined in 2 tumor models.
RESULTS: TF12 internalizes, but a substantial fraction remained accessible on the tumor surface. Fluorescence-activated cell sorting analysis showed only a minor change in fluorescent signal when the tumor was probed with a fluorescent hapten-peptide over 4 h, and microscopy showed substantial membrane staining when reassessed at 24 h after TF12 exposure. Only 40.1% of (111)In-TF12 was internalized after 24 h. In vivo, excellent tumor localization of the (111)In-labeled peptide was observed in several tumor models.
CONCLUSION: TF12 was retained sufficiently on the cell surface in several epithelial cancers, thereby making it suitable for pretargeted imaging and therapy of various Trop-2-expressing carcinomas.
Guerra E, Trerotola M, Aloisi AL, et al.The Trop-2 signalling network in cancer growth.
Oncogene. 2013; 32(12):1594-600 [PubMed
] Related Publications
Our findings show that upregulation of a wild-type Trop-2 has a key controlling role in human cancer growth, and that tumour development is quantitatively driven by Trop-2 expression levels. However, little is known about the regulation of expression of the TROP2 gene. Hence, we investigated the TROP2 transcription control network. TROP2 expression was shown to depend on a highly interconnected web of transcription factors: TP63/TP53L, ERG, GRHL1/Get-1 (grainyhead-like epithelial transactivator), HNF1A/TCF-1 (T-cell factor), SPI1/PU.1, WT (Wilms' tumour)1, GLIS2, AIRE (autoimmune regulator), FOXM1 (forkhead box M1) and FOXP3, with HNF4A as the major network hub. TROP2 upregulation was shown to subsequently drive the expression and activation of CREB1 (cyclic AMP-responsive-element binding protein), Jun, NF-κB, Rb, STAT1 and STAT3 through induction of the cyclin D1 and ERK (extracellular signal regulated kinase)/MEK (MAPK/ERK kinase) pathways. Growth-stimulatory signalling through NF-κB, cyclin D1 and ERK was shown to require an intact Trop-2 cytoplasmic tail. Network hubs and interacting partners are co-expressed with Trop-2 in primary human tumours, supporting a role of this signalling network in cancer growth.Related: Cancer Prevention and Risk Reduction Signal Transduction FOXM1
Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation.METHODS:
Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-à-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5.RESULTS:
CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes.CONCLUSIONS:
These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy.Related: Azacitidine Prostate Cancer
The tumor-associated calcium signal transducer (TACSTD) genes, originally designated epithelial cell adhesion molecule (EpCAM) and TROP2, represent true oncogenes. Little is known about EpCAM and TROP2 gene expression in non-small cell lung carcinoma (NSCLC). This study evaluated EpCAM and TROP2 protein expression and clinicopathologic significance in cases of NSCLC.METHODS:
Tissue microarray blocks acquired from 164 cases of NSCLC, including 100 cases of adenocarcinoma (AdC) and 64 of squamous cell carcinoma (SCC), were examined by immunohistochemical staining for EpCAM, and TROP2. The results were correlated with clinicopathologic data.RESULTS:
EpCAM and TROP2 were significantly overexpressed in SCC than in AdC (P < 0.01). In AdC, EpCAM overexpression was closely related to sex, histologic grade, pathologic T stage, pathologic N stage, and TNM stage, and TROP2 overexpression was only related to histologic grade (P < 0.05, respectively). In SCC, correlations were evident between EpCAM overexpression and TNM stage (P = 0.01), and between TROP2 overexpression and pathologic T stage (P = 0.02). EpCAM overexpression showed no significance with overall survival in AdC and SCC patients. However, TROP2 overexpression in AdC had a positive influence on overall survival (P = 0.02) and disease-free survival (P = 0.03). In particular, AdC patients with stage II or III showed better overall survival (P = 0.05) and disease-free survival (P = 0.04).CONCLUSIONS:
While EpCAM and TROP2 show weak and non-complete membranous staining in normal bronchial epithelium and pneumocyte, their complete membranous expression in carcinoma suggests their role in carcinogenesis. EpCAM and TROP2 were more frequently overexpressed in SCC. EpCAM overexpression had no prognostic value in this study, but TROP2 overexpression showed better survival in AdC patients and might be a better prognostic marker in advanced stage AdC.Related: Non-Small Cell Lung Cancer Lung Cancer Signal Transduction
Trop-2 is a transmembrane glycoprotein upregulated in several human carcinomas, including prostate cancer (PrCa). Trop-2 has been suggested to regulate cell-cell adhesion, given its high homology with the other member of the Trop family, Trop-1/EpCAM, and its ability to bind the tight junction proteins claudin-1 and claudin-7. However, a role for Trop-2 in cell adhesion to the extracellular matrix has never been postulated. Here, we show for the first time that Trop-2 expression in PrCa cells correlates with their aggressiveness. Using either shRNA-mediated silencing of Trop-2 in cells that endogenously express it, or ectopic expression of Trop-2 in cells that do not express it, we show that Trop-2 inhibits PrCa cell adhesion to fibronectin (FN). In contrast, expression of another transmembrane receptor, α(v) β(5) integrin, does not affect cell adhesion to this ligand. We find that Trop-2 does not modulate either protein or activation levels of the prominent FN receptors, β(1) integrins, but acts through increasing β(1) association with the adaptor molecule RACK1 and redistribution of RACK1 to the cell membrane. As a result of Trop-2 expression, we also observe activation of Src and FAK, known to occur upon β(1) -RACK1 interaction. These enhanced Src and FAK activities are not mediated by changes in either the activity of IGF-IR, which is known to bind RACK1, or IGF-IR's ability to associate with β(1) integrins. In summary, our data demonstrate that the transmembrane receptor Trop-2 is a regulator of PrCa cell adhesion to FN through activation of the β(1) integrin-RACK1-FAK-Src signaling axis.Related: ITGB1 Prostate Cancer Signal Transduction EPCAM
We evaluated the expression of human trophoblastic cell-surface marker (Trop-2) and the potential of hRS7 - a humanized monoclonal anti-Trop-2 antibody - as a therapeutic strategy against treatment-refractory human uterine (UMMT) and ovarian (OMMT) carcinosarcoma cell lines.MATERIALS AND METHODS:
Trop-2 expression was evaluated by immunohistochemistry (IHC) in paraffin-embedded tumor tissues, by real-time polymerase-chain-reaction (RT-PCR) and flow-cytometry in cell lines. Sensitivity to hRS7 antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested using 5-hour chromium-release assays against UMMT and OMMT cells.RESULTS:
Trop-2 expression was elevated in 9 of 26 (35%) UMMT and 8 of 14 (57%) OMMT tissues tested by IHC. Positivity for Trop-2 mRNA by RT-PCR and surface expression by flow cytometry were detected in 2 of 4 cell lines, with high positivity noted in OMMT-ARK-2. OMMT-ARK-2 was highly sensitive to hRS7 ADCC (range: 34.7-41.0%; P < 0.001) with negligible cytotoxicity seen in the absence of hRS7 or in the presence of control antibody (range: 1.1-2.5%). Human IgG did not significantly inhibit ADCC while human complement increased, hRS7-mediated-cytotoxicity against OMMT-ARK-2.CONCLUSION:
Trop-2 is overexpressed in a proportion of UMMT and OMMT, and hRS7 may represent a novel, potentially highly effective treatment option for patients with treatment-refractory carcinosarcomas overexpressing Trop-2.Related: Ovarian Cancer
An important feature that emerges from analyzing gene regulatory networks is the "switch-like behavior" or "bistability", a dynamic feature of a particular gene to preferentially toggle between two steady-states. The state of gene switches plays pivotal roles in cell fate decision, but identifying switches has been difficult. Therefore a challenge confronting the field is to be able to systematically identify gene switches.RESULTS:
We propose a top-down mining approach to exploring gene switches on a genome-scale level. Theoretical analysis, proof-of-concept examples, and experimental studies demonstrate the ability of our mining approach to identify bistable genes by sampling across a variety of different conditions. Applying the approach to human breast cancer data identified genes that show bimodality within the cancer samples, such as estrogen receptor (ER) and ERBB2, as well as genes that show bimodality between cancer and non-cancer samples, where tumor-associated calcium signal transducer 2 (TACSTD2) is uncovered. We further suggest a likely transcription factor that regulates TACSTD2.CONCLUSIONS:
Our mining approach demonstrates that one can capitalize on genome-wide expression profiling to capture dynamic properties of a complex network. To the best of our knowledge, this is the first attempt in applying mining approaches to explore gene switches on a genome-scale, and the identification of TACSTD2 demonstrates that single cell-level bistability can be predicted from microarray data. Experimental confirmation of the computational results suggest TACSTD2 could be a potential biomarker and attractive candidate for drug therapy against both ER+ and ER- subtypes of breast cancer, including the triple negative subtype.Related: Breast Cancer
Varughese J, Cocco E, Bellone S, et al.Cervical carcinomas overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibody.
Am J Obstet Gynecol. 2011; 205(6):567.e1-7 [PubMed
] Free Access to Full Article Related Publications
We evaluated the expression of human trophoblast cell-surface marker (Trop-2) and the potential of hRS7, a humanized monoclonal anti-Trop-2 antibody, against treatment-refractory cervical cancer.STUDY DESIGN:
Trop-2 expression was evaluated by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. Sensitivity to hRS7 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in 5-hour chromium release assays. The effect of interleukin (IL)-2 on hRS7 ADCC was also investigated.RESULTS:
Membrane Trop-2 expression was observed in 8 of 8 (100%) of the cancer samples tested by immunohistochemistry, but not in normal cervix. High messenger RNA expression by real-time polymerase chain reaction and high Trop-2 surface expression by flow cytometry were detected in 80% of cervical cancers (4 of 5 cell lines). Although these tumors were resistant to natural killer cell-dependent cytotoxicity in vitro (mean killing, 6.0%), Trop-2-positive cell lines showed high sensitivity to hRS7 ADCC (range of killing, 30.6-73.2%). Incubation with IL-2 further increased the level of cytotoxicity against Trop-2-positive tumors.CONCLUSION:
hRS7 may represent a novel treatment option for patients with cervical cancer refractory to conventional treatment modalities.Related: Monoclonal Antibodies Interleukin 2 (Aldesleukin) Cervical Cancer
Vinagre RM, Corvelo TC, Arnaud VC, et al.Determination of strains of Helicobacter pylori and of polymorphism in the interleukin-8 gene in patients with stomach cancer.
Arq Gastroenterol. 2011 Jan-Mar; 48(1):46-51 [PubMed
] Related Publications
Gastric neoplasia is the second most common cause of death by cancer in the world and H. pylori is classified as a type I human carcinogen by the World Health Organization. However, despite the high prevalence of infection by H. pylori around the world, less than 3% of individuals carrying the bacteria develop gastric neoplasias. Such a fact indicates that evolution towards malignancy may be associated with bacterial factors in the host and the environment.OBJECTIVES:
To investigate the association between polymorphism in the region promoting the IL-8 (-251) gene and the H. pylori genotype, based on the vacA alleles and the presence of the cagA gene, using clinical and histopathological data.METHODS:
In a prospective study, a total of 102 patients with stomach cancer and 103 healthy volunteers were analysed. Polymorphism in interleukin 8 (-251) was determined by the PCR-restriction fragment length polymorphism reaction and sequencing. PCR was used for genotyping the vacA alleles and the cagA in the bacterial strains PCR. Gastric biopsies were histologically assessed.RESULTS:
The H. pylori serology was positive for 101 (99%) of all patients analysed, and 98 (97%) of them were colonized by only one strain. In patients with monoinfection, 82 (84%) of the bacterial strains observed had the s1b/m1 genotype. The cagA gene was detected in 74 (73%) of patients infected by H. pylori. The presence of the cagA gene was demonstrated as associated with the presence of the s1b/m1 genotype of the vacA gene (P = 0.002). As for polymorphism in the interleukin 8 (-251) gene we observed that the AA (P = 0.026) and AT (P = 0.005) genotypes were most frequent in the group of patients with gastric adenocarcinoma. By comparing the different types of isolated bacterial strains with the interleukin -8 (-251) and the histopathological data we observed that carriers of the A allele (AT and AA) infected by virulent strains (m1s1 cagA+) demonstrated a greater risk of presenting a degree of inflammation (OR = 24.75 CI 95% 2.29-267.20 P = 0.004) and increased neutrophilic activity (OR = 28.71 CI 95% 2.62-314 P = 0.002) in the gastric mucosa.CONCLUSION:
Our results demonstrate that the interaction between polymorphism in the interleukin -8 (-251) gene, particularly with carriers of the A allele and the infecting type of H. pylori strain (s1m1 cagA positive) performs an important function in development of gastric adenocarcinoma.Related: Polymorphisms Stomach Cancer Gastric Cancer
Ghezzi TL, Brum IS, Biolchi V, et al.Is there any association between TACSTD2, KIAA1253, Ku70 and mutant KRAS gene expression and clinical-pathological features of colorectal cancer?
Exp Oncol. 2011; 33(1):28-32 [PubMed
] Related Publications
To determine the quantitative gene expression of KRAS codon 12 mutant, TACSTD2, Ku70 and SERIN1 in samples of tumor tissue and to relate them with clinical-pathological characteristics of colorectal cancer.METHODS:
Samples of tumor and normal tissue of patients surgically treated for colorectal cancer between July 2005 and July 2009 were stored in a tissue bank. These samples were studied with the technique of real-time polymerase chain reaction in respect to expression of the following genes: KRAS codon 12 mutation, TACSTD2, Ku70, and SERIN1.RESULTS:
Tumor samples of 37 patients were studied. The mean age was 65.5 years. Twenty one patients (56.8%) were male. Nine patients (24.3%) were classified as TNM stage I, 11 patients (29.8%) as TNM stage II, eight patients (21.6%) as TNM stage III and nine patients (24.3%) as TNM stage IV. The Ku70 expression in poorly-differentiated tumors is significantly higher than in well and moderately-differentiated tumors (2.76 vs. 1.13; p < 0.05). SERIN1, TACSTD2 and KRAS codon 12 mutation are not associated with clinical-pathological characteristics of colorectal cancer.CONCLUSION:
Ku70 expression in poorly-differentiated tumors is significantly higher than in well and moderately-differentiated colorectal tumors.Related: Colorectal (Bowel) Cancer KRAS gene
Jerónimo C, Esteller MDNA methylation markers for prostate cancer with a stem cell twist.
Cancer Prev Res (Phila). 2010; 3(9):1053-5 [PubMed
] Related Publications
This perspective on Ibragimova et al. (beginning on page 1084 in this issue of the journal) highlights the potential role of DNA methylation-based markers in the early detection of prostate cancer (PCa), with a focus on the global reactivation of expression of genes epigenetically silenced in PCa cell lines. Novel findings of these investigators identified four genes methylated specifically in PCa, including the stem cell marker TACSTD2, which seems to discriminate PCa (methylated TACSTD2) from prostatic intraepithelial neoplasia (unmethylated). These genes add significantly to the list of epigenetic markers showing promise for clinical early detection of PCa in the near future.Related: Prostate Cancer
Transcriptional silencing associated with aberrant promoter hypermethylation is a common mechanism of inactivation of tumor suppressor genes in cancer cells. To globally profile the genes silenced by hypermethylation in prostate cancer, we screened a whole genome expression microarray for genes reactivated in the LNCaP, DU-145, PC-3, and MDA2b prostate tumor cell lines after treatment with the demethylating drug 5-aza-2-deoxycytidine and the histone deacetylation-inhibiting drug trichostatin A. A total of 2,997 genes showed at least 2-fold upregulation of expression after drug treatment in at least one prostate tumor cell line. For validation, we examined the first 45 genes, ranked by upregulation of expression, which had a typical CpG island and were known to be expressed in the normal cell counterpart. Two important findings were, first, that several genes known to be frequently hypermethylated in prostate cancer were apparent, and, second, that validation studies revealed eight novel genes hypermethylated in the prostate tumor cell lines, four of which were unmethylated in normal prostate cells and hypermethylated in primary prostate tumors (SLC15A3, 66%; KRT7, 54%; TACSTD2, 17%; GADD45b, 3%). Thus, we established the utility of our screen for genes hypermethylated in prostate cancer cells. One of the novel genes was TACSTD2/TROP2, a marker of human prostate basal cells with stem cell characteristics. TACSTD2 was unmethylated in prostatic intraepithelial neoplasia and may have utility in emerging methylation-based prostate cancer tests. Further study of the hypermethylome will provide insight into the biology of the disease and facilitate translational studies in prostate cancer.Related: Prostate Cancer
Genes that are highly overexpressed in tumor cells can be required for tumor cell survival and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRCs) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or short-hairpin RNAs (shRNAs), i.e., HMGA1, TACSTD2, RRM2, RPS2 and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAi-specific gene expression signatures allowed the identification of the functional space in which the five genes operate and showed enrichment for cancer-specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas, we could recapitulate these defined RNAi signatures, therefore, establishing the biological relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1 and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.Related: Colorectal (Bowel) Cancer
Kobayashi H, Minami Y, Anami Y, et al.Expression of the GA733 gene family and its relationship to prognosis in pulmonary adenocarcinoma.
Virchows Arch. 2010; 457(1):69-76 [PubMed
] Related Publications
The GA733 gene family is composed of GA733-1 (TROP2) and GA733-2 (Ep-CAM), whose expression has been examined in various carcinomas and reported to be significantly associated with prognosis. The aim of this study was to investigate the expression of GA733 gene family members and to compare their prognostic significance in pulmonary adenocarcinoma. One hundred thirty paraffin-embedded specimens of small-sized pulmonary adenocarcinoma, less than 2 cm in diameter, were categorized using the classification of small-sized pulmonary adenocarcinoma devised by Noguchi et al. (Cancer 75:2844-2852, 1995) and examined immunohistochemically using a murine monoclonal antibody against Ep-CAM and a goat polyclonal antibody against TROP2. The patient survival rate was calculated using the Kaplan-Meier method. Ep-CAM and TROP2 were similarly expressed in many small-sized pulmonary adenocarcinomas. The expression of Ep-CAM was significantly related to a favorable outcome (p = 0.0185), whereas TROP2 tended to be expressed in cases with an unfavorable outcome (p = 0.0564), and was significantly associated with an unfavorable outcome in nonlepidic-type adenocarcinomas (p = 0.0125). Multivariate analysis showed that TROP2 overexpression and lymph node metastasis were independent prognostic markers. Although the two GA733 proteins share structural similarity, they appear to have opposite biological significances in small-sized adenocarcinomas. As the expression of TROP2 was detected in more poorly differentiated tumors, the protein may have oncogenic activity.Related: Lung Cancer EPCAM