Research IndicatorsGraph generated 13 March 2017 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 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TIAM1 (cancer-related)
OBJECTIVE: To investigate the characteristics of Tiam1 gene expression in human cholangiocarcinoma tissues and benign bile duct tissues, and to analyze the correlations between Tiam1 gene expression and the degree of tumor differentiation, invasive and metastatic abilities. To explore the effect of targeted inhibiting Tiam1 gene expression on proliferation and migration activity of human cholangiocarcinoma cells.
METHODS: Expression of Tiam1 in 83 cases of cholangiocarcinoma tissues and 25 cases of benign bile tissues was detected using immunohistochemistry. The clinical data of patients with cholangiocarcinoma were collected. The correlations between Tiam1 gene expression and the clinicopathologic features in patients with cholangiocarcinoma were analyzed. The human cholangiocarcinoma RBE cells were divided into 3 groups. Cells in experimental group and control group were respectively transfected with Tiam1 shRNA lentiviral vectors and negative shRNA lentiviral control vectors. Cells in blank group received no treatment. Real-time PCR endogenesis was used to verify Tiam1 gene expression. Cell cycle experiments and MTT assay were used to measure cell proliferation activity. Transwell test was used to detect cell migration activity.
RESULTS: The negative rate Tiam1 protein expression in cholangiocarcinoma tissues was significantly higher than that in benign bile tissues (P<0.001). Tiam1 protein expression in cholangiocarcinoma tissues had correlations with cholangiocarcinoma differentiation degree, TNM stage and lymph node metastasis (P<0.05), and had no significant correlations with gender, age and distant metastasis (P>0.05). Real-time PCR detection indicated that Tiam1 expression of experimental group was significantly lower than that in control group and blank group (P<0.05), demonstrating that Tiam1 shRNA was effective on Tiam1 gene silencing in RBE cells. Cell cycle experiment showed that the percentage of S phase in cell cycle in experimental group was lower than that in control group and blank group (P<0.05), demonstrating that after the down-regulation of Tiam1 gene expression, the speed of cell proliferation was inhibited. MTT assay results showed that the total growth speed in experimental group was significantly lower than that in control group and blank group (P<0.05), indicating that the proliferation activity of cholangiocarcinoma cells was inhibited after targeted inhibition of Tiam1 gene expression. Transwell detection results showed that the metastasis rate in experimental group was significantly lower than that in control group and blank group (P<0.05), demonstrating that targeted inhibition of Tiam1 gene expression could significantly inhibit migration ability of RBE cells.
CONCLUSION: Tiam1 expression significantly increased in cholangiocarcinoma tissues, and increased along with the degree of malignancy of cholangiocarcinoma. Targeted silencing Tiam1 expression could inhibit proliferation and migration activity of cholangiocarcinoma cells.
Zheng L, Zhang Y, Lin S, et al.Down-regualtion of miR-106b induces epithelial-mesenchymal transition but suppresses metastatic colonization by targeting Prrx1 in colorectal cancer.
Int J Clin Exp Pathol. 2015; 8(9):10534-44 [PubMed
] Free Access to Full Article Related Publications
Accumulating evidence identified that epithelial-mesenchymal transition (EMT) is acquired during progression to metastatic, but whether it is an absolute requirement is still controversial. MiR-106b has been confirmed to promote cancer cell proliferation; however few studies are available on its functions in EMT and metastasis in colorectal cancer (CRC). In this study, we found that knocking down miR-106b induced EMT conferring migratory and invasive properties. MiR-106b knockdown induced cytoskeletal reorganization through staining intracellular F-actin. The expression of Rho GTPases (Rac1 and Cdc42) and Tiam1 was significantly enforced after miR-106b down-regulation. However, miR-106b knocking down could suppress metastatic colonization in vivo. Correspondingly, over expression of miR-106b obtained an opposite effect. We identified Prrx1 was a direct target of miR-106b through using target prediction algorithms and dual-Luciferase reporter assay. Moreover, Moreover, we also found TGF-β1 could down-regulate miR-106b, and simultaneously miR-106b also influences the expression of TGF-β1, establishing a negative feedback loop to regulate the expression of Prrx1 together. Taken together, these findings demonstrated that miR-106b knockdown could induce EMT which conferring cells migratory and invasive properties but could not accomplish distant metastatic colonization efficiently.
Guo X, Wang M, Zhao Y, et al.Par3 regulates invasion of pancreatic cancer cells via interaction with Tiam1.
Clin Exp Med. 2016; 16(3):357-65 [PubMed
] Related Publications
The conserved polarity complex, which comprises partitioning-defective proteins Par3, Par6, and the atypical protein kinase C, affects various cell-polarization events, including assembly of tight junctions. Control of tight junction assembly is closely related to invasion and migration potential. However, as the importance of conserved polarity complexes in regulating pancreatic cancer invasion and metastasis is unclear, we investigated their role and mechanism in pancreatic cancers. We first detect that the key protein of the conserved polarity complex finds that only Par3 is down-regulated in pancreatic cancer tissues while Par6 and aPKC show no difference. What is more, Par3 tissues level was significantly and positively associated with patient overall survival. Knocking-down Par3 promotes pancreatic cancer cells invasion and migration. And Par3 requires interaction with Tiam1 to affect tight junction assembly, and then affect invasion and migration of pancreatic cancer cells. Then, we find that tight junction marker protein ZO-1 and claudin-1 are down-regulated in pancreatic cancer tissues. And the relationship of the expression of Par3 and ZO-1 in pancreatic cancer tissue is linear correlation. We establish liver metastasis model of human pancreatic cancer cells in Balb/c nude mice and find that knocking down Par3 promotes invasion and metastasis and disturbs tight junction assembly in vivo. Taken together, these results suggest that the Par3 regulates invasion and metastasis in pancreatic cancers by controlling tight junction assembly.
BACKGROUND: Osteosarcoma is the most common primary bone malignancy in children and young adults. Increasing results suggest that discovery of microRNAs (miRNAs) might provide a novel therapeutical target for osteosarcoma.
METHODS: MiR-182 expression level in osteosarcoma cell lines and tissues were assayed by qRT-PCR. MiRNA mimics or inhibitor were transfected for up-regulation or down-regulation of miR-182 expression. Cell function was assayed by CCK8, migration assay and invasion assay. The target genes of miR-182 were predicated by bioinformatics algorithm (TargetScan Human).
RESULTS: MiR-182 was down-regulated in osteosarcoma tissues and cell lines. Overexpression of miR-182 inhibited tumor growth, migration and invasion. Subsequent investigation revealed that TIAM1 was a direct and functional target of miR-182 in osteosarcoma cells. Overexpression of miR-182 impaired TIAM1-induced inhibition of proliferation and invasion in osteosarcoma cells.
CONCLUSIONS: Down-expression of miR-182 in osteosarcoma promoted tumor growth, migration and invasion by targeting TIAM1. MiR-182 might act as a tumor suppressor gene whose down-regulation contributes to the progression and metastasis of osteosarcoma, providing a potential therapy target for osteosarcoma patients.
Zhu G, Fan Z, Ding M, et al.An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis.
Oncogene. 2015; 34(49):5971-82 [PubMed
] Related Publications
Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival, and its overactivation drives cancer development. One important branch of EGFR signaling is through activation of GTPase Rac1, which further promotes cell proliferation, survival and cancer metastasis. Here, we show that EGFR activates Rac1 via inducing the accumulation of its specific guanine nucleotide exchange factor, T-cell lymphoma invasion and metastasis 1 (Tiam1) in non-small-cell lung cancer and colon cancer cells. Conversely, elevated Tiam1 is required for EGFR-induced tumorigenesis. In human lung adenocarcinoma and colon cancer specimens, Tiam1 expression strongly correlates with EGFR expression. We further reveal that AKT, a key downstream protein kinase of EGFR, phosphorylates Tiam1 at several consensus sites, facilitates the interaction of Tiam1 with scaffold proteins 14-3-3 and leads to an increase of Tiam1 stability. Subsequently, Tiam1 is dephosporylated and destabilized by PP2A. Together, our study identifies a bidirectional (phosphorylation and dephosphorylation) regulatory mechanism controlling Tiam1 stability and provides new insights on how EGFR signaling triggers Rac1 activation and cancer development.
Zhu H, Yang M, Zhang H, et al.Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways for gastric adenocarcinoma.
Tumour Biol. 2015; 36(7):5635-9 [PubMed
] Related Publications
To demonstrate candidate single nucleotide polymorphisms that might affect susceptibility to gastric adenocarcinoma as well as their potential mechanisms and pathway hypotheses, we performed a genome-wide association study dataset of gastric adenocarcinoma. Our study included 472,342 single nucleotide polymorphisms from 2766 cases of gastric cardia adenocarcinoma cases and 11,013 subjects from north central China as control groups. The identify candidate causal SNPs and pathways (ICSNPathway) analysis was employed to identify 13 candidate single nucleotide polymorphisms, nine genes, and 15 pathways. The top three candidate SNPs were rs3765524 (-log10(p) = 8.556), rs2274223 (-log10(p) = 8.633), and rs2076472 (-log10(p) = 3.205). The strongest mechanism involved the modulation of rs4745 and rs12904, thereby affecting their regulatory roles in ephrin receptor binding (p = 0.001; FDR = 0.005). The second strongest hypothetical biological mechanism was that rs932972 and rs1052177 alters the regulatory role of the glycolysis pathway (p < 0.001; FDR = 0.013). The most significant pathway was the regulation of the ephrin receptor binding pathway, which involved EFNA1, TIAM1, EFNA5, EFNB2, and EFNB3.
Wang S, Li S, Tang Q, et al.Overexpression of Tiam1 promotes the progression of laryngeal squamous cell carcinoma.
Oncol Rep. 2015; 33(4):1807-14 [PubMed
] Related Publications
T-lymphoma invasion and metastasis‑inducing factor 1 (Tiam1) has been reported in various types of human cancer, which play important roles in facilitating the meta-stasis of malignant tumor. However, the investigation of Tiam1 in laryngeal squamous-cell carcinoma is extremely rare. The aim of the present study was to assess Tiam1 expression and examine its function in tumorigenesis and the metastasis of laryngeal squamous cell carcinoma (LSCC) in vitro. Tiam1 expression in 98 primary LSCC tissue specimens was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients' survival. To investigate the effects of Tiam1 on the progression of LSCC, Tiam1/C1199 plasmid was transfected into LSCC, and proliferation, apoptosis, migration and invasion of transfected cells were examined using MTT, flow cytometry, wound-healing and Transwell assay, respectively. The results showed that, Tiam1 was detected in all primary LSCC samples. Additionally, Tiam1 overexpression was closely correlated with tumor progression and patient survival. Tiam1 overexpression was statistically significant, and served as an independent predictor of prognosis for patients with LSCC. The upregulation of Tiam1 by Tiam1/C1199 plasmid had no effect on the prolife-ration of transfected cells, but decreased the apoptotic rate of transfected cells, while the ability of migration and invasion was increased. These results suggested that Tiam1 overexpression in LSCC is possibly involved in the promotion of migration and invasion, and is a promising therapeutic target in the prevention of the progression of LSCC.
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Emerging evidence has shown that abnormal microRNAs (miRNAs) expression is involved in tumorigenesis. MiR-329 was previously reported to act as a tumor suppressor or oncogene in some types of cancer. However, its function in gastric cancer (GC) is unclear. Here, we found that miR-329 was down-regulated in GC compared with adjacent controls. Enforced expression of miR-329 inhibited proliferation, migration and invasion of gastric cancer cells in vitro. We identified T lymphoma invasion and metastasis 1 (TIAM1) gene as potential target of miR-329. MiR-329 levels inversely correlated with TIAM1 expression in GC. Importantly, TIAM1 rescued the miR-329-mediated inhibition of cell invasion and proliferation. Finally, reintroduction of miR-329 significantly inhibited tumor formation of GC in the xenograft mice. Our findings suggest that miR-329 is a tumor suppressor and potential therapeutic target of GC.
The E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC.
Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.
Wang B, Li W, Liu H, et al.miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition.
Cell Death Dis. 2014; 5:e1335 [PubMed
] Free Access to Full Article Related Publications
Recently, the role of miR-29b in colorectal carcinoma (CRC) development appears to be controversial. Until now, the expression and function of miR-29b in CRC have not been clarified clearly. We showed that decreased expression of miR-29b usually occurred in CRC cell lines and tissue samples. Loss- and gain-of-function assays in vitro revealed suppressive effects of miR-29b on cell proliferation and migration. Endogenous overexpression of miR-29b was sufficient to suppress aggressive behavioral phenotypes in mice. Proteomic analysis showed that miR-29b involved in integrate several key biological processes. In addition, miR-29b mediated the inhibition of epithelial-mesenchymal transition (EMT) and the inactivation of mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signal transduction pathway. Further studies found that T lymphoma invasion and metastasis 1 (Tiam1) was identified as a direct target of miR-29b. In contrast to the phenotypes induced by miR-29b restoration, Tiam1-induced cell proliferation and migration partly rescued miR-29b-mediated biological behaviors. Our results illustrated that miR-29b as a suppressor has a critical role in CRC progression, which suggests its potential role in the molecular therapy of patients with advanced CRC.
Ding Y, Chen B, Huang J, et al.Overexpression of Tiam1 is associated with malignant phenotypes of nasopharyngeal carcinoma.
Oncol Rep. 2014; 32(2):607-18 [PubMed
] Related Publications
The aim of the present study was to analyze the roles of T lymphoma invasion and metastasis 1 (Tiam1) in nasopharyngeal carcinoma (NPC) progression and its correlation with clinicopathological features, including the survival of patients with NPC. Tiam1 protein expression in NPC tissues was examined using immunohistochemistry. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence staining were performed to detect the expression of Tiam1 in 6 NPC cell lines. Stable Tiam1-overexpressing NPC cells using a transfection technique and Tiam1-silencing NPC cells using short hairpin RNA were constructed. Subsequently, MTT assay, plate and soft agar colony formation assays, cell adhesion, migration, invasion assays and experimental animal models were carried out to detect the biological functions of Tiam1 in vitro and in vivo. Immunohistochemical analysis revealed that Tiam1 had high expression in 96 of 140 (68.6%) paraffin-embedded archival NPC biopsies. Tiam1 overexpression was significantly associated with N classification (P=0.004), distant metastasis (P=0.042) and clinical stage (P=0.042). Patients with higher levels of Tiam1 expression had poorer overall survival (P=0.002). Multivariate analysis revealed that Tiam1 expression is an independent prognostic indicator for the overall survival of NPC patients. Using the approaches of exogenous overexpression and the knockdown of Tiam1 expression, respectively, it was confirmed that Tiam1 promoted cell proliferation, adhesion, invasion and migration in vitro and in vivo. These data support the notion that Tiam1 plays an important role in the progression of NPC, and the overexpression of Tiam1 is associated with malignant phenotypes of NPC.
BACKGROUND: We have demonstrated that T lymphoma invasion and metastasis 1 (Tiam1) gene is associated with the poor prognosis of patients with hepatocellular carcinoma (HCC), and we used a computational approach to identify miR-141 as a Tiam1-targeting microRNA (miRNA). Here, we explored the function of miR-141 and the relationship between miR-141 and Tiam1 gene in HCC.
METHODS: The miR-141 expression in HCC tissues and cell lines was detected and its roles in regulation of HCC cell proliferation, migration and invasion and target gene expression was investigated. Tiam1 was identified as a novel target of miR-141. Ethics statement: our study was approved by the Nanfang Hospital Medical Ethics Committee Ethics statement. Written informed consent was obtained before collection.
RESULTS: Based on in situ hybridization (ISH) analysis, miR-141 was down-regulated in the same HCC samples. Kaplan-Meier analysis demonstrated that patients with low miR-141 expression had poorer overall survival rate than that of the patients with high miR-141 expression. Furthermore, multivariate Cox regression analysis indicated that miR-141 could serve as an independent prognostic factor in HCC. MiR-141 significantly inhibited in vitro cell proliferation, migration and invasion as proved by gain- and loss- of function studies, while the mRNA and protein levels of Tiam1 were reduced in cells over-expressing miR-141. Moreover, Tiam1 treatment antagonized this effect, while knockdown of Tiam1 by Tiam1 short hairpin RNA (shTiam1) induced inhibitory effects.
CONCLUSIONS: These findings indicated that miR-141 functions as a tumor suppressor and inhibits the migration and invasion of HCC cells by targeting Tiam1, which may provide novel prognostic and treatment strategies for HCC patients.
Hofbauer SW, Krenn PW, Ganghammer S, et al.Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.
Blood. 2014; 123(14):2181-8 [PubMed
] Related Publications
Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but not Rac1 activation, whereas chemokine-induced CLL cell motility was Rac1-independent. Coculture of CLL cells with activated T cells induced their activation and subsequent proliferation. Here, Tiam1 expression was induced in the malignant cells in line with increased Ki-67 and c-Myc expression. Rac1 or Tiam1 knockdown using siRNA or treatment with the Tiam1/Rac inhibitor NSC-23766 attenuated c-Myc transcription. Furthermore, treatment of CLL cells with NSC-23766 reduced their proliferation. Rac inhibition also antagonized the chemoresistance of activated CLL cells toward fludarabine. Collectively, our data suggest a dynamic regulation of Rac1 function in the CLL microenvironment. Rac inhibition could be of clinical use by selectively interfering with CLL cell proliferation and chemoresistance.
Li Z, Lei H, Luo M, et al.DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer.
Gastric Cancer. 2015; 18(1):43-54 [PubMed
] Related Publications
BACKGROUND: MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC.
METHODS: Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues (n = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues (n = 29).
RESULTS: We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2'-deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene.
CONCLUSIONS: Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC.
BACKGROUND: MiRNAs play important roles in diverse biological processes including tumorigenesis. However, little is known about the function and mechanism of miR-451 in nasopharyngeal carcinoma (NPC).
METHODS: Quantitative RT-PCR was used to quantify miR-451 expression in NPC cell lines and clinical tissues. Kaplan-Meier curves were used to estimate the association between miR-451 expression and survival. The MTT, colony formation, Transwell migration and invasion assays, and a xenograft model were performed. A miR-451 target was confirmed using luciferase reporter assays, quantitative RT-PCR, and Western blotting.
RESULTS: MiR-451 was significantly downregulated in NPC cell lines and clinical tissues (P < 0.01). Patients with low expression of miR-451 had poorer overall survival (HR, 1.98; 95% CI, 1.16-3.34; P = 0.01) and disease-free survival (HR, 1.68; 95% CI, 1.07-2.62; P = 0.02) than patients with high expression. MiR-451 was an independent prognostic factor in NPC in multivariate Cox regression analysis. Ectopic expression of miR-451 suppressed cell viability, colony formation, and cell migration and invasion in vitro, and inhibited xenograft tumor growth in vivo. MIF was verified as a direct target of miR-451, and MIF regulated NPC cell growth and invasion.
CONCLUSIONS: The newly identified miR-451/MIF pathway provides insight into NPC initiation and progression, and may represent a novel therapeutic target.
BACKGROUND: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.
METHODS: Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA).
RESULTS: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10(-4)) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10(-7)) at a false discovery rate of 6%.
CONCLUSIONS: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.
IMPACT: A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
Cardama GA, Comin MJ, Hornos L, et al.Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines.
Anticancer Agents Med Chem. 2014; 14(6):840-51 [PubMed
] Free Access to Full Article Related Publications
Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy.
The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger).
T lymphoma invasion and metastasis protein (Tiam1) is up-regulated in variety of cancers and its expression level is related to metastatic potential of the type of cancer. Earlier, Tiam1 was shown to be overexpressed in retinoblastoma (RB) and we hypothesized that it was involved in invasiveness of RB. This was tested by silencing Tiam1 in RB cell lines (Y79 and Weri-Rb1) using siRNA pool, targeting different regions of Tiam1 mRNA. The cDNA microarray of Tiam1 silenced cells showed gene regulations altered by Tiam1 were predominantly on the actin cytoskeleton interacting proteins, apoptotic initiators and tumorogenic potential targets. The silenced phenotype resulted in decreased growth and increased apoptosis with non-invasive characteristics. Transfection of full length and N-terminal truncated construct (C1199) clearly revealed membrane localization of Tiam1 and not in the case of C580 construct. F-actin staining showed the interaction of Tiam1 with actin in the membrane edges that leads to ruffling, and also imparts varying invasive potential to the cell. The results obtained from our study show for the first time that Tiam1 modulates the cell invasion, mediated by actin cytoskeleton remodeling in RB.
Jin J, Cai L, Liu ZM, Zhou XSmiRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9.
Asian Pac J Cancer Prev. 2013; 14(6):3681-4 [PubMed
] Related Publications
Deregulated miRNAs participate in osteosarcoma genesis. In this study, the expression of miRNA-218 in human osteosarcomas, adjacent normal tissues and Saos-2 human osteosarcoma cells was first assessed. Then the precise role of miRNA-218 in osteosarcoma cells was investigated. Upon transfection with a miR-218 expression vector, the proliferation of Saos-2 human osteosarcoma cells determined using the ATPlite assay was significantly suppressed, whilw migration of Saos-2 cells detected by wound healing and invasion determined using transwells were dramatically inhibited. Potential target genes of miR-218 were predicted and T-cell lymphoma invasion and metastasis 1 (TIAM1) and matrix metalloproteinase 2 (MMP2) and 9 (MMP9) were identified. This was confirmed by western blotting, which showed that miR-218 expression inhibited TIAM1, MMP2 and MMP9 protein expression. Collectively, these data suggest that miR-218 acts as a tumor suppressor in osteosarcomas by down-regulating TIAM1, MMP2 and MMP9 expression.
Zhu JM, Yu PWDownregulation of T‑cell lymphoma invasion and metastasis‑inducing factor 1 induces cytoskeletal rearrangement and inhibits the invasive capacity of gastric cancer cells.
Mol Med Rep. 2013; 8(2):425-33 [PubMed
] Related Publications
T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam-1) is an important member of the diffuse B-cell lymphoma (Dbl) oncogene family. In a previous study, the overexpression of Tiam-1 protein was identified by immunohistochemistry in human gastric cancer tissues, indicating that Tiam-1 may represent a candidate biomarker of the invasive and metastatic capacity of gastric cancer and for patient prognosis. In the present study, in vitro adhesion selection was used to separate two subpopulations with high (MH) or low (ML) invasive and metastatic potential from the MKN-45 human gastric cancer cell line (M0). A positive correlation was observed between Tiam-l mRNA and protein expression levels and the invasive capacity of the cells using RT-PCR and quantitative cellular-ELISA, respectively. To determine the mechanism by which Tiam-1 affects the invasive capacities of gastric cancer cells, Tiam-1 expression was downregulated in the MH subclone by liposomal transfection of antisense oligodeoxynucleotides (ASODNs). Following 48 h of treatment with ASODNs (0.43 µM), Tiam-1 mRNA transcription and protein expression levels in MH cells was decreased by 80 and 24%, respectively, compared with untreated controls. In addition, the in vitro invasive potential of MH cells was suppressed by 60%. Morphological and ultrastructural observations also demonstrated that ASODN-treated MH cells exhibited a smooth surface with markedly reduced filopodia and microspikes, which resembled M0 and ML cells. In addition, cytoskeletal distribution was markedly altered from disordered to regular with reduced long filament-like structures, projections, pseudopodia on the cell surface and decreased actin bodies in the cytoplasm. Results of the current study indicate that the overexpression of Tiam-1 contributes to the invasive phenotypes of gastric cancer cells. These observations are likely to provide an improved insight into the biological mechanisms of Tiam-1 and promote the development of novel treatment strategies in gastric cancer.
Huang YH, Lin YH, Chi HC, et al.Thyroid hormone regulation of miR-21 enhances migration and invasion of hepatoma.
Cancer Res. 2013; 73(8):2505-17 [PubMed
] Related Publications
Thyroid hormone (T(3)) signaling through the thyroid hormone receptor (TRα1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T(3). Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of β-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRα1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P = 0.005) between the tumor/nontumor ratios of TRα1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion.
Li B, Song Y, Liu TJ, et al.miRNA-22 suppresses colon cancer cell migration and invasion by inhibiting the expression of T-cell lymphoma invasion and metastasis 1 and matrix metalloproteinases 2 and 9.
Oncol Rep. 2013; 29(5):1932-8 [PubMed
] Related Publications
Emerging evidence has demonstrated the altered expression of mRNAs in cancer development and progression. In this study, the precise role of miRNA-22 (miR-22) in colon cancer cells was investigated. Upon transfection with a miR-22 expression vector, the viability of HCT-116 human colon cancer cells was significantly reduced and tumor cell migration and invasion capacity were also suppressed. Computational in silico analysis predicted that T-cell lymphoma invasion and metastasis 1 (TIAM1) is a target gene of miR-22. This was confirmed by qRT-PCR and western blotting, which showed that miR-22 expression inhibited TIAM1 mRNA and protein expression, respectively. In addition, the expression of pro-invasive gene matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and pro-angiogenic protein vascular endothelial growth factor (VEGF) were also reduced by miR-22 expression. Collectively, these data suggest that miR-22 may act as a tumor suppressor in colon cancer, most likely by targeting TIAM1 expression.
Shi YL, Miao RZ, Cheng L, et al.Up-regulation of T-lymphoma and metastasis gene 1 in gastric cancer and its involvement in cell invasion and migration.
Chin Med J (Engl). 2013; 126(4):640-5 [PubMed
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BACKGROUND: T-lymphoma and metastasis gene 1 (Tiam1) produces a guanine nucleotide exchange factor (GNEF) that regulates guanosine triphosphatase, which transforms guanosine diphosphate to guanosine triphosphate. Recently published data indicate that Tiam1 was associated with gastric cancer. The aim of this study was to investigate biological effects and potential mechanisms of Tiam1 in gastric carcinoma.
METHODS: We analyzed the expression of Tiam1 in 114 pair-matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time PCR. We investigated Tiam1 expression and its prognostic value for gastric cancer. Furthermore, the functions of Tiam1 over-expression were analyzed with stable-expression Tiam1 plasmid in human gastric cancer cell lines.
RESULTS: Tiam1 expression was significantly associated with cell differentiation and lymphatic metastasis; expression of Tiam1 mRNA was up-regulated in gastric cancer compared to pair-matched adjacent non-tumor tissues. Analyses of surgical tissue samples and 5-year survival of gastric cancer patients showed that those with strong Tiam1 expression had significantly shorter overall survival time than those with negative Tiam1 expression. Ectopic expression of Tiam1 promoted cell growth, migration and invasion of gastric cancer cells in vitro.
CONCLUSIONS: In gastric cancer cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may be a marker of gastric cancer progression and metastasis in a subset of cancer.
Guo X, Wang M, Jiang J, et al.Balanced Tiam1-rac1 and RhoA drives proliferation and invasion of pancreatic cancer cells.
Mol Cancer Res. 2013; 11(3):230-9 [PubMed
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Tiam1 is a rac1-specific guanine nucleotide exchange factor, and Tiam1-rac1 is involved in a number of cellular processes. Rac1 and RhoA act as molecular switches that cycle between GTP- and GDP-bound states to balance the activities of rac1 and RhoA. The downregulation of rac1 activity leads to upregulation of RhoA activity, which promotes invasion and migration of pancreatic cancers cells. At present, however, the role of Tiam1-rac1 and RhoA in pancreatic cancers is not fully understood. We found that Tiam1 was upregulated in pancreatic cancers and was significantly expressed in tumors without lymph node involvement or distant metastasis compared with cancers where there was involvement. Although Tiam1-rac1 signaling promoted pancreatic cancer cell proliferation and tumor growth via the Wnt signaling pathway in vitro and in vivo, inhibiting Tiam1-rac1 signaling did not prolong the overall survival time in vivo. This provided evidence that there was a balance between rac1 and RhoA activities in pancreatic cancers. Furthermore, only the combined inhibition of Tiam1-rac1 and RhoA had a beneficial effect on the growth of pancreatic cancers in vivo. Taken together, these results suggest that the progression of pancreatic tumors is partially controlled by the balance between Tiam1-rac1 and RhoA.
BACKGROUND: It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements.
RESULTS: We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing-55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer-in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator.
CONCLUSIONS: This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.
The ability of cells to invade into the dermis is a critical event in the development of cutaneous melanoma and ultimately an indicator of poor prognosis. However, the molecular events surrounding the acquisition of this invasive phenotype remain incompletely understood. Mutations in B-RAF are frequent in melanoma and are known to regulate the invasive phenotype. In this study, we sought to determine the molecular mechanisms controlling melanoma invasion. We found that mutant B-RAF signaling regulates a cadherin switch. In melanoma cells expressing mutant B-RAF we observed high levels of N-cadherin and low levels of E-cadherin. Depletion of mutant B-RAF, by small interfering RNA, caused a decrease in the levels of N-cadherin and an increase in the levels of E-cadherin. Mechanistically, we found that this cadherin switch required the activity of Rac1 and its GEF, Tiam1, both of which show suppressed activity in the presence of mutant B-RAF. Consistent with the work of others, we found that depletion of mutant B-RAF decreased the invasive capacity of the melanoma cells. However, simultaneous depletion of B-RAF and Rac or Tiam1 resulted in invasive capacity similar to that of control cells. Taken together, our results suggest that mutant B-RAF signaling downregulates Tiam1/Rac activity resulting in an increase in N-cadherin levels and a decrease in E-cadherin levels and ultimately enhanced invasion.
Liu N, Tang LL, Sun Y, et al.MiR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma.
Cancer Lett. 2013; 329(2):181-8 [PubMed
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Based on microarray analysis, we previously reported that miR-29c is significantly downregulated in nasopharyngeal carcinoma (NPC). However, little is known about the effect and molecular mechanisms of action of miR-29c deregulation during the development and progression of NPC. Quantitative RT-PCR demonstrated that miR-29c was significantly downregulated in NPC cell lines and clinical specimens. Wound healing, Transwell migration and lung metastasis assays demonstrated that ectopic expression of miR-29c inhibited NPC cell migration and invasion in vitro and suppressed the formation of lung metastases in vivo. T cell lymphoma invasion and metastasis 1 (TIAM1) was confirmed as a miR-29c target gene using luciferase reporter assays, quantitative RT-PCR and Western blotting. Ectopic expression of TIAM1 significantly promoted the migration and invasion of SUNE-1 cell line stably overexpressing miR-29c. The prognostic value of TIAM1 was analyzed in 217 NPC patients using immunohistochemistry. Strikingly, patients with high TIAM1 expression had poorer overall, disease-free and distant metastasis-free survival than patients with low TIAM1 expression. Furthermore, multivariate Cox regression analysis revealed that TIAM1 could serve as an independent prognostic factor in NPC. The newly identified miR-29c/TIAM1 pathway further elucidates the molecular mechanisms regulating invasion and metastasis in NPC, and may provide novel prognostic and treatment strategies for NPC patients.
Huang J, Ye X, Guan J, et al.Tiam1 is associated with hepatocellular carcinoma metastasis.
Int J Cancer. 2013; 132(1):90-100 [PubMed
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We have previously demonstrated that overexpression of T lymphoma invasion and metastasis 1 (Tiam1) is correlated with poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we tried to further investigate the potential roles of Tiam1 in the progression of HCC in a larger set of samples. By detecting Tiam1 expression in 213 HCC patients, we observed that Tiam1 had a higher probability of being overexpressed in HCC patients with metastasis than those without metastasis (68.3% vs. 52.7%, p = 0.036). In addition, the cell line with high metastatic potential expressed more Tiam1 than did the cell line with low metastatic potential. Overexpression of Tiam1 was suggested to be significantly correlated with HCC metastasis. We stably upregulated Tiam1 expression in MHCC97L as well as knocked down Tiam1 expression in HCCLM6. We also investigated the effects of Tiam1 overexpression and knockdown on HCC cells proliferation, migration and invasion in vitro and on tumorigenicity and metastasis in vivo. Overexpression of Tiam1 increased proliferation, migration and invasion of MHCC97L cells, while knockdown of Tiam1 in HCCLM6 cells resulted in the reverse. In vivo functional studies showed upregulation of Tiam1 expression led to an enhancement of tumorigenicity and metastatic potential in mice. However, knockdown of Tiam1 expression exhibited nearly 2.2-fold retardation in tumor growth and great inhibition on tumor metastases. Our results indicate that Tiam1, as a metastasis-related gene, may contribute to HCC invasion and metastasis, and consequently, it may be a useful biomarker for therapeutic strategy and control in HCC treatment.