7074

TIAM1

T-cell lymphoma invasion and metastasis 1;TIAM1;T-cell lymphoma invasion and metastasis 1

T-lymphoma invasion and metastasis-inducing protein 1|TIAM-1|human T-lymphoma invasion and metastasis inducing TIAM1 protein

21q22.11

protein-coding

OBJECTIVE: To investigate the expression of T lymphoma invasion and metastasis inducing factor 1 (Tiam1) in breast carcinomas, and explore its association with the clinicopathological features of breast carcinoma. METHODS: Immunohistochemistry was used to detect Tiam1 expression in normal breast tissue and 126 breast carcinoma tissues, and the expression levels of Tiam1 mRNA and protein were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting, respectively. RESULTS: The expression of Tiam1 was significantly higher in breast carcinomas than in normal breast tissue (P<0.05). Tiam1 expression was not correlated to the age of the patients or the histological type (P>0.05), but to lymph node metastasis and clinical stages of the tumor (P<0.01). Tiam1 mRNA and protein expressions were stronger in breast carcinoma cell line MDA-MB-435 with high metastatic potential than in breast carcinoma cell line MCF-7. CONCLUSION: Tiam1 is closely related to the metastasis of breast carcinoma, and may play an important role in promoting metastasis of breast carcinoma.

OBJECTIVE: To investigate the significance of Tiam1 in invasion and metastasis of breast carcinoma and its mechanisms. METHODS: Immunohistochemistry was used to detect Tiam1 expression in tumor tissue of 126 breast carcinomas. Tiam1 was silenced by siRNA in breast carcinoma cell line MDA-MB-435, then the expressions of phosphor-ERK 1, ERK 2 and VEGF were detected, and electrophoretic mobility shift assay (EMSA) was used to examine the transcription activiy of AP-1. RESULTS: There was a significant relationship between Tiam1 expression and lymph node metastasis (P < 0.05). Furthermore, after silencing of Tiam1, the expressions of phosphor-ERK 1, ERK 2 and VEGF were decreased, and the transcription activity of AP-1 was down-regulated in the MDA-MB-435 cells. CONCLUSION: Tiam1 is closely related with invasion and metastasis of breast carcinoma, and the cascade Tiam1 through ERK, AP-1 and VEGF pathways may play an important role in enhancing angiogenesis, therefore, to promote invasion and metastasis of breast carcinoma.

AIM: To explore the expression of Tiam1 gene in colorectal carcinoma and its correlation with tumor metastasis. METHODS: expressions of Tiam1 gene in 8 colorectal carcinoma cell lines were detected by reverse transcriptase-polymerase chain reaction. In vitro invasiveness was determined by means of Matrigel invasion assay. The correlation of Tiam1 expression with the invasive ability was also analyzed. RESULTS: Tiam1 gene was highly expressed in LoVo and SW620, which were established from metastatic colorectal carcinomas in comparison with LS174T, SW480, HCT116, LST, HRT-18 and Hee8693, which were established from primary colorectal carcinomas. In vitro cell invasion demonstrated that LoVo and SW620 had a higher invasive ability than LS174T, SW480, HCT116, LST, HRT-18 and Hee8693. The expression of Tiam1 gene was highly related to the metastatic potential of colorectal carcinoma cells. CONCLUSION: Tiam1 gene may play an important role in invasion and metastasis of colorectal carcinoma and is a metastasis-related gene.

The guanine nucleotide exchange factor Tiam1 regulates numerous biologic properties including migration and invasion. We demonstrated previously that colon tumor cells biologically selected for increased migration were increased in Tiam1 expression. Cells selected for increased Tiam1 expression or that ectopically overexpress Tiam1 were increased in metastatic potential. Here, we demonstrate that Tiam1 regulates additional functions associated with metastasis, including reduced cellular adhesion and resistance to anoikis. Tiam1 effects on cellular migration are mediated through its downstream substrate, Rac. Increased Tiam1 expression also leads to anoikis-resistance, whereas decreasing Tiam1 expression by siRNA sensitizes cells to this form of apoptosis; however, Tiam1s regulation of anoikis is Rac-independent. Staurosporine sensitivity is also Rac-independent, suggesting Tiam1s effects on apoptosis require other effectors. As many of the observed phenotypes are characteristic of a transition of transformed epithelial cells to a mesenchymal-like phenotype, we also examined biochemical properties associated with an EMT. We demonstrate an increase in vimentin expression in cell lines that overexpress Tiam1 and have a more metastatic phenotype. Concomitant with this increase, we observe a decrease in E-cadherin expression in these cells. Lastly, we stained a panel of human colorectal specimens and adjacent normal tissue, and demonstrate that Tiam1 is overexpressed in a subset of human colorectal tumors. In summary, in colon tumor cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may represent a marker of colon tumor progression and metastasis in a subset of tumors.

T lymphoma invasion and metastasis 1 (Tiam1) is a metastasis-related gene of T lymphoma that is also involved in the metastasis of a variety of other cancers. In this study, we tested the hypothesis that Tiam1 is a determinant of proliferation and metastasis in colorectal cancer, and we examined the effect of the inhibition of Tiam1 expression on proliferation and metastasis. We succeeded in establishing the Tiam1 knockdown colorectal cancer cell line using human immunodeficiency virus lentivirus-mediated RNA interference (RNAi) and found that the silencing of Tiam1 resulted in the effective inhibition of in vitro cell growth and of the invasive ability of colorectal cancer cells. Using an orthotopic xenograft model in nude mice, we confirmed that Tiam1 silencing could reduce tumor growth by subcutaneous injection and could suppress lung and liver metastases of colorectal cancer cells. Our results suggest that Tiam1 truly plays a causal role in the metastasis of colorectal cancer and that RNAi-mediated silencing of Tiam1 may provide an opportunity to develop a new treatment strategy for colorectal cancer.

OBJECTIVE: To observe the effect of Tiam-l gene silencing on the metastasis of human colorectal carcinoma cell line SW480 in nude mice by real-time whole-body fluorescence imaging. METHODS: Enhanced green fluorescence protein (EGFP)-labeled human colorectal carcinoma cells, SW480/EGFP(+)/Tiam-1(-) and SW480/EGFP(+), were implanted into nude mice via tail vein injection or orthotopic colonal inoculation, and real-time whole-body fluorescence imaging was performed to compare the difference in tumor progression and metastasis between the two cells. RESULTS: Both SW480/EGFP(+) and SW480/ EGFP(+)/Tiam-1(-) cells stably expressed EGFP, and Tiam1 gene expression was reduced in SW480/EGFP(+)Tiam-1(-) to 30% of the expression level in SW480/EGFP(+) cells. The growth rate of the two cell lines had no significant difference in vitro (P>0.05), but SW480/EGFP(+)/Tiam1(-) cell proliferation and metastasis were depressed obviously in comparison with SW480/EGFP(+) in vivo (P<0.05). CONCLUSION: Tiam-1 gene may play an important role in invasion and metastasis of human colorectal cancer.

OBJECTIVE: To confirm the role of Tiam1 (T lymphoma invasion and metastasis 1) gene in the proliferation and metastasis of colorectal cancer. METHODS: Proliferative and metastatic abilities of Tiam1 transfectant were investigated by subcutaneous injection of cells and surgical orthotopic transplantation (SOI) in mice. RESULTS: The expression of Tiam1 led to a pronounced increase in HT29/Tiam1 cell growth starting from day 7, up to 2.5 fold increase of tumor volume at day 20 post injection. tumors in the HT29/Tiam1 group receiving surgical orthotopic implantation were significantly heavier than those in HT29/mock group (t = -14.916, P < 0.01). In vivo metastasis assay by SOI showed that in HT29/Tiam1 group, 7/7 of mice developed peritoneal metastases and 4/7 had hepatic lesions. In addition, one of the seven HT29/Tiam1 group mice had tumors in lung, spleen and lymph nodes. In the HT29/mock group, only 2/7 of animals had peritoneal metastases and none produced detectable tumor in the liver. CONCLUSIONS: Tiam1 gene plays an important role in the proliferation, invasion and metastasis of colorectal cancer. It may serve as a useful clinical marker for tumor progression and metastasis of colorectal cancer.

Tiam1 (T-cell lymphoma invasion and metastasis-inducing protein 1), a guanine nucleotide exchange factor that activates Rac, is a colorectal cancer metastasis-related gene. In this study, we aimed to better understand the mechanism underlying Tiam1-mediated metastasis. We applied gene microarray and proteome analysis and compared expression of genes and proteins in a stable Tiam1-silencing colorectal cancer cell line and in a control cell line. Our analysis identified three genes, high-mobility group box1 (HMGB1), annexin IV (ANXA4) and phosphoglycerate mutase 1 (PGAM1) that were associated with Tiam1. Analysis of these proteins, which may be directly or indirectly regulated by Tiam1, may provide insight into the role and mechanism of Tiam1 in colorectal cancer metastasis.

OBJECTIVE: To investigate the relationship between T lymphoma invasion and metastasis 1 (Tiam1) and epithelial-mesenchymal transition (EMT) in human colorectal carcinomas. METHODS: Tiam1, E-cadherin, CK, and vimentin expressions in normal colorectal epithelium, colorectal carcinomas (CRC) and CRC with lymphatic metastasis were determined by immunohistochemistry using a two-step method. RESULTS: Tiam1 expression was significantly higher in CRC than in normal colorectal epithelium (P<0.01) in close correlation to the degree of tumor differentiation (P<0.05). Higher Tiam1 expression was detected in CRC with lymphatic metastasis than in primary CRC (P<0.05). The expressions of E-cadherin and CK in CRC tissues were significantly lowered in comparison with those in normal colorectal epithelium (P<0.01), showing a correlation to tumor differentiation (P<0.01) but not to lymphatic metastasis. Vimentin was significantly overexpressed in CRC (P<0.01) and correlated to tumor differentiation (P<0.01) but not to lymphatic metastasis. Tiam1 expression was inversely correlated to E-cadherin and CK, but positively to vimentin. CONCLUSION: Tiam1 is related to the metastasis of colorectal carcinoma, and may induce EMT to promote CRC metastasis.

T-lymphoma invasion and metastasis 1 has been implicated in tumor invasion and metastasis. However, the regulatory mechanisms underlying aberrant T-lymphoma invasion and metastasis 1 expression in human colorectal cancer have not been well defined. To investigate the relationship between methylation status and expression levels of T-lymphoma invasion and metastasis 1 gene, methylation-specific polymerase chain reaction, and immunohistochemistry staining were performed in 232 matched samples of human colorectal cancer tissue and normal colorectal mucosa. Results showed that T-lymphoma invasion and metastasis 1 protein was overexpressed in colorectal cancer, especially in metastatic cases (P < .001). The degree of T-lymphoma invasion and metastasis 1 promoter methylation was a little lower in cancer tissues than in matched normal mucosa (P < .05), and the expression level of T-lymphoma invasion and metastasis 1 was inversely related to the methylation status in cancer tissues (P < .001). Colon cancer cell lines HT29 and LS174T were treated with demethylating agent 5-aza-2-deoxycytidine, resulting in promoter hypomethylation accompanied by reexpression of T-lymphoma invasion and metastasis 1 mRNA and protein. In contrast, colon cancer cell lines SW620 and LoVo were treated with hypermethylation agent S-adenosylmethionine, resulting in T-lymphoma invasion and metastasis 1 promoter hypermethylation, accompanied by suppression of T-lymphoma invasion and metastasis 1 expression and inhibition of cell growth, plate colony formation, and migration. The present study demonstrates that overexpression of T-lymphoma invasion and metastasis 1 is associated with hypomethylation status of T-lymphoma invasion and metastasis 1 promoter region in colorectal cancer tissues. It suggests that promotor hypomethylation of T-lymphoma invasion and metastasis 1 may play a role in the progression and metastasis of colorectal cancer. Pharmacologic reversal of T-lymphoma invasion and metastasis 1 promoter hypomethylation may inhibit cell proliferation and migration.

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.

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 microM), 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.

PURPOSE: T-lymphoma invasion and metastasis inducing factor 1 (Tiam1) overexpression has been reported in a variety of human cancers. However, the investigation of Tiam1 in squamous-cell carcinoma of the head and neck (SCCHN) is extremely rare. The aim of the present study is to assess Tiam1 expression and to explore its role in SCCHN. METHODS: Tiam1 expression in 119 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patients' survival. Additionally, 12 paired SCCHN tissues were evaluated for Tiam1 expression by Western blotting. RESULTS: Western blotting indicated that Tiam1 expression levels in SCCHN carcinomas were significantly higher than those in the corresponding paraneoplastic tissues (P<0.001). Immmunohistochemistry staining revealed that Tiam1 was detected in all primary tumour samples, moreover, Tiam1 overexpression was significantly correlated with lymph node metastasis (P<0.001), clinical stage (P<0.001), histological grade (P=0.001) and recurrence (P<0.001). Survival analysis demonstrated that high Tiam1 expression was significantly correlated with shorter disease-free survival and overall survival (both P<0.001). When combining the Tiam1 expression and lymph node status, Kaplan-Meier survival showed that patients with Tiam1 overexpression/lymph node metastasis (+) had both shorter disease-free and overall survival than others (both P<0.001). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastasis, histological grade and Tiam1 overexpression were statistically significant, independent predictor of prognosis for patients with SCCHN. CONCLUSION: Tiam1 may contribute to SCCHN progression, and represent as a novel prognostic indicator as well as a potential therapeutic target for SCCHN.

OBJECTIVE: T-cell lymphoma invasion and metastasis 1 (Tiam1) specifically activates Rho-like GTPases (e.g. Rac1) and Tiam1-Rac1 pathway affects the migration and invasion of many tumors, such as nasopharyngeal carcinoma, breast cancer and retinoblastoma. However, no studies have yet comprehensively examined the involvement of Tiam1-Rac1 pathway in hepatocellular carcinoma. In this study, we examined the relationship of the up-regulation of Tiam1 and Rac1 with clinicopathological features in patients with hepatocellular carcinoma. METHODS: expression of Tiam1 and Rac1 was assessed in 242 hepatocellular carcinoma tissues and their adjacent normal hepatic tissues by performing immunohistochemistry and was gauged regarding stage, grade and survival. RESULTS: Immunohistochemistry showed that patients with a high clinical stage hepatocellular carcinoma (III-IV) and alpha-fetoprotein levels had a higher tendency to express Tiam1 and Rac1 on tumor cells than the patients with low pathologic grade hepatocellular carcinoma (I-II) (P = 0.008 and 0.01, respectively) and low alpha-fetoprotein levels (P = 0.006 and 0.002, respectively). In addition, Tiam1 and Rac1 up-regulation was also significantly associated with vascular invasion status (both P = 0.02), intrahepatic metastasis status (P = 0.009 and 0.01, respectively) and histological differentiation (P = 0.008 and 0.009, respectively) of patients with hepatocellular carcinoma. Moreover, post-operative survival analysis indicated that hepatocellular carcinoma patients with strong Tiam1 (P = 0.01) and Rac1 (P = 0.02) expression had shorter disease-specific survival than those with weak expression. Multivariate analysis also showed that Tiam1 and Rac1 overexpression could be two predictors of poor prognosis (P = 0.02 and 0.03, respectively). CONCLUSIONS: The current study demonstrated for the first time that the Tiam1-Rac1 pathway may play a critical role in tumor progression of hepatocellular carcinoma. The expression of Tiam1 and Rac1 can be considered as the two useful indicators for predicting the prognosis of hepatocellular carcinoma.

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.

As a specific guanine nucleotide exchange factor of Rac1, Tiam1 (T-lymphoma invasion and metastasis inducing protein 1) is involved in a number of cellular events, such as cytoskeleton reorganization, cell adhesion, and cell migration. Since Tiam1 was implicated in the invasion and metastasis of T-lymphoma cells and breast tumor cells, we compared the expression level of Tiam1 in two human giant-cell lung carcinoma cell strains with high or low metastasis potential, and found that Tiam1 expression level in high-metastatic 95D cells was higher than that in low-metastatic 95C cells. To further confirm the role of Tiam1 in invasion and metastasis, we constructed the antisense Tiam1 expression plasmid (pcDNA3-anti-Tiam1), which was transfected into 95D cells. A stable transfected clone with decreased Tiam1 expression was screened and selected for further research. Transwell assay showed that down-regulation of endogenous Tiam1 by anti-Tiam1 can reduce the in vitro invasiveness of 95D cells. Our results suggested that Tiam1 signaling contributed to the invasion and metastasis of the human giant-cell lung carcinoma cells.

OBJECTIVE: To investigate the relationship between the expression of T lymphoma invasion and metastasis inducing factor 1 (Tiam1) and the progression, metastasis, TNM stage, and histological types of lung carcinoma. METHODS: Immunohistochemistry was performed to detect the expression of Tiam1 in 116 lung carcinoma specimens. The expression intensity (measured in positive unit, PU) of Tiam1 in these tissues was assessed quantitatively using Imagepro Plus image analysis software. RESULTS: The PU of Tiam1 was significantly greater in primary lung carcinomas with lymph node metastases than in those without metastases (t=-2.089, P=0.039). Lung cancers of TNM stage II-IV had stronger expression than those of stage I (t=-2.272, P=0.025). The PU of Tiam1 differed significantly between different histological types of lung cancer, and squamouscell cell carcinoma had a lower PU than adenocarcinoma, large cell carcinoma and small cell carcinoma (P<0.05). The intensity of Tiam1 expression was not associated with the patients' gender, age, general types, smoking history, pneumoconiosis or differentiation of lung carcinoma. CONCLUSION: These results strongly suggest that Tiam1 is an invasion and metastasis inducing factor of lung carcinoma. The overexpression of Tiam1 is closely associated with lymph node metastases, TNM stage and histological types of lung carcinoma.

The aim of this study was to analyze T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam1) expression in lung cancer patients. A total of 204 patients with lung cancer tissue lesions were enrolled in the present study, along with 40 cases of normal lung tissue and 40 of normal fetal lung tissue. Tiam1 protein expression level was determined using intensity quantitative analysis, for comparison in lung cancer, metastatic, normal lung, and fetal lung tissue. The positive unit (PU) of Tiam1 was 13.5 +/- 5.42 in lung cancer, 5.67 +/- 1.56 in normal epithelial cells, and 5.89 +/- 1.45 in fetal lung epithelial cells. The value in the lung cancer tissue was significantly higher than that in the normal lung tissue and the fetal lung tissue (P<0.01). The Tiam1 PU values with lymph node metastasis and without lymph node metastasis were 15.2 +/- 4.34 and 12.5 +/- 4.23, respectively, and the difference was statistically significant (P<0.05). The Tiam1 PU values in different tumor, nodes, metastasis (TNM) stages, III-IV period, and I-II phase were 14.7 +/- 4.14 and 11.0 +/- 5.34 (P <0.05). A correlation was found between Tiam1 expression and the age of patient, tumor size, tumor type, and tumor differentiation. Tiam1 protein expression in the lung tumor tissue is significantly higher than that in the normal lung tissue and fetal lung tissue. Tiam1 expression may be closely related to lung cancer development and metastasis.

BACKGROUND: To assess the value of Tiam1 in predicting lymph node metastasis and survival after curative resection in patients with lung adenocarcinoma. METHODS: Immunohistochemical staining for Tiam1 was performed on 98 adenocarcinoma and 30 normal lung tissues. The association of Tiam1 protein expression with the clinicopathological characteristics and the prognosis of lung adenocarcinoma were subsequently assessed. RESULTS: Immunohistochemical analysis showed that 60 of 98 (61.22%) adenocarcinoma tissues showed high expression of Tiam1, and high Tiam1 expression was significantly associated with advanced TNM stage (P < 0.0005) and lymph node status (P < 0.0005) of lung adenocarcinoma. Moreover, the lung adenocarcinoma patients with low Tiam1 expression had higher overall survival than patients with high Tiam1 expression (log rank value = 10.805, P = 0.001). High expression of Tiam1 predicted poor overall survival of patients in stages I + II (P = 0.006). Furthermore, multivariate analysis indicated that high expression of Tiam1 protein was an independent prognostic factor for overall survival (P = 0.011) in patients with lung adenocarcinoma. CONCLUSION: These findings suggest for the first time that Tiam1 expression may be beneficial in predicting lymph node metastasis and survival of patients with lung adenocarcinoma. A future study will investigate whether Tiam1 can serve as a novel therapeutic target in lung adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1377798917111123.

The Rac exchange factor Tiam1 is involved in diverse cell functions and signaling pathways through multiple protein interactions, raising the question of how signaling and functional specificity are achieved. We have shown that Tiam1 interactions with different scaffold proteins activate different Rac-dependent pathways by recruiting specific Rac effector proteins, and reasoned that there must be regulatory mechanisms governing each interaction. Fibroblasts express at least two Tiam1-interacting proteins, insulin receptor substrate protein 53 kDa (IRSp53) and spinophilin. We used fluorescent resonance energy transfer (FRET) to measure localized Rac activation associated with IRSp53 and spinophilin complexes in individual fibroblasts to test this hypothesis. Pervanadate or platelet-derived growth factor induced localized Rac activation dependent on Tiam1 and IRSp53. Forskolin or epinephrine induced localized Rac activation dependent on Tiam1 and spinophilin. In spinophilin-deficient cells, Tiam1 co-localized with IRSp53 in response to pervanadate or platelet-derived growth factor. In IRSp53-deficient cells, Tiam1 co-localized with spinophilin in response to forskolin or epinephrine. Total cellular levels of activated Rac were affected only in cells with exogenous Tiam1, and were primarily increased in the membrane fraction. Downstream effects of Rac activation were also stimulus and scaffold-specific. Cell ruffling, spreading, and cell adhesion were dependent on IRSp53, but not spinophilin. Epinephrine decreased IRSp53-dependent adhesion and increased cell migration in a Rac and spinophilin-dependent fashion. These results support the idea that Tiam1 interactions with different scaffold proteins couple distinct upstream signals to localized Rac activation and specific downstream pathways, and suggest that manipulating Tiam1-scaffold interactions can modulate Rac-dependent cellular behaviors.

The co-evolution of tumors and their microenvironment involves bidirectional communication between tumor cells and tumor-associated stroma. Various cell types are present in tumor-associated stroma, of which fibroblasts are the most abundant. The Rac exchange factor Tiam1 is implicated in multiple signaling pathways in epithelial tumor cells and lack of Tiam1 in tumor cells retards tumor growth in Tiam1 knockout mouse models. Conversely, tumors arising in Tiam1 knockout mice have increased invasiveness. We have investigated the role of Tiam1 in tumor-associated fibroblasts as a modulator of tumor cell invasion and metastasis, using retroviral delivery of short hairpin RNA to suppress Tiam1 levels in three different experimental models. In spheroid co-culture of mammary epithelial cells and fibroblasts, Tiam1 silencing in fibroblasts led to increased epithelial cell outgrowth into matrix. In tissue-engineered human skin, Tiam1 silencing in dermal fibroblasts led to increased invasiveness of epidermal keratinocytes with pre-malignant features. In a model of human breast cancer in mice, co-implantation of mammary fibroblasts inhibited tumor invasion and metastasis, which was reversed by Tiam1 silencing in co-injected fibroblasts. These results suggest that stromal Tiam1 may have a role in modulating the effects of the tumor microenvironment on malignant cell invasion and metastasis. This suggests a set of pathways for further investigation, with implications for future therapeutic targets.

OBJECTIVE: To study the relation between T lymphoma invasion/metastasis1 (Tiam1) gene and nasopharyngeal carcinoma progression. METHOD: Using of reverse transcription polymerase chain (RT-PCR) technique on 41 nasopharyngeal carcinoma tissue and 20 normal nasopharyngeal tissue to proceed the test of mRNA overexpression. RESULT: Average expression of the Tiam1 gene in nasopharyngeal carcinoma tissue (1.183 +/- 0.73) is higher than in normal nasopharyngeal tissue (0.87 +/- 0.45) (P < 0.01). The positive relationship between the frequency of Tiam1 overexpression and clinical staging and T staging was very significant (P < 0.05) and increased gradually; The frequency of Tiam1 overexpression was 59.3% (16/27) in patients with lymph node metastasis, 21.4% (3/ 14) in patients without lymph node metastasis, overexpression between them was very significant (P < 0.05). CONCLUSION: Average expression of the Tiam1 gene in nasopharyngeal carcinoma tissue is higher than in normal nasopharyngeal tissue. Our data suggest that the overexpression of the Tiam1 gene correlates invasion and metastasis of nasopharyngeal carcinoma.

OBJECTIVE: To investigate the relationship between the protein expression of T-lymphoma invasion and metastasis gene 1 (Tiam-1) and the biological behaviors of nasopharyngeal carcinoma (NPC). METHODS: Immunohistochemistry was performed to detect the expressions of Tiam-1 protein in 60 specimens of NPC tissue, 20 specimens of chronic nasopharyngitis (CN) tissue, and 6 tumor tissues from nude mice inoculated with metastatic human NPC cells. RESULTS: The positivity rate and average score for Tiam-1 expression were significantly higher in NPC tissues than in CN tissue (63.33% vs 36.67%, 2.9167 +/- 1.3057 vs 0.7000 +/- 0.9234; chi(2)=20.429, P=0.001; t=7.0162, P=0.0000, respectively). No difference was found in Tiam-1 expression among NPC patients in different T stages (F=2.36, P=0.0811), while the expression differed significantly between the patients with lymph node metastasis and those without metastasis, and also between patients with organ metastasis and those without (P=0.0001). High Tiam-1 expressions were found in the tumor tissues in nude mice inoculated with metastatic NPC cells. CONCLUSION: Tiam-1 expression is closely associated with the invasiveness and metastasis of NPC, indicating that Tiam-1 is an important factor that promotes the invasion and metastasis of NPC.

OBJECTIVE: To explore biological aspects of Tiam1 gene expression in nasopharyngeal carcinoma cells. METHODS: Tiam1/C1199HA expression plasmids were transfected into nasopharyngeal carcinoma cells of C666-1 and CNE1 by lipofectamine2000. RT-PCR, real-time PCR and Western blot Analyses were performed to evaluate the expression of Tiam1 mRNA and protein levels, respectively. In vitro cell adhesion, wound healing and matrigel invasion assays were used to study the biological impact of Tiam1 on cell adhesion, mobility and invasion. RESULTS: Tiam1 over expression significantly increased the abilities of adhesion, migratory and invasion of C666-1 and CNE1 cells, comparing with that of the control untransfected cells (P < 0.05). CONCLUSION: Tiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells.

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.

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.