Tiam1 Protein Expression Research Articles

Functional Characterization of SLC2A3 in Rheumatoid Arthritis: Unraveling Its Role in Ferroptosis and Inflammatory Pathways.

Hence, we investigated that the function and effects of SLC2A3 in rheumatoid arthritis (RA) and the underlying mechanism. C57BL/6 mice were immunized with bovine type II collagen to induce mice model of RA. The expression of serum SLC2A3 was down-regulated, and was negative correlation with CRP, RF or anti-CCP in patients with RA. In mice model of RA, SLC2A3 mRNA and protein expression in joint tissue were reduced. Sh-SLC2A3 promoted RA and inflammation in mice model. SLC2A3 promoted cell growth and osteogenic differentiation of MC3T3-E1 cells invitro model of RA. SLC2A3 reduced ferroptosis invitro model or mice model of RA. SLC2A3 induced Tiam1 protein expression, and SLC2A3 protein linked with Tiam1 protein in model of RA. Tiam1 reduced the effects of sh-SLC2A3 on RA and inflammation in mice model. Tiam1 inhibitor the effects of SLC2A3 on osteogenic differentiation and ferroptosis invitro model of RA. Collectively, SLC2A3 reduced inflammation levels and ferroptosis through the inactivation of mitochondrial damage by Tiam1 in model of RA, could serve as a potent therapeutic agent for alleviating RA.

Tiam1 mediates Rac1 activation and contraction‐induced glucose uptake in skeletal muscle cells

Contraction-stimulated glucose uptake in skeletal muscle requires Rac1, but the molecular mechanism of its activation is not fully understood. Treadmill running was applied to induce C57BL/6 mouse hind limb skeletal muscle contraction in vivo and electrical pulse stimulation contracted C2C12 myotube cultures in vitro. The protein levels or activities of AMPK or the Rac1-specific GEF, Tiam1, were manipulated by activators, inhibitors, siRNA-mediated knockdown, and adenovirus-mediated expression. Activated Rac1 was detected by a pull-down assay and immunoblotting. Glucose uptake was measured using the 2-NBD-glucose fluorescent analog. Electrical pulse stimulated contraction or treadmill exercise upregulated the expression of Tiam1 in skeletal muscle in an AMPK-dependent manner. Axin1 siRNA-mediated knockdown diminished AMPK activation and upregulation of Tiam1 protein expression by contraction. Tiam1 siRNA-mediated knockdown diminished contraction-induced Rac1 activation, GLUT4 translocation, and glucose uptake. Contraction increased Tiam1 gene expression and serine phosphorylation of Tiam1 protein via AMPK. These findings suggest Tiam1 is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.

Upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome

T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, is involved in the tumorigenesis of a number of malignancies. This study was aimed to explore the role of Tiam1 in cervical cancer progression, and evaluate the prognostic values. Tiam1 protein expression levels were detected by immunohistochemical (IHC) staining in 174 cervical cancer tissues, 92 of CINs (cervical intraepithelial neoplasia) and 32 of normal cervical epithelia tissues. Clinicopathological parameters and overall survival data were collected and compared between different Tiam1 statuses. The role of Tiam1 in cervical cancer proliferation, migration and angiogenesis were detected using si-RNA (small interfering RNA) transfection. In results, Tiam1 protein showed a cytoplasmic and nuclear staining pattern in cervical cancer tissues. The strongly positive expression of Tiam1 protein was observed in 51.72% (90/174) of cervical cancers, which was significantly higher than in CINs and normal cervical epithelia tissues (9.38%, 3/32). High Tiam1 protein expression was closely associated with advanced clinical stage, differentiation, lymph node (LN) metastasis, HPV infection and lower overall survival (OS) rates in cervical cancer. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with clinical stage, in patients with cervical cancer. Additionally, Tiam1 depletion by RNAi in cervical cancer cells significantly decreased cell proliferation, migration and angiogenesis. In conclusion, our study demonstrated that upregulation of Tiam1 contributes to cervical cancer disease progression and indicates poor survival outcome.

Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma.

T lymphoma invasion and metastasis 1 (Tiam1), a guanine nucleotide exchange factor, was originally identified as an invasion- and metastasis-inducing gene in T lymphoma cells. High expression levels of the human Tiam1 gene have been found in numerous human malignancies, suggesting a potential role as a modifier of tumor initiation and progression. However, little is known about the status of Tiam1 in ovarian carcinoma. The present study aimed to investigate the clinicopathological significance of high Tiam1 expression in serous ovarian carcinoma. Immunohistochemical staining for Tiam1 was performed in 182 patients with serous ovarian carcinoma, in 76 patients with ovarian borderline tumors and in 72 patients with benign ovarian tumors. Immunofluorescence staining was also performed to detect the subcellular localization of Tiam1 protein in SK-OV-3 ovarian carcinoma cells. The correlations between high Tiam1 expression and the clinicopathological features of the ovarian carcinomas were evaluated by the χ2 test and Fisher's exact test. The overall survival (OS) rates were calculated by the Kaplan-Meier method, and the association between prognostic factors and patient survival was analyzed by the Cox proportional hazard model. Tiam1 protein showed a cytoplasmic and nuclear staining pattern in ovarian carcinoma. Strongly-positive Tiam1 protein expression was observed in 59.3% (108/182) of ovarian carcinomas, which was significantly higher than in benign serous tumors (12.5%; 9/72). Moreover, the rate of strongly-positive Tiam1 expression in borderline serous tumors (31.6%; 24/76) was also significantly higher than that in benign serous tumors. High Tiam1 protein expression was closely associated with a high histological grade, metastasis, advanced clinical stage and lower OS rates in ovarian carcinoma. Multivariate analysis indicated that Tiam1 was an independent prognostic factor, along with metastasis and clinical stage, in patients with ovarian carcinoma. In conclusion, Tiam1 expression is strongly associated with grade and outcome in ovarian carcinoma, and may serve as a useful molecular marker for clinical management.

Clinicopathological implications of Tiam1 overexpression in invasive ductal carcinoma of the breast.

BackgroundT-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) has been implicated in tumor occurrence and progression. Recent studies have shown that high expression levels of Tiam1 protein appear to be associated with the progression of numerous human tumors. This study attempted to explore the role of Tiam1 protein in tumor progression and the prognostic evaluation of breast cancer.MethodsThe localization of the Tiam1 protein was determined in the MDA-MB-231 breast cancer cell line using immunofluorescence (IF) staining. In addition, a total of 283 breast tissue samples, including 153 breast cancer tissues, 67 ductal carcinoma in situ (DCIS) and 63 adjacent non-tumor breast tissues, were analyzed by immunohistochemical (IHC) staining of the Tiam1 protein. The correlation between Tiam1 expression and clinicopathological characteristics was evaluated by Chi-square test and Fisher’s exact tests. Disease-free survival (DFS) and 10-year overall survival (OS) rates were calculated by the Kaplan-Meier method. Additionally, univariate and multivariate analyses were performed by the Cox proportional hazards regression models.ResultsTiam1 protein showed a mainly cytoplasmic staining pattern in breast cancer cells; however, nuclear staining was also observed. Tiam1 protein expression was significantly higher in breast cancers (42.5 %, 65/153) and DCIS (40.3 %, 27/67) than in adjacent non-tumor tissues (12.7 %, 8/63). In addition, Tiam1 associated with tumor stage and Ki-67 expression, but negatively correlated with receptor tyrosine-protein kinase erbB-2 (Her2) expression. Moreover, survival analyses showed that DFS and 10-year OS rates were significantly lower in breast cancer patients with high Tiam1 expression than those with low Tiam1 expression. Univariate analysis suggested that molecular types, clinical stage, Her2 expression levels and Tiam1 expression levels were also significantly associated with DFS and 10-year OS rates of breast cancer patients. Furthermore, multivariate analysis suggested that Tiam1 expression is a significant independent prognostic factor along with tumor stage in patients with breast cancer.ConclusionsTiam1 expression is frequently up-regulated in breast cancer. Tiam1 expression correlated with clinicopathological parameters, suggesting that it may be a useful prognostic biomarker and potential therapeutic target for patients with breast cancer.

The prognostic value of Tiam1 protein expression in head and neck squamous cell carcinoma: a retrospective study.

IntroductionHead and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide and has a poor prognosis. A biomarker predicting the clinical outcome of HNSCC patients could be useful in guiding treatment planning. Overexpression of the T lymphoma invasion and metastasis 1 (Tiam1) protein has been implicated in the migration and invasion of neoplasms. However, its role in HNSCC progression needs to be further validated. We detected the expression of Tiam1 in normal and tumor tissues and determined its association with clinical outcomes in patients with HNSCC.MethodsWe measured the expression of Tiam1 in normal and cancerous tissue samples from the patients with HNSCC treated at Sun Yat-sen University Cancer Center between 2001 and 2008. The Tiam1 expression was scored from 0 to 12 based on the percentage of positively stained cells and the staining intensity. We then determined the diagnostic performance of this score in predicting overall survival (OS) and disease-free survival (DFS).ResultsOf the 194 evaluable patients, those with advanced disease, lymph node metastasis at diagnosis, and recurrence or metastasis during follow-up had a higher tendency of having high Tiam1 expression as compared with their counterparts (P < 0.05). The proportion of samples with high Tiam1 expression was also higher in cancerous tissues than in non-cancerous tissues (57.7% vs. 13.9%, P < 0.001). Cox proportional hazards regression analysis revealed that Tiam1 expression scores of 5 and greater independently predicted short OS and DFS.ConclusionThe Tiam1 expression is shown as a promising biomarker of clinical outcomes in patients with HNSCC and should be evaluated in prospective trials.

Overexpression of Tiam1 is associated with malignant phenotypes of nasopharyngeal carcinoma.

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.

Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo.

Our previous study demonstrated that Tiam1 was highly expressed in esophageal squamous cell carcinoma (ESCC) tissues. In the present study, we investigated the therapeutic role of Tiam1 siRNA in combination with sorafenib in xenografted human ESCC. Our results demonstrated that expression of Tiam1 protein in EC9706 cells was significantly higher than those in ESCC cells (Eca109 and EC1) and normal esophageal epithelial cells Het-1A (P < 0.05). Tiam1 siRNA markedly suppressed Tiam1 protein expression in tumor tissues of nude mice, but sorafenib did not alter Tiam1 level. In addition, Tiam1 siRNA or sorafenib alone evidently inhibited tumor growth, reduced Ki-67 proliferation index, and induced cell apoptosis in xenografted nude mice, and their combinations had the strongest effect. Notably, Tiam1 siRNA or sorafenib alone obviously increased p27 level, but reduced Mcl-1 and bcl-2 levels in xenografted nude mice, and their combinations reached the best effect. These findings suggest that combination of Tiam1 siRNA with sorafenib may be the novel molecular therapy target for the patients with ESCC.

Expression of Tiam1 predicts lymph node metastasis and poor survival of lung adenocarcinoma patients

BackgroundTo assess the value of Tiam1 in predicting lymph node metastasis and survival after curative resection in patients with lung adenocarcinoma.MethodsImmunohistochemical 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.ResultsImmunohistochemical 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.ConclusionThese 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 slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1377798917111123.

Expression of Tiam1 in Lung Cancer and its Clinical Significance

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.

Expression and clinical significance of T-lymphoma invasion and metastasis 1 protein in renal cell carcinoma

Objective To explore the expression of Tiaml in clear cell renal cell carcinoma and analyze its correlations to pathology of disease and prognosis.Methods The expressions of Tiam1 protein in 107 specimens of human clear cell renal cell carcinoma and 20 specimens of normal renal tissues were detected by immunohistochemical staining and its clinical significance was then analyzed.Results The expression of Tiam1 protein was higher in renal cancers than in the adjacent normal tissues ( P ＜ 0.01 ).Tiam1 protein expression rates were 47.6％ and 72.7％ in Ⅰ - Ⅱ and Ⅲ - Ⅳ tumors,while 49.3％ and 76.5％ in T1 - T2 and T3 - T4 tumors,respectively ( P ＜ 0.01 ).Expression of Tiam1 protein was higher in lymph node positive renal carcinoma tissues than in lymph node negative renal carcinoma tissues ( 71.7％ versus 47.5％,P ＜ 0.05 ).The expression of Tiam1 in carcinoma tissues showed a positive relationship with tumor vascular invasion (81.3％ versus 48.0％,P ＜ 0.01 ).In patients followed-up 5 - 8 years,Kaplan-meier analysis and the log-rank test showed that the 5-year survival was significantly different between the group of lower and higher Tiaml expression groups ( 84.4％ versus 46.8％,P ＜ 0.05 ).Conclusions The expression of Tiaml protein was higher in human primary renal carcinoma than in normal renal tissues.The positive rate of Tiam1 protein expression was related to classification,TNM stage,lymph node metastasis and vascular invasion.The detection of the expression of Tiaml protein may be helpful in the diagnosis and prognosis of renal carcinoma. Key words: Kidney neoplasms ; T-lymphoma invasion and metastasis 1 ; Immunohistochemistry

Prognostic relevance of Tiam1 protein expression in prostate carcinomas

The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (P<0.001) and prostate carcinomas (P<0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. ⩾3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P=0.016), the presence of lymph vessel invasion (P=0.031) and high Gleason scores (GS) (i.e. ⩾7) (P=0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk= 3.75, 95% confidence interval=1.06–13.16; P=0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.