7048

TGFBR2

transforming growth factor, beta receptor II (70/80kDa);TGFBR2;transforming growth factor, beta receptor II (70/80kDa)

TGF-beta receptor type IIB|TGF-beta receptor type-2|TGF-beta type II receptor|tbetaR-II|transforming growth factor beta receptor type IIC|transforming growth factor, beta receptor II alpha|transforming growth factor, beta receptor II beta|transforming gro

3p22

protein-coding

In the case of operated breast cancer (BC), prognostic markers help to determine if the patient needs additional treatment and predictive markers help the clinician to decide which treatment to use. Thus, a better knowledge of known predictive and prognostic markers and the identification of new markers, may improve the treatment of BC patients. The transforming growth factor-beta type II receptor (TGF-betaRII), a main receptor of transforming growth factor beta pathway, is a potential new prognostic marker. The aims of the present study were to investigate both the predictive and prognostic impact of TGF-betaRII in BC samples. TGF-betaRII protein expression was evaluated using immunohistochemistry on a tissue microarray containing 110 TNM stage III BC samples obtained prior to doxorubicin-based neoadjuvant chemotherapy (NAC). Our results demonstrate that TGF-betaRII did not predict the response to NAC. On the other hand, an association between TGF-betaRII-negative tumor and higher risk of metastasis to lungs and bones was verified. TGF-betaRII negativity was an independent prognostic factor for decreased disease-free and overall survival.

Microsatellite instability (MSI), which occurs in 15% of colorectal cancer, has been shown to have a lower incidence of metastasis and better patient survival rates compared with microsatellite stable colorectal cancer. However, a mechanistic understanding of the basis for this difference is very limited. Here, we show that restoration of TGFbeta signaling by re-expression of TGFbeta receptor II in MSI colon cancer cells increased PI3K/AKT activation, conferred resistance to growth factor deprivation stress-induced apoptosis, and promoted cell motility in vitro. Treatment with a potent PI3K inhibitor (LY294002) blocked the prosurvival and promotility effects of TGFbeta, indicating that TGFbeta-mediated promotion of cell survival and motility is dependent upon activation of the PI3K/AKT pathway. Analysis of apoptotic effectors that are affected by TGFbeta signaling indicated that Bim is an effector of TGFbeta-mediated survival. In addition, TGFbeta-induced down-regulation of E-cadherin contributed to the prosurvival effect of TGFbeta, and restoration of TGFbeta signaling in MSI colon cancer cells increased liver metastasis in an orthotopic model in vivo. Taken together, our results demonstrate that restoration of TGFbeta signaling promotes cell survival, motility, and metastatic progression in MSI colon cancer cells and indicate that TGFbeta receptor II mutations contribute to the favorable outcomes in colon cancer patients with MSI.

The transforming growth factor beta (TGF-beta) signaling pathway has been considered both a tumor suppressor and a cancer promoter. Additionally, downregulation of cell adhesion molecules such as E-cadherin plays an important role in the metastatic potential of colorectal cancer (CRC). The aim of the present study was to evaluate TGF-beta, TGF-beta type I receptor (TGF-betaR1), TGF-beta type II receptor (TGF-betaR2), Smad4, pSmad2/3, and E-cadherin expression in colorectal carcinoma and to correlate the obtained data with other standard prognostic parameters, such as disease stage, metastases, and patient survival. TGF-beta, TGF-betaR1, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin expression was evaluated immunohistochemically in 195 unrelated CRC specimens and the results subjected to various statistical analyses. TGF-beta was expressed in 71.28%, TGF-betaR1 in 61.0%, TGF-betaR2 in 54.4%, Smad4 in 61.5%, pSmad2/3 in 71.3%, and E-cadherin in 50.26% of the colorectal carcinoma samples tested. The correlation of immunoexpression with the clinicopathological parameters of CRC revealed that the high expression of TGF-beta and low expression of TGF-betaR1, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin were correlated with tumor-node-metastasis (TNM) stage of disease. High TGF-beta expression and low TGF-betaR1, TGF-betaR2, Smad4, and pSmad2/3 expression were also correlated with lymph node metastasis. The Kaplan-Meier survival curves demonstrated a clear association of cancer-specific overall survival with high TGF-beta, as well as low TGF-betaR1, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin expression. Our results suggest that TGF-beta, TGF-betaR1, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin are closely related to TNM stage of CRC. Moreover, TGF-beta, TGF-betaR2, Smad4, pSmad2/3, and E-cadherin emerge as valuable independent biomarkers of prognosis in CRC patients.

BACKGROUND: TGFbeta signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFbeta signaling. METHODS: To test the importance of TGFbeta signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFbeta response (FET), or tumorigenic with TGFbeta response (FETalpha) or tumorigenic with abrogated TGFbeta response via introduction of dominant negative TGFbetaRII (FETalpha/DN) and their ability to metastasize. metastatic competency was assessed by orthotopic transplantation. metastatic colony formation was assessed histologically and by imaging. RESULTS: Abrogation of TGFbeta signaling through introduction of a dominant negative TGFbeta receptor II (TGFbetaRII) in non-metastatic FETalpha human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFbeta signaling in FETalpha-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFbeta signaling is a metastasis suppressor, we rescued TGFbeta signaling in CBS metastatic colon cancer cells that had lost TGFbeta receptor expression due to epigenetic repression. Restoration of TGFbeta signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFbeta signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. CONCLUSIONS: The observations presented here indicate a metastasis suppressor role for TGFbeta signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFbeta signaling may be imprudent in some patient populations with residual TGFbeta tumor suppressor activity.

BACKGROUND AND OBJECTIVE: Recent studies have revealed that TGF-beta/Smads signaling pathway plays a pivotal role in the oncogenesis and development of malignant tumors, and may closely relate to the biological behaviors of some malignant tumors, such as gastric carcinoma. This study was to investigate the expression of transforming growth factor-beta receptor II (TGF-betaRII), Smad4 and Smad7 proteins in gastric carcinoma, and explore their correlations to clinicopathologic characteristics and prognosis of gastric carcinoma. METHODS: The expression of TGF-betaRII, Smad4, and Smad7 was detected by SABC immunohistochemistry and tissue microarray which containing 200 specimens of primary human gastric carcinoma and 56 specimens of adjacent gastric tissue. RESULTS: The positive rates of TGF-betaRII, Smad4, and Smad7 in gastric carcinomas were 25.5%, 67.0%, and 47.0%, respectively. TGF-betaRII expression was related with depth of invasion, lymph node metastasis, tumor differentiation, and Lauren classification (Chi2=6.214, Chi2=11.308, Chi2=14.633, and Chi2=8.216, respectively, all P<0.05). Smad4 expression was related with tumor differentiation and Lauren classification (Chi2=16.162 and Chi2=13.100, all P<0.05). Smad7 expression was related with tumor differentiation and Lauren classification (Chi2=4.710 and Chi2=5.297, all P<0.05). Smad4 expression was positively correlated to TGF-betaRIIexpression (r =0.191, P=0.007). Smad4 expression was related with patients survival (Chi2=4.090, P=0.043). CONCLUSIONS: Abnormal expression of TGF-Smad signaling pathway proteins occurs in gastric carcinoma. Smad4-positive gastric carcinoma patients have better prognosis than Smad4-negative patients.

RATIONALE: Lung adenocarcinoma histology and clinical outcome are heterogeneous and associated with tumor invasiveness. OBJECTIVES: We hypothesized that invasiveness is associated with a distinct molecular signature and that genes differentially expressed in tumor or adjacent stroma will identify cell surface signal transduction and matrix remodeling pathways associated with the acquisition of invasiveness in lung adenocarcinoma. MAIN RESULTS: Microarray analysis of microdissected noninvasive bronchioloalveolar carcinoma (BAC) and invasive adenocarcinoma and adenocarcinoma-mixed type with BAC features identified transcriptional profiles of lung adenocarcinoma invasiveness. Among the signature set that was lower in adenocarcinoma-mixed compared with BAC was the type II transforming growth factor beta (TGF-beta) receptor, suggesting downregulation of TGFbetaRII is an early event in lung adenocarcinoma metastasis. Immunostaining in independently acquired specimens demonstrated a correlation between TbetaRII expression and length of tumor invasion. Repression of TGFbetaRII in lung cancer cells increased tumor cell invasiveness and activated p38 mitogen-activated protein kinases. Microarray analysis of invasive cells identified potential downstream mediators of TGFbetaRII with differential expression in lung adenocarcinomas. CONCLUSIONS: The repression of type II TGF-beta receptor may act as a significant determinant of lung adenocarcinoma invasiveness, an early step in tumor progression toward metastasis.

Transforming growth factor beta (TGF-beta) is overexpressed in a wide variety of cancer types including lung adenocarcinoma (LAC), and the TGF-beta signaling pathway plays an important role in tumor development. To determine whether blockade of the TGF-beta signaling pathway can inhibit the malignant biological behavior of LAC, RNA interference (RNAi) technology was used to silence the expression of TGF-beta receptor, type II (TGFbetaRII) in the LAC cell line, A549, and its effects on cell proliferation, invasion and metastasis were examined. Three specific small interfering RNAs (siRNAs) designed for targeting human TGFbetaRII were transfected into A549 cells. The expression of TGFbetaRII was detected by Western blot analysis. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by fl ow cytometry. The invasion and metastasis of A549 cells were investigated using the wound healing and Matrigel invasion assays. The expression of PI3K, phosphorylated Smad2, Smad4, Akt, Erk1/2, P38 and MMPs was detected by Western blot analysis. The TGFbetaRII siRNA signi fi cantly reduced the expression of TGFbetaRII in A549 cells. The knockdown of TGFbetaRII in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis. In addition to the Smad-dependent pathway, independent pathways including the Erk MAPK, PI3K/Akt and p38 MAPK pathways, as well as the expression of MMPs and VEGF, were inhibited. In conclusion, TGF-beta signaling is required for LAC progression. Therefore, the blockade of this signaling pathway by the down-regulation of TGFbetaRII using SiRNA may provide a potential gene therapy for LAC.

OBJECTIVE: The aim of this study was to investigate the expression of transforming growth factor-beta1 (TGF-beta1) and its signaling pathway molecules in oral squamous cell carcinoma (OSCC) and analyze the association between these factors and genesis and metastasis of OSCC. METHODS: The express of TGF-beta1, TbetaRI, TbetaRII and Smad4, a pivotal downstream molecule of its signaling, in 10 normal oral mucosa tissues and 108 OSCC was detected by SP immunohistochemistry, and thier correlation with genesis and metastasis of OSCC were assessed. RESULTS: The expressions of TbetaRII and Smad4 were lower in the tumors (34.3%, 38.9%) than those in the normal oral epithelium (80.0%, 100.0%, P < 0.05). The positive expression rates of TGF-beta1 and TbetaRI in the normal oral epithelium and OSCC were not significantly different (P > 0.05). There was an inverse correlation between TGF-beta1, Smad4, TbetaRII, TbetaRI expression and clinical stages (P < 0.01). The expression of TGF-beta1 was related with histological differentiation and tumor localization (P < 0.05). There was a relationship beteween Smad4 expression and histological differentiation and lymph node metastasis (P < 0.05). The expression of TbetaRII in the samples with lymph node metastasis was less than that in the ones without lymph node metastasis (P < 0.01), although there was no association between expression of TbetaRII and lymph node metastasis status. CONCLUSION: There is an important relationship between the abnormal TGF-beta1/Smad4 signal pathway and genesis and development of OSCC, while the low expressed Smad4 and TbetaRII may promote the metastasis of OSCC.

Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patient-matched tissue, we have identified aberrations in the transforming growth factor beta (TGFbeta) signaling pathway in RCC. We observed loss of type III TGFbeta receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFbeta receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFbeta responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFbeta. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFbeta-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFbeta-mediated signaling. Based on these data, we propose that dysregulation in TGFbeta signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.