10553

HTATIP2

HIV-1 Tat interactive protein 2, 30kDa;HTATIP2;HIV-1 Tat interactive protein 2, 30kDa

30 kDa HIV-1 TAT-interacting protein|HIV-1 TAT-interactive protein 2|Tat-interacting protein (30kD)|oxidoreductase HTATIP2|short chain dehydrogenase/reductase family 44U, member 1

11p15.1

protein-coding

metastasis is the most frequent cause of death in patients with breast cancer. Tip30/CC3 gene is a putative metastasis suppressor gene, which was first identified by a differential display analysis of messenger RNA from the highly metastatic human variant small cell lung carcinoma (SCLC) versus less metastatic classic SCLC cell lines. The aim of this study was to analyze the relationship between expression of TIP30/CC3 and clinical prognosis in 87 patients with surgically removed breast carcinoma. tumor tissues were stained immunohistochemically with anti-TIP30/CC3 antibody. We demonstrated that the expression of TIP30/CC3 was inversely associated with axillary lymph node metastasis (P = .0008) and vascular invasion (P = .0016). expression of TIP30/CC3 was not correlated with tumor grade, estrogen, progesterone, and P53 expression. Inhibition of TIP30/CC3 expression by RNA-mediated interference greatly enhanced breast cancer cell invasion through the extracellular matrix, whereas overexpression of TIP30/CC3 by adenovirus vector suppressed invasion through the extracellular matrix. These data supported the theory that the expression of TIP30/CC3 had a suppressive function on tumor metastasis. In summary, the decrease in expression of TIP30/CC3 is related to metastasis and may represent a new prognosticator in breast carcinoma.

OBJECTIVE: To explore the clinical significance of CC3/TIP30 protein's expression in breast carcinoma and its correlation with HER-2/neu. METHODS: The expression of CC3/TIP30 and HER-2/neu protein was detected in 112 breast cancer tissues which was collected from January 2004 to January 2005 by immunohistochemistry and the relationship with clinic pathological parameters and prognosis was analyzed. Small interfering RNA (siRNA) which target to knock out CC3/TIP30 were transfected into SK-BR-3 cells. Real-time PCR were used to detect the level of CC3/TIP30 and HER-2/neu mRNA. RESULTS: The results of immunohistochemistry showed CC3/TIP30 protein was correlated with TNM stage, lymph node status, HER-2 status and molecule classification (P = 0.048, 0.019, 0.027, 0.011), but there was no association with age, tumor size, estrogen receptor and progesterone receptor. Real-time PCR results revealed that CC3/TIP30 siRNA down-regulation the level of its mRNA, accompanied by a decline in the expression of HER-2/neu gene mRNA, the difference was statistically significant (F = 56.797, P = 0.000; F = 165.101, P = 0.000). In addition, Kaplan-Meier curves of disease-specific survival analysis showed a marked difference in the subtype of HER-2 protein positive between CC3/TIP30 positive group and negative group (chi(2) = 10.732, P = 0.001). CONCLUSIONS: The loss of CC3/TIP30 is related to occurrence and development in breast cancer, suggesting early onset of metastasis and recurrence. Perhaps CC3/TIP30 can be considered as a sub-typing indicator in HER-2 positive breast cancer.

PURPOSE: The human CC3/TIP30 gene is a putative metastasis suppressor gene, based on the results of experimental studies using lung, colon and melanoma cell lines. However, there is very little evidence from studies on clinical material, in support of such a role for the gene. In this study, we evaluated the expression of CC3/TIP30 in human breast cancer tissue and investigated the possible associations with the clinicopathological parameters. METHODS: Total RNA and proteins were extracted from the frozen breast tumor and matched normal tissues. Evaluation of CC3/TIP30 expression was assessed by reverse transcription (RT)-PCR and reverse phase protein array. Immunohistochemistry of CC3/TIP30 on breast tissue microarrays was also analyzed. RESULTS: We have found that CC3/TIP30 expression is significantly associated with positive HER-2/neu status at both mRNA (P=0.023) and protein (P=0.016) levels. Immunohistochemical analysis on tissue microarrays also shows a positive correlation between CC3 expression and HER-2/neu status (P=0.0028). CONCLUSION: Our findings suggest a potential link between the expression of CC3/TIP30 gene and the HER-2/neu oncogene-mediated signal pathway.These findings could not have been predicted from previous experimental studies, and suggest that CC3/TIP30 may play a complex role in breast cancer.

TIP30, also called CC3 or Htatip2, is a putative metastasis suppressor that promotes apoptosis and inhibits angiogenesis. Although TIP30 has several characteristic features of a tumor suppressor in in vitro analyses, tumor development as a result of TIP30 inactivation has not been demonstrated in vivo, and abnormal expression of TIP30 in human cancer has not been reported. Using genetically engineered mice and cells deficient in TIP30, we show that TIP30-deficient mice have a high incidence of hepatocellular carcinoma and other tumors, and loss of TIP30 enhances susceptibility of fibroblasts to transformation by the SV40 large T antigen. Furthermore, immunohistochemical analysis indicates that reduced TIP30 expression is associated with 33% of human hepatocellular carcinomas. Some of these carcinomas harbor missense mutations in the Tip30 gene, which cause abnormal expression of TIP30. Together, these results demonstrate that the Tip30 gene is a tumor susceptibility gene playing an important role in the suppression of hepatocarcinogenesis.

It has been previously demonstrated that the 30-kDa Tat-interacting protein (TIP30) plays an important role in the suppression of hepatocarcinogenesis by acting as a tumor suppressor. Here we report that TIP30 suppresses metastasis of hepatocellular carcinoma (HCC) through inhibiting the transcription of osteopontin (OPN), a key molecule in the development of tumor metastasis. The expression of TIP30 messenger RNA was reverse to that of OPN messenger RNA in HCC cell lines. Ectopic expression of TIP30 greatly suppressed OPN expression, inhibited invasion of HCC cells through extracellular matrix (ECM) and adhesion with fibronectin in vitro, whereas down-regulation of TIP30 by RNA-mediated interference enhanced OPN expression and promoted metastatic abilities of HCC cells in vitro. Moreover, overexpression of TIP30 significantly inhibited the growth and lung metastases of HCC cells in nude mice. In contrast, down-regulation of TIP30 greatly promoted tumor cell growth and metastases in vivo. TIP30 repressed OPN transcription through interaction with Ets-1 and suppressed the transcriptional activity of Ets-1 and synergistic actions of Ets-1 and alkaline phosphatase-1. Thus, TIP30 may act as an Ets-1 modulator and inhibit tumor metastasis through abrogating Ets-1-dependent transcription. Moreover, expression of TIP30 was inversely associated with OPN expression in HCC tissue samples as detected by immunohistochemistry assay. CONCLUSION: Our results reveal a novel pathway by which OPN and possibly other Ets-1 target genes involved in tumor metastasis are regulated by TIP30 and elucidate a mechanism for metastasis promoted by TIP30 deficiency.

Resistance to apoptosis and ability to promote angiogenesis are integral features of the metastatic phenotype. Human gene CC3 is a metastasis suppressor for variant small cell lung carcinoma and a mouse melanoma in vivo. We have shown previously that metastasis-suppressing function of CC3 might be due at least in part to the ability of CC3 protein to predispose tumor cells to apoptosis. Here we demonstrate that CC3 has a previously unidentified effect on the ability of tumor cells to induce angiogenesis in vitro. expression of CC3 in three different tumor cell lines significantly diminished their angiogenic character as manifested in the in vitro proliferation and migration assays with endothelial cells of both macro- and microvascular origin. expression of CC3 induced changes in RNA levels of several angiogenic modulators consistent with the overall reduction in angiogenic properties. These results indicate that expression of CC3 has a dual effect on phenotype of tumor cells ultimately inhibiting their metastatic potential.

PURPOSE: The human CC3/TIP30 gene is a putative metastasis suppressor gene, based on the results of experimental studies using lung, colon and melanoma cell lines. However, there is very little evidence from studies on clinical material, in support of such a role for the gene. In this study, we evaluated the expression of CC3/TIP30 in human breast cancer tissue and investigated the possible associations with the clinicopathological parameters. METHODS: Total RNA and proteins were extracted from the frozen breast tumor and matched normal tissues. Evaluation of CC3/TIP30 expression was assessed by reverse transcription (RT)-PCR and reverse phase protein array. Immunohistochemistry of CC3/TIP30 on breast tissue microarrays was also analyzed. RESULTS: We have found that CC3/TIP30 expression is significantly associated with positive HER-2/neu status at both mRNA (P=0.023) and protein (P=0.016) levels. Immunohistochemical analysis on tissue microarrays also shows a positive correlation between CC3 expression and HER-2/neu status (P=0.0028). CONCLUSION: Our findings suggest a potential link between the expression of CC3/TIP30 gene and the HER-2/neu oncogene-mediated signal pathway.These findings could not have been predicted from previous experimental studies, and suggest that CC3/TIP30 may play a complex role in breast cancer.

The HIV Tat-interacting protein (TIP30), also called CC3 or HTIP2, is encoded by Tip30, a putative tumor-suppressor gene located on human chromosome 11p15.1. In this study, we investigated the role of TIP30 in the progression and metastasis of lung cancer. TIP30 expression was analyzed in 206 paired lung cancers and adjacent non-tumor tissues, as well as in 70 matched lymph node metastases using a high-density tissue microarray. Results were compared with the clinicopathologic features of the patients from whom the tissues were taken. Low TIP30 expression levels were found in all 9 cases of small cell lung cancer and in 36.5% (72/197) of non-small cell lung cancer, which were correlated with lymph node metastasis in non-small cell lung cancer and with poor differentiation and advanced stage of tumor cells in squamous cell carcinoma. The immunostaining scores were significantly lower in the metastatic lesions than in the primary lesions. Down-regulation of TIP30 by a short hairpin RNA enhanced cell survival, migration, and invasion through Matrigel in vitro, and promoted lung metastasis and vascularization in nude mice. Further studies revealed that the down-regulation of TIP30 enhanced the expression of osteopontin, as well as matrix metalloproteinase-2 and vascular endothelial growth factor. Our results suggest that the down-regulation of TIP30 promotes metastatic progression of lung cancer, hence it could serve as a potential target for the development of lung cancer therapies.

Resistance to apoptosis and ability to promote angiogenesis are integral features of the metastatic phenotype. Human gene CC3 is a metastasis suppressor for variant small cell lung carcinoma and a mouse melanoma in vivo. We have shown previously that metastasis-suppressing function of CC3 might be due at least in part to the ability of CC3 protein to predispose tumor cells to apoptosis. Here we demonstrate that CC3 has a previously unidentified effect on the ability of tumor cells to induce angiogenesis in vitro. expression of CC3 in three different tumor cell lines significantly diminished their angiogenic character as manifested in the in vitro proliferation and migration assays with endothelial cells of both macro- and microvascular origin. expression of CC3 induced changes in RNA levels of several angiogenic modulators consistent with the overall reduction in angiogenic properties. These results indicate that expression of CC3 has a dual effect on phenotype of tumor cells ultimately inhibiting their metastatic potential.

PURPOSE: The human CC3/TIP30 gene is a putative metastasis suppressor gene, based on the results of experimental studies using lung, colon and melanoma cell lines. However, there is very little evidence from studies on clinical material, in support of such a role for the gene. In this study, we evaluated the expression of CC3/TIP30 in human breast cancer tissue and investigated the possible associations with the clinicopathological parameters. METHODS: Total RNA and proteins were extracted from the frozen breast tumor and matched normal tissues. Evaluation of CC3/TIP30 expression was assessed by reverse transcription (RT)-PCR and reverse phase protein array. Immunohistochemistry of CC3/TIP30 on breast tissue microarrays was also analyzed. RESULTS: We have found that CC3/TIP30 expression is significantly associated with positive HER-2/neu status at both mRNA (P=0.023) and protein (P=0.016) levels. Immunohistochemical analysis on tissue microarrays also shows a positive correlation between CC3 expression and HER-2/neu status (P=0.0028). CONCLUSION: Our findings suggest a potential link between the expression of CC3/TIP30 gene and the HER-2/neu oncogene-mediated signal pathway.These findings could not have been predicted from previous experimental studies, and suggest that CC3/TIP30 may play a complex role in breast cancer.

CC3/TIP30 is a metastasis and tumor suppressor, with reduced or absent expression in a variety of aggressive tumors. Overexpression of CC3 in tumor cells predisposes them to apoptosis in response to different death signals. We found that silencing of CC3 expression does not increase apoptotic resistance of cells. However, it strongly improves survival of tumor cells in response to glucose limitation. HeLa cells with silenced CC3 survive long-term in low glucose, and, in comparison to control HeLa cells, show superior metabolic adaptation to glucose limitation. First, unlike the parental HeLa cells, HeLa with silenced CC3 activate and maintain high levels of mitochondrial respiration that is critical for their ability to thrive in low glucose. Second, silencing of CC3 leads to higher expression levels of mitochondrial proteins in respiration complexes when cells are continuously cultured in limiting glucose. Third, HeLa cells with silenced CC3 maintain higher levels of c-MYC and the M2 isoform of pyruvate kinase in low glucose, contributing to more efficient glycolysis. Fourth, HeLa cells with silenced CC3 fail to fully activate AMPK in response to glucose limitation. Inhibition of AMPK, either pharmacologic or via siRNA, protects control HeLa cells from death in low glucose. The metabolic flexibility acquired by cells after silencing of CC3 could be directly relevant to the development of metastatic and aggressive human tumors that frequently have low or absent expression of CC3.

Tat-interacting protein 30 (TIP30), a transcriptional repressor for ERalpha-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis.

The human gene CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC) in vivo. The ability of CC3 to impair the apoptotic resistance of tumor cells is likely to contribute to metastasis suppression. We describe here an alternatively spliced RNA of CC3, designated TC3, that encodes an unstable protein with antiapoptotic activity. TC3 and CC3 proteins share amino-terminal sequences, but TC3 has a unique short hydrophobic carboxyl terminus. Overexpression of CC3 results in massive death of rodent fibroblasts, but TC3 protects cells from CC3-induced death and from other death stimuli such as treatment with tumor necrosis factor or overexpression of Bax protein. The death-inducing activity of CC3 resides within its amino-terminal domain, which is conserved in TC3. The carboxyl terminus of TC3 is responsible for the antiapoptotic function of TC3; mutations in this domain abolish the ability of TC3 to protect cells from apoptosis. TC3 protein is short-lived due to its rapid degradation by proteasome, and it forms complexes with a regulatory subunit of proteasome known as s5alpha. The signal for the rapid degradation of TC3 resides within its carboxyl terminus, which is capable of conferring instability on a heterologous protein. The proapoptotic activity of CC3 in SCLC cells is induced by a wide variety of signals and involves disruption of the mitochondrial membrane potential (Deltapsim). The CC3 protein has sequence similarity to bacterial short-chain dehydrogenases/reductases and might represent a phylogenetically old effector of cell death similar to the recently identified apoptosis-inducing factor. CC3 and TC3 have opposing functions in apoptosis and represent a novel dual regulator of cell death.

CC3 is a metastasis suppressor that inhibits metastasis of the variant small cell lung carcinoma (v-SCLC) by predisposing cells to apoptosis. The same protein was also reported as a cellular cofactor, TIP30, which stimulates HIV-1 Tat-activated transcription by interacting with both Tat and RNA polymerase II. We report here that TIP30/CC3 is a novel serine/threonine kinase. It phosphorylates the heptapeptide repeats of the C-terminal domain (CTD) of the largest RNA polymerase II subunit in a Tat-dependent manner. Amino acid substitutions in the putative ATP binding motif that abolish the TIP30 kinase activity also inhibit the ability of TIP30 to enhance Tat-activated transcription or to sensitize NIH 3T3 and v-SCLC cells to apoptosis. Furthermore, ectopic expression of TIP30/CC3 in v-SCLC cells induces expression of a number of genes that include the apoptosis-related genes Bad and Siva, as well as metastasis suppressor NM23-H2. These data demonstrate a molecular mechanism for TIP30/CC3 function and suggest a novel pathway for regulating apoptosis.

Resistance to apoptosis and ability to promote angiogenesis are integral features of the metastatic phenotype. Human gene CC3 is a metastasis suppressor for variant small cell lung carcinoma and a mouse melanoma in vivo. We have shown previously that metastasis-suppressing function of CC3 might be due at least in part to the ability of CC3 protein to predispose tumor cells to apoptosis. Here we demonstrate that CC3 has a previously unidentified effect on the ability of tumor cells to induce angiogenesis in vitro. expression of CC3 in three different tumor cell lines significantly diminished their angiogenic character as manifested in the in vitro proliferation and migration assays with endothelial cells of both macro- and microvascular origin. expression of CC3 induced changes in RNA levels of several angiogenic modulators consistent with the overall reduction in angiogenic properties. These results indicate that expression of CC3 has a dual effect on phenotype of tumor cells ultimately inhibiting their metastatic potential.

metastasis is the most frequent cause of death in patients with breast cancer. Tip30/CC3 gene is a putative metastasis suppressor gene, which was first identified by a differential display analysis of messenger RNA from the highly metastatic human variant small cell lung carcinoma (SCLC) versus less metastatic classic SCLC cell lines. The aim of this study was to analyze the relationship between expression of TIP30/CC3 and clinical prognosis in 87 patients with surgically removed breast carcinoma. tumor tissues were stained immunohistochemically with anti-TIP30/CC3 antibody. We demonstrated that the expression of TIP30/CC3 was inversely associated with axillary lymph node metastasis (P = .0008) and vascular invasion (P = .0016). expression of TIP30/CC3 was not correlated with tumor grade, estrogen, progesterone, and P53 expression. Inhibition of TIP30/CC3 expression by RNA-mediated interference greatly enhanced breast cancer cell invasion through the extracellular matrix, whereas overexpression of TIP30/CC3 by adenovirus vector suppressed invasion through the extracellular matrix. These data supported the theory that the expression of TIP30/CC3 had a suppressive function on tumor metastasis. In summary, the decrease in expression of TIP30/CC3 is related to metastasis and may represent a new prognosticator in breast carcinoma.