Gene Summary

Gene:HTATIP2; HIV-1 Tat interactive protein 2
Aliases: CC3, TIP30, SDR44U1
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:oxidoreductase HTATIP2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HTATIP2 (cancer-related)

Li Y, Cai B, Chen S, et al.
Overexpression of Tat-interacting protein 30 inhibits the proliferation, migration, invasion and promotes apoptosis in bladder cancer cells.
J Cancer Res Ther. 2018; 14(Supplement):S713-S718 [PubMed] Related Publications
Aims: Tat-interacting protein 30 (TIP30), a transcriptional repressor, possesses antitumor effect in different cancer cells. However, little is known about the function of TIP30 in bladder cancer till now.
Materials and Methods: A TIP30-overexpressing plasmid was transfected into the bladder cancer cells (T24). The cell cycle and apoptosis were detected by flow cytometry. The cell proliferation was analyzed using the cell counting kit-8 assay. The migrative and invasive abilities of T24 cells were measured by the transwell assay. The expression of TIP30, cell cycle proteins, migration-related proteins, and cell apoptosis-related proteins was assessed by Western blotting.
Results: The cell proliferation, migration, and invasion of T24 cells were inhibited by overexpression of TIP30. Moreover, the rate of cell apoptosis was increased by the overexpression of TIP30. The expression of cell cycle proteins, phosphorylated EGFR, p-Akt, Bcl-2, cyclin D, cyclin E), migration-related proteins (matrix metalloproteinases 2 [MMP2], MMP6, MMP9), were downregulated, and cell apoptosis-related proteins (bax, cleaved caspase3) were upregulated.
Conclusions: These results suggest that TIP30, as a tumor suppressor in the bladder cancer, might be served as a target in cancer therapies in the future.

Foglietta F, Spagnoli GC, Muraro MG, et al.
Anticancer activity of paclitaxel-loaded keratin nanoparticles in two-dimensional and perfused three-dimensional breast cancer models.
Int J Nanomedicine. 2018; 13:4847-4867 [PubMed] Free Access to Full Article Related Publications
Purpose: Taxanes are highly effective cytotoxic drugs for progressing breast cancer treatment. However, their poor solubility and high toxicity urge the development of innovative formulations of potential clinical relevance.
Materials and methods: By using a simple and straightforward aggregation method, we have generated paclitaxel (PTX) loaded in keratin nanoparticles (KER-NPs-PTX). Their activities were tested against human breast cancer MCF-7 and MDA MB 231 cell lines in conventional two-dimensional (2D) cultures and in a dynamic three-dimensional (3D) model with perfused bioreactor (p3D). Moreover, KER-NPs-PTX activity was compared to free PTX and to PTX loaded in albumin nanoparticles (HSA-NPs-PTX). Cell viability, induction of apoptosis, and gene expression analysis were used as readouts.
Results: In 2D cultures, KER-NPs-PTX was able to inhibit tumor cell viability and to induce apoptosis similarly to PTX and HSA-NPs-PTX. In the p3D model, a lower sensitivity of tumor cells to treatments was observed. Importantly, only KER-NPs-PTX was able to induce a statistically significant increase in apoptotic cell percentages following 24 h treatment for MCF-7 (16.7±4.0 early and 11.3±4.9 late apoptotic cells) and 48 h treatment for MDA MB 231 (21.3±11.2 early and 10.5±1.8 late apoptotic cells) cells. These effects were supported, at least for MCF-7 cells, by significant increases in the expression of proapoptotic
Conclusion: KER-NPs-PTX, generated by a simple procedure, is characterized by high water solubility and enhanced PTX-loading ability, as compared to HSA-NPs-PTX. Most importantly, it appears to be able to exert effective anticancer activities on breast cancer cells cultured in 2D or in p3D models.

Liu YP, Chen CH, Yen CH, et al.
Human immunodeficiency virus Tat-TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines.
Cancer Sci. 2018; 109(10):3105-3114 [PubMed] Free Access to Full Article Related Publications
Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non-HIV-infected cells. The loss of function of Tat-interacting protein 30 (TIP30) has been linked to metastasis in non-small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor-β-induced epithelial-to-mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin-β, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat-interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.

Yang Q, Guo X, Yang L
Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30).
Med Sci Monit. 2018; 24:2225-2234 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Regorafenib (RGF) is the drug of choice for treating hepatic carcinoma (HCC), but the drug has drawbacks due to resistance and associated adverse effects. Thus, it becomes crucial to understand the causal 'map' of the resistance conferred by RGF, so that its clinical potency can be amplified, resulting in enhanced efficacy with reduced adverse effects. Metformin (MTF) has been reported to target NLK (Nemo-like kinase) to inhibit non-small lung cancer cells. Based on the literature, the present investigation was carried out to reveal the effect of RGF and MTF, with an expectation that MTF can synergize therapeutic potential as well reduce chances of resistance. MATERIAL AND METHODS Protein expression of hypoxia inducible factors (HIF)-2α, 30 kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK were assessed by Western blot analysis. RGF and MTF were exposed to MHCC97H cell and proliferation was quantified by assay of cell viability. Gene silencing and chromatin immunoprecipitation assay were done to reveal the relationship between TIP30 and HIF-2α. The impact of RGF and MTF together on postoperative recurrence and lung metastasis of hepatocellular carcinoma was investigated using tumor engrafted mice after administration of MTF and RGF once daily for 35 days. Immunohistochemistry was used to reveal CD31, Ki67, and TUNEL. RESULTS The results suggested MTF-RGF combination lowered expression of HIF-2α gene silencing and suggested increased TIP30 after reduction of HIF-2α. The chromatin immunoprecipitation study indicated that under hypoxia, HIF-2α could bind with TIP30 promoter. Cell number quantification (CCK8), viable cell count, and apoptosis data (using Annexin V-FITC) indicated co-administration of RGF and MTF reduced cell proliferation, encouraging cell apoptosis, and reduced epithelial-mesenchymal transition course. Thus, in orthotopic mice, the RGF-MTF combination exhibited substantial reduction of HCC in lung metastasis and postoperative relapse. CONCLUSIONS MTF can enhance the potential of RGF and inhibit the recurrence and metastasis of HCC after postoperative liver section by regulating the levels of TIP30 and HIF-2α.

Nanok C, Jearanaikoon P, Proungvitaya S, Limpaiboon T
Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma.
Mol Med Rep. 2018; 17(3):4145-4153 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is the most common primary liver cancer in Northeastern Thailand where liver fluke infection is highly endemic. Although aberrant DNA methylation in CCA has been reported by several investigators, little is known regarding the associations between them. In the present study, the results obtained from our previously published methylation array were analyzed and 10 candidate genes involved in DNA repair [protein phosphatase 4 catalytic subunit (PPP4C)], apoptosis [runt related transcription factor 3 (RUNX3), interferon regulatory factor 4 (IRF4), ubiquitin C‑terminal hydrolase L1 (UCHL1) and tumor protein p53 inducible protein 3 (TP53I3)], cell proliferation [cyclin D2 (CCND2) and Ras association domain family member 1 (RASSF1)], drug metabolism [aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and solute carrier family 29 member 1 (SLC29A1)] and angiogenesis [human immunodeficiency virus‑1 tat interactive protein 2 (HTATIP2)] were selected for quantification of their methylation levels in 54 CCA and 19 adjacent normal tissues using methylation‑sensitive high‑resolution melting. The associations between the methylation status of the individual genes and clinical parameters were statistically analyzed. High methylation levels were observed in UCHL1, IRF4, CCND2, HTATIP2 and TP53I3. The median methylation level of UCHL1 was 57.3% (range, 3.15 to 88.7%) and HTATIP2 was 13.6% (range, 7.5 to 36.7%). By contrast, low methylation of HTATIP2 and UCHL1 was identified in adjacent normal tissues. The methylation status of HTATIP2 and UCHL1 was associated with patients' overall survival. CCA patients with high methylation of HTATIP2 and low methylation of UCHL1 exhibited longer overall survival. In addition, multivariate Cox regression analysis demonstrated that UCHL1 methylation was an independent factor for CCA with hazard ratio of 1.81 (95% confidence interval, 1.01‑3.25) in high methylation group. The combination of HTATIP2 and UCHL1 methylation status strongly supported their potential predictive biomarker in which patients with CCA who had high methylation of HTATIP2 and low methylation of UCHL1 showed longer overall survival than those with low HTATIP2 methylation and high UCHL1 methylation. In conclusion, the present study revealed the value of aberrant DNA methylation of HTATIP2 and UCHL1, which may serve as a potential predictive biomarker for CCA.

Xu T, Jin Z, Yuan Y, et al.
Tat-Interacting Protein 30 (TIP30) Expression Serves as a New Biomarker for Tumor Prognosis: A Systematic Review and Meta-Analysis.
PLoS One. 2016; 11(12):e0168408 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tat-interacting protein 30 (TIP30) is a tumor suppressor protein that has been found to be expressed in a wide variety of tumor tissues. TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. The methylation of the TIP30 promoter is also associated with tumor prognosis. To evaluate this topic further, we conducted a systematic meta-analysis to explore the clinicopathological and prognostic significance of TIP30 for tumor patients.
METHODS: We searched PubMed and EMBASE for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroup analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients.
RESULTS: Fourteen studies with 1705 patients were included in this meta-analysis. A significant association was observed between high expression of TIP30 in patients with cancer with a good overall survival (hazard ratio = 0.53, 95% confidence interval: 0.41-0.69), and good recurrence-free survival or disease free survival (hazard ratio = 0.49, 95% confidence interval: 0.37-0.66). Lack of expression of TIP30 had an association with lymph node metastasis (odds ratio = 3.90, 95% confidence interval: 2.21-6.89) and high tumor node metastasis clinical stage (odds ratio = 2.10, 95% confidence interval: 1.68-2.62). The methylation of the TIP30 promoter did not significantly influence the overall survival (hazard ratio = 0.99, 95% confidence interval: 0.88-1.13) or disease free survival (hazard ratio = 0.62, 95% confidence interval: 0.19-2.02).
CONCLUSIONS: TIP30 expression is associated with a good prognosis in patients with tumors. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between tumor prognosis and TIP30.

Peng X, Xue H, Lü L, et al.
Accumulated promoter methylation as a potential biomarker for esophageal cancer.
Oncotarget. 2017; 8(1):679-691 [PubMed] Free Access to Full Article Related Publications
We performed a two-stage molecular epidemiological study to explore DNA methylation profiles for potential biomarkers of esophageal squamous cell carcinoma (ESCC) in a Chinese population. Infinium Methylation 450K BeadChip was used to identify genes with differentially methylated CpG sites. Sixteen candidate genes were validated by sequencing 1160 CpG sites in their promoter regions using the Illumina MiSeq platform. When excluding sites with negative changes, 10 genes (BNIP3, BRCA1, CCND1, CDKN2A, HTATIP2, ITGAV, NFKB1, PIK3R1, PRDM16 and PTX3) showed significantly different methylation levels among cancer lesions, remote normal-appearing tissues, and healthy controls. PRDM16 had the highest diagnostic value with the AUC (95% CI) of 0.988 (0.965-1.000), followed by PIK3R1, with the AUC (95% CI) of 0.969 (0.928-1.000). In addition, the methylation status was higher in patients with advanced cancer stages. These results indicate that aberrant DNA methylation may be a potential biomarker for the diagnosis of ESCC.

Liu Z, Yang Z, Jiang S, et al.
MCM2 and TIP30 are prognostic markers in squamous cell/adenosquamous carcinoma and adenocarcinoma of the gallbladder.
Mol Med Rep. 2016; 14(5):4581-4592 [PubMed] Free Access to Full Article Related Publications
The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder remain to be fully elucidated, due to the fact that it is a rare gallbladder cancer subtype. In the current study, the expression of minichromosome maintenance complex component 2 (MCM2) and HIV‑1 tat interactive protein 2 (TIP30) was measured in 46 cases of SC/ASC and 80 adenocarcinomas (AC) using immunohistochemistry. Positive MCM2 and negative TIP30 expression were significantly associated with large tumor size, high TNM stage, invasion, lymph node metastasis and lack of surgical curability in SC/ASC and AC. Positive MCM2 and negative TIP30 expression were significantly associated with poor differentiation in AC, whereas only MCM2 was correlated with differentiation in SC/ASC. Univariate Kaplan‑Meier analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and surgical curability were significantly associated with post‑operative survival in patients with SC/ASC and AC. Multivariate Cox regression analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and lack of surgical curability were also independent predictors of poor prognosis in patients with SC/ASC and AC. These data suggest that positive MCM2 and negative TIP30 expression are closely correlated with the clinical, pathological and biological parameters, in addition to poor prognosis in patients with gallbladder cancer.

Zhang X, Lv L, Ouyang X, et al.
Association of TIP30 expression and prognosis of hepatocellular carcinoma in patients with HBV infection.
Cancer Med. 2016; 5(9):2180-9 [PubMed] Free Access to Full Article Related Publications
Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high-density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha-fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC (P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect (P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30(++/+++) ) had a better 5-year overall survival rate than those with low/negative (TIP30(+/-) ) expression (P < 0.001). TIP30(+/-/) HBV(+) patients had the worst 5-year overall survival rate, whereas TIP30(++/+++) /HBV(-) patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV(+) hepatoblastoma cell-line HepG2 2.2.15 and HCC cell-line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC.

Jiang B, Sun R, Fang S, et al.
Lnc-CC3 increases metastasis in cervical cancer by increasing Slug expression.
Oncotarget. 2016; 7(27):41650-41661 [PubMed] Free Access to Full Article Related Publications
Although screening has reduced mortality rates, metastasis still results in poor survival and prognosis in cervical cancer patients. We compared cervical cancer ESTs libraries with other ESTs libraries to identify candidate genes and cloned a novel cervical cancer-associated lncRNA, lnc-CC3. Overexpression of lnc-CC3 promoted migration and invasion by SiHa cervical cancer cells in vitro and in vivo, increased Slug expression, and reduced the expression of the epithelial cell marker E-cadherin. Conversely, lnc-CC3 knockdown altered SiHa cell morphology and increased the expression of E-cadherin, thereby suppressing migration and invasion. These results suggest lnc-CC3 may be a useful marker of metastasis in cervical cancer.

Stelma T, Chi A, van der Watt PJ, et al.
Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential.
IUBMB Life. 2016; 68(4):268-80 [PubMed] Related Publications
The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets.

You A, Cao M, Guo Z, et al.
Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models.
J Hematol Oncol. 2016; 9:20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy.
METHODS: The protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot. Cell viability assays were performed to study the influence of metformin and sorafenib on cell proliferation. Annexin V-FITC apoptosis assays were used to detect the influence of metformin and sorafenib on cell apoptosis. The relationship between HIF-2α and TIP30 was studied using gene silencing approach and chromatin immunoprecipitation assay. To investigate the effect of metformin and sorafenib on postoperative recurrence and lung metastasis of HCC in tumor-bearing mice, the mice were orally treated either with metformin or sorafenib once a day for continuous 37 days after the operation to remove the lobe where the tumor was implanted. CD31, Ki67, and TUNEL were examined by immunohistochemistry.
RESULTS: Our study demonstrated that metformin synergized with sorafenib reduced HIF-2α expression as examined by Western blot. Gene silencing approach indicated TIP30 was upregulated after knocking-down of HIF-2α and chromatin immunoprecipitation assay revealed that HIF-2α could bind to TIP30 promoter under hypoxic condition. Cell Counting Kit-8 (CCK8) cell viability assay and Annexin V-FITC apoptosis assay showed that metformin in combination with sorafenib suppressed cell proliferation and promoted cell apoptosis. Besides, combined therapy suppressed epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. Moreover, metformin in combination with sorafenib significantly minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression.
CONCLUSIONS: Metformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30.

Guo Z, Cao M, You A, et al.
Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30.
Cancer Sci. 2016; 107(4):507-13 [PubMed] Free Access to Full Article Related Publications
We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP-activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib.

Yu X, Li Z, Wu WK
TIP30: A Novel Tumor-Suppressor Gene.
Oncol Res. 2014; 22(5-6):339-48 [PubMed] Related Publications
TIP30/CC3 was first identified and characterized as a "candidate" tumor-suppressor gene in 1997. Recently, the TIP30 tumor-suppressor status has been fully established since several studies have described that TIP30 protein expression is frequently downregulated in diverse types of human tumors, and the downregulation is often associated with tumor progression. TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. Moreover, TIP30(-/-) mice spontaneously develop hepatocellular carcinoma and other tumors at a higher incidence than that of wild-type mice. In this review, we provide an overview of current knowledge concerning the role of TIP30 in tumor development and progression. To our knowledge, this is the first review about the role of novel tumor-suppressor gene TIP30 in tumor development and progression.

Karginova O, Siegel MB, Van Swearingen AE, et al.
Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer.
Mol Cancer Ther. 2015; 14(4):920-30 [PubMed] Free Access to Full Article Related Publications
Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation.

Dong X, Deng Q, Nie X, et al.
Downregulation of HTATIP2 expression is associated with promoter methylation and poor prognosis in glioma.
Exp Mol Pathol. 2015; 98(2):192-9 [PubMed] Related Publications
Glioma is an aggressive tumor with poor prognosis. Identification of precise prognostic marker and effective therapeutic target is important in the treatment of glioma. HTATIP2 is a novel tumor suppressor gene, which is frequently silenced by epigenetic mechanisms in many caners. However, the expression of HTATIP2 and how it is regulated in glioma are unknown. Hence, we assessed whether loss of HTATIP2 expression occurs in glioma, and, if so, what is the mechanism of such loss. We found that HTATIP2 expression was absent or diminished in primary gliomas compared with normal brain tissue. In vitro experiments showed that HTATIP2 expression could be restored via 5-aza-2'deoxycytidine treatment in U87 and U251 cell lines. Methyl-specific PCR indicated that the two cell lines and 60% primary gliomas carried aberrant methylated HTATIP2 alleles while normal brain tissue did not. Pyrosequencing confirmed these results and showed a higher density of methylation in the minimal promoter element, which contains four Sp1 binding sites in primary gliomas, than in normal brain tissue. Finally, we found that the overall survival was significantly higher in patients with positive HTATIP2 expression than those with loss of HTATIP2 expression. Overexpression of HTATIP2 inhibited glioma proliferation and growth in vitro. Taken together, the present study showed that loss of HTATIP2 expression was a frequent event in glioma and is associated with poor prognosis. Promoter methylation may be an underlying mechanism.

Bu F, Liu X, Li J, et al.
TGF-β1 induces epigenetic silence of TIP30 to promote tumor metastasis in esophageal carcinoma.
Oncotarget. 2015; 6(4):2120-33 [PubMed] Free Access to Full Article Related Publications
TGF-β1, a potent EMT (epithelial-mesenchymal transition) inducer present in the tumor microenvironment, is involved in the metastasis and progression of various carcinomas, including esophageal squamous cell carcinoma (ESCC). TIP30 (30kDa HIV-1 Tat interacting protein) is a putative tumor metastasis suppressor. Here, we found TIP30 was decreased in cells undergoing EMT induced by TGF-β1, an occurrence that was related to promoter hypermethylation. TGF-β1 induced TIP30 hypermethylation via increasing DNMT1 and DNMT3A expression, which could be restored by TGF-β antibodies. In our in vitro and in vivo studies, we showed that silence of TIP30 led to EMT, enhanced migrative and invasive abilities of ESCC cells, promoted tumor metastasis in xenografted mice; alternatively, overexpression of TIP30 inhibited TGF-β1-induced EMT, and metastatic abilities of ESCC cells. Mechanically, TIP30 silencing induced the nuclear translocation and transcriptional activation of β-catenin in an AKT-dependent manner, which further resulted in the initiation of EMT. Consistently, TIP30 was frequently methylated and downregulated in ESCC patients. Loss of TIP30 correlated with nuclear β-catenin and aberrant E-cadherin expression. TIP30 was a powerful marker in predicting the prognosis of ESCC. Taken together, our results suggest a novel and critical role of TIP30 involved in TGF-β1-induced activation of AKT/β-catenin signaling and ESCC metastasis.

Dong W, Shen R, Cheng S
Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b.
Biochem Biophys Res Commun. 2014; 453(4):772-7 [PubMed] Related Publications
TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p=0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3'untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3'UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC.

Shuai S, Yan X, Zhang J, et al.
TIP30 nuclear translocation negatively regulates EGF-dependent cyclin D1 transcription in human lung adenocarcinoma.
Cancer Lett. 2014; 354(1):200-9 [PubMed] Related Publications
Aberrant epidermal growth factor (EGF)-dependent signaling plays a key role in the progression of human carcinomas. We found that TIP30, a tumor suppressor protein, translocated into the nucleus of human lung adenocarcinoma cells following EGF treatment, and the selective inhibitors of EGFR signaling pathways blocked this effect. Chromatin immunoprecipitation assays revealed that TIP30 negatively regulated EGF-dependent transcriptional activation of CCND1 through a HDAC1-dependent mechanism. In lung adenocarcinoma patients, the level of nuclear TIP30 was inversely correlated with that of EGFR and cyclin D1. These findings suggest that nuclear TIP30-induced downregulation of cyclin D1 transcription antagonizes EGFR signaling and suppresses tumorigenesis.

Chen F, Li A, Gao S, et al.
Tip30 controls differentiation of murine mammary luminal progenitor to estrogen receptor-positive luminal cell through regulating FoxA1 expression.
Cell Death Dis. 2014; 5:e1242 [PubMed] Free Access to Full Article Related Publications
Estrogen receptor-alpha positive (ER(+)) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER(+) mammary luminal tumors arising in Tip30(-/-)MMTV-Neu mice exhibited increased enrichment of luminal progenitor gene signature. Deletion of the Tip30 gene increased proportion of mammary stem and progenitor cell populations, and raised susceptibility to ER(+) mammary luminal tumors in female Balb/c mice. Moreover, Tip30(-/-) luminal progenitors displayed increases in propensity to differentiate to mature ER(+) luminal cells and FoxA1 expression. Knockdown of FoxA1 expression in Tip30(-/-) progenitors by shRNA specific for FoxA1 reduced their differentiation toward ER(+) mature luminal cells. Taken together, our results suggest that TIP30 is a key regulator for maintaining ER(+) and ER(-)luminal pools in the mammary luminal lineage, and loss of it promotes expansion of ER(+) luminal progenitors and mature cells and ER(+) mammary tumorigenesis.

Zhu M, Yin F, Fan X, et al.
Decreased TIP30 promotes Snail-mediated epithelial-mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma.
Oncogene. 2015; 34(11):1420-31 [PubMed] Related Publications
The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to tumor recurrence and metastases. Recently, epithelial-mesenchymal transition (EMT) has been implicated in tumor invasion and metastasis. However, the underlying molecular mechanisms are yet to be elucidated. Here, we show that 30-kDa Tat-interacting protein (TIP30), also called CC3, is significantly downregulated during transforming growth factor-β-induced EMT. In our in vitro and in vivo studies, we show that decreased TIP30 expression leads to EMT, as well as enhanced motility and invasion of HCC cells. Also, increased self-renewal ability and chemotherapeutic resistance are observed with TIP30 depletion. Moreover, Snail is one of the key transcription factors promoting EMT, and overexpression of TIP30 greatly decreased nucleic accumulation in Snail through the regulation of intracellular localization. Small interfering RNAs targeting Snail attenuated EMT and tumor-initiating properties induced by TIP30 deficiency. We further confirmed that TIP30 competitively interrupted the interaction of Snail with importin-β2 to block the nuclear import of Snail. Consistently, TIP30 expression significantly correlates with E-cadherin expression in HCC patients. TIP30 or combination of E-cadherin is a powerful marker in predicting the prognosis of HCC. Taken together, our results suggest a novel and critical role of TIP30 involved in HCC progression and aggressiveness.

Ouyang H, Gore J, Deitz S, Korc M
microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions.
Oncogene. 2014; 33(38):4664-74 [PubMed] Free Access to Full Article Related Publications
Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal-regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3'-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-β) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-β receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-β on cell migration and epithelial-mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF-TGF-β cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF-TGF-β interactions and antagonize the metastatic process at various levels.

Kumtepe Y, Halici Z, Sengul O, et al.
High serum HTATIP2/TIP30 level in serous ovarian cancer as prognostic or diagnostic marker.
Eur J Med Res. 2013; 18:18 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is an evolutionarily conserved gene that is expressed ubiquitously in human tissues and some tumor tissues. This protein has been found to be associated with some gynecological cancers; as such, this study aimed to investigate blood HTATIP2/TIP30 levels in patients with ovarian cancer.
METHODS: Twenty-three women with ovarian cancer and 18 patients with various non-cancerous gynecological complaints (for example, dysfunctional uterine bleeding, fibroids, and urinary incontinence) were included in the study. The pathological diagnosis of ovarian cancer was adenocarcinoma. HTATIP2/TIP30 concentration in the patients' blood samples was determined using ELISA kits.
RESULTS: The HTATIP2/TIP30 level was significantly higher in the cancer group than in the control group (1.84 ± 0.82 versus 0.57 ± 0.13 ng/ml, mean ± SD).
CONCLUSIONS: We demonstrated the potential role of HTATIP2/TIP30 in ovarian cancer for the first time, thereby enlightening future studies targeting HTATIP2/TIP30 in ovarian cancer treatment, diagnosis, and prevention.

Lu L, Sun HC, Zhang W, et al.
Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma.
PLoS One. 2013; 8(5):e65023 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AIMS: We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma (HCC), which is mediated by down-regulation of tumor suppressor HTATIP2. The aim of the present study was to determine whether aspirin minimizes this effect and improves survival.
METHODS: The effects of sorafenib, aspirin, and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice. Tumor growth, intrahepatic metastasis (IHM), lung metastasis, and survival were assessed. Polymerase chain reaction (PCR) array, real-time (RT)-PCR, and Western blotting were used to examine gene expression. The anti-invasion and anti-metastasis effects of aspirin were studied in HTATIP2-knockdown and HTATIP2-overexpressing HCC cell lines. The molecular mechanism of HTATIP2 regulation by aspirin was explored.
RESULTS: Aspirin suppressed the pro-invasion and pro-metastasis effects of sorafenib in HCC and up-regulated HTATIP2 expression. Aspirin did not inhibit the proliferation of HCC cells, but it decreased the invasiveness of HCC with lower expression of HTATIP2 and increased expression of a set of markers, indicating a mesenchymal-to-epithelial transition in tumor cells. The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase (COX) 2 expression.
CONCLUSIONS: Aspirin minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor HTATIP2; this mechanism is mediated through inhibition of COX2.

Omaruddin RA, Roland TA, Wallace HJ, Chaudhry MA
Gene expression as a biomarker for human radiation exposure.
Hum Cell. 2013; 26(1):2-7 [PubMed] Related Publications
Accidental exposure to ionizing radiation can be unforeseen, rapid, and devastating. The detonation of a radiological device leading to such an exposure can be detrimental to the exposed population. The radiation-induced damage may manifest as acute effects that can be detected clinically or may be more subtle effects that can lead to long-term radiation-induced abnormalities. Accurate identification of the individuals exposed to radiation is challenging. The availability of a rapid and effective screening test that could be used as a biomarker of radiation exposure detection is mandatory. We tested the suitability of alterations in gene expression to serve as a biomarker of human radiation exposure. To develop a useful gene expression biomonitor, however, gene expression changes occurring in response to irradiation in vivo must be measured directly. Patients undergoing radiation therapy provide a suitable test population for this purpose. We examined the expression of CC3, MADH7, and SEC PRO in blood samples of these patients before and after radiotherapy to measure the in vivo response. The gene expression after ionizing radiation treatment varied among different patients, suggesting the complexity of the response. The expression of the SEC PRO gene was repressed in most of the patients. The MADH7 gene was found to be upregulated in most of the subjects and could serve as a molecular marker of radiation exposure.

Zhang W, Sun HC, Wang WQ, et al.
Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice.
Gastroenterology. 2012; 143(6):1641-1649.e5 [PubMed] Related Publications
BACKGROUND & AIMS: Antiangiogenic agents can sometimes promote tumor invasiveness and metastasis, but little is known about the effects of the antiangiogenic drug sorafenib on progression of hepatocellular carcinoma (HCC).
METHODS: Sorafenib was administered orally (30 mg · kg(-1) · day(-1)) to mice with orthotopic tumors grown from HCC-LM3, SMMC7721, or HepG2 cells. We analyzed survival times of mice, along with tumor growth, metastasis within liver and to lung, and induction of the epithelial-mesenchymal transition. Polymerase chain reaction arrays were used to determine the effects of sorafenib on gene expression patterns in HCC cells. We analyzed regulation of HIV-1 Tat interactive protein 2 (HTATIP2) by sorafenib and compared levels of this protein in tumor samples from 75 patients with HCC (21 who received sorafenib after resection and 54 who did not).
RESULTS: Sorafenib promoted invasiveness and the metastatic potential of orthotopic tumors grown from SMMC7721 and HCC-LM3 cells but not from HepG2 cells. In gene expression analysis, HTATIP2 was down-regulated by sorafenib. HCC-LM3 cells that expressed small hairpin RNAs against HTATIP2 (knockdown) formed less invasive tumors in mice following administration of sorafenib than HCC-LM3 without HTATIP2 knockdown. Alternatively, HepG2 cells that expressed transgenic HTATIP2 formed more invasive tumors in mice following administration of sorafenib. Sorafenib induced the epithelial-mesenchymal transition in HCC cell lines, which was associated with expression of HTATIP2. Sorafenib regulated expression of HTATIP2 via Jun-activated kinase (JAK) and signal transducer and activator of transcription (STAT)3 signaling. Sorafenib therapy prolonged recurrence-free survival in patients who expressed lower levels of HTATIP2 compared with higher levels.
CONCLUSIONS: Sorafenib promotes invasiveness and the metastatic potential of orthotopic tumors from HCC cells in mice, down-regulating expression of HTATIP2 via JAK-STAT3 signaling.

Li A, Zhang C, Gao S, et al.
TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice.
Oncogene. 2013; 32(18):2273-81, 2281e.1-12 [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses epidermal growth factor receptor (EGFR). However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 (30kDa HIV-1 Tat interacting protein) is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II (AT2) cells, and also increased expression of EGFR and its downstream signaling factors in the lung of Tip30(-/-) mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung, and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30-expression lung adenocarcinoma.

Wierinckx A, Roche M, Raverot G, et al.
Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors.
Brain Pathol. 2011; 21(5):533-43 [PubMed] Related Publications
Integrative genomics approaches associating DNA structure and transcriptomic analysis should allow the identification of cascades of events relating to tumor aggressiveness. While different genome alterations have been identified in pituitary tumors, none have ever been correlated with the aggressiveness. This study focused on one subtype of pituitary tumor, the prolactin (PRL) pituitary tumors, to identify molecular events associated with the aggressive and malignant phenotypes. We combined a comparative genomic hybridization and transcriptomic analysis of 13 PRL tumors classified as nonaggressive or aggressive. Allelic loss within the p arm region of chromosome 11 was detected in five of the aggressive tumors. Allelic loss in the 11q arm was observed in three of these five tumors, all three of which were considered as malignant based on the occurrence of metastases. Comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. Data filtering allowed us to highlight five deregulated genes (DGKZ, CD44, TSG101, GTF2H1, HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumors. Our combined genomic and transcriptomic analysis underlines the importance of chromosome allelic loss in determining the aggressiveness and malignancy of tumors.

Arai Y, Honda S, Haruta M, et al.
Genome-wide analysis of allelic imbalances reveals 4q deletions as a poor prognostic factor and MDM4 amplification at 1q32.1 in hepatoblastoma.
Genes Chromosomes Cancer. 2010; 49(7):596-609 [PubMed] Related Publications
In a single-nucleotide polymorphism array-based analysis of 56 hepatoblastoma (HB) tumors, allelic imbalances were detected in 37 tumors (66%). Chromosome gains were found in 1q (28 tumors), 2q (24), 6p (8), 8q (8), 17q (6), and 20pq (10), and losses in 1p (6), 4q (9), and 16q (4). Fine mapping delineated the shortest overlapping region (SOR) of gains at 1q32.1 (1.3 Mb) and 2q24.2-q24.3 (4.8 Mb), and losses at 4q34.3-q35.2 (8.7 Mb) and 4q32.3 (1.6 Mb). Uniparental disomy of 11pter-11p15.4 (IGF2) and loss of 11pter-p14.1 were found in 11 and 2 tumors, respectively. Expression of HTATIP2 (11p15.1) was absent in 9 of 20 tumors. Amplification was identified in four tumors at 1q32.1, where the candidate oncogene MDM4 is located. In the 4q32.3-SRO, ANXA10S, a variant of the candidate tumor suppressor ANXA10, showed no expression in 19 of 24 tumors. Sequence analysis of ANXA10S identified a missense mutation (E36K, c.106G>A) in a HB cell line. Multivariate analysis revealed that both 4q deletion and RASSF1A methylation (relative risks: 4.21 and 7.55, respectively) are independent prognostic factors. Our results indicate that allelic imbalances and gene expression patterns provide possible diagnostic and prognostic markers, as well as therapeutic targets in a subset of HB.

Swift S, Xu J, Trivedi V, et al.
A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization.
J Biol Chem. 2010; 285(15):11402-10 [PubMed] Free Access to Full Article Related Publications
Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor that plays critical roles in cancer, angiogenesis, inflammation, and thrombosis. Proteolytic cleavage of the extracellular domain of PAR1 generates a tethered ligand that activates PAR1 in an unusual intramolecular mode. The signal emanating from the irreversibly cleaved PAR1 is terminated by G protein uncoupling and internalization; however, the mechanisms of PAR1 signal shut off still remain unclear. Using a yeast two-hybrid screen, we identified Bicaudal D1 (BicD1) as a direct interactor with the C-terminal cytoplasmic domain of PAR1. BICD was originally identified as an essential developmental gene associated with mRNA and Golgi-endoplasmic reticulum transport. We discovered a novel function of BicD1 in the modulation of G protein signaling, cell proliferation, and endocytosis downstream of PAR1. BicD1 and its C-terminal CC3 domain inhibited PAR1 signaling to G(q)-phospholipase C-beta through coiled-coil interactions with the cytoplasmic 8th helix of PAR1. Unexpectedly, BicD1 was also found to be a potent suppressor of PAR1-driven proliferation of breast carcinoma cells. The growth-suppressing effects of BicD1 required the ability to interact with the 8th helix of PAR1. Silencing of BicD1 expression impaired endocytosis of PAR1, and BicD1 co-localized with PAR1 and tubulin, implicating BicD1 as an important adapter protein involved in the transport of PAR1 from the plasma membrane to endosomal vesicles. Together, these findings provide a link between PAR1 signal termination and internalization through the non-G protein effector, BicD1.

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