Oncogene database

10542

LAMTOR5

late endosomal/lysosomal adaptor, MAPK and MTOR activator 5;LAMTOR5;late endosomal/lysosomal adaptor, MAPK and MTOR activator 5

HBV X-interacting protein|HBx-interacting protein|hepatitis B virus x interacting protein|hepatitis B virus x-interacting protein (9.6kD)|late endosomal/lysosomal adaptor and MAPK and MTOR activator 5|ragulator complex protein LAMTOR5

1p13.3

protein-coding

We have reported that hepatitis B X-interacting protein (HBXIP) promotes the proliferation and migration of breast cancer cells. However, the underlying mechanism is poorly understood. In this study, we report that HBXIP works in the event through up-regulating S100A4. We observed that HBXIP expression was positively correlated to that of S100A4 in 87 clinical breast cancer tissue samples. Then, we identified that HBXIP was able to up-regulate S100A4 expression in breast cancer cells. Notably, we observed the HBXIP nuclear localization, implying that HBXIP may be associated with the promoter of S100A4. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) showed that HBXIP was able to bind to the nucleotides +200~+239 region of S100A4 promoter, containing two putative recognition motif of transcription factor STAT4 and GRbeta. It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. In addition, we identified another pathway of S100A4 up-regulation mediated by HBXIP. We found that HBXIP activated the PTEN/PI3K/AKT signaling by inducing DNA methylation of PTEN, which subsequently boosted S100A4 expression. In function, we demonstrated that HBXIP enhanced the growth or migration of breast cancer cells through S100A4 in vivo and in vitro. Collectively, we conclude that HBXIP up-regulates S100A4 through activating S100A4 promoter involving STAT4 and inducing PTEN/PI3K/AKT signaling to promote growth and migration of breast cancer cells. Our finding provides new insight into the mechanism of HBXIP in promotion of the development of breast cancer.

Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein that plays critical role in the development of cancer. In this study, we report that HBXIP activates LIM-only protein 4 (LMO4), a transcriptional coregulatory protein, in promotion of cell proliferation. We observed that the messenger RNA (mRNA) expression levels of HBXIP were positively associated with those of LMO4 in clinical breast cancer tissues. We further identified that HBXIP upregulated LMO4 at the levels of promoter, mRNA and protein in MCF-7 and LM-MCF-7 breast cancer cell lines. The expression of cyclin D1 and cyclin E, downstream effectors of LMO4, could be upregulated by HBXIP through LMO4. Then, chromatin immunoprecipitation (ChIP) assay revealed that HBXIP was able to interact with the promoter region of LMO4. Electrophoretic mobility shift assay showed that HBXIP occupied the -237/-206 region of LMO4 promoter containing Sp1 binding element. The mutant of Sp1 binding site in the LMO4 promoter impeded the interaction of HBXIP with the promoter. Co-immunoprecipitation, ChIP and luciferase reporter gene assays showed that HBXIP activated LMO4 promoter through binding to Sp1. In function, flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2 -deoxyuridine (EdU) incorporation assays and animal transplantation assays demonstrated that HBXIP-enhanced cell proliferation of breast cancer through upregulating LMO4 in vitro and in vivo. Thus, we concluded that oncoprotein HBXIP is able to activate the transcriptional coregulatory protein LMO4 through transcription factor Sp1 in promotion of proliferation of breast cancer cells. HBXIP may serve as a driver gene to activate transcription in the development of cancer.

Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein and plays a key role in the development of breast cancer. However, its mechanisms of action are poorly understood. Lin28B functions as an oncogene in a variety of human cancers. In our study, we report that HBXIP acts with its partner Lin28B to contribute to carcinogenesis. Our data showed that the expression levels of HBXIP were significantly positively correlated with those of Lin28B in clinical breast cancer tissues. Then, we found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that HBXIP occupied the promoter region (-1199/-1073 nt) of Lin28B. Importantly, co-immunoprecipitation (Co-IP) and GST pull-down assay validated that HBXIP directly bound to the TATA-binding protein (TBP), a basal subunit of transcription factor TF II D complex. In addition, we discovered that Lin28B could block the downregulation of HBXIP via suppressing miR-520b which directly targeted HBXIP mRNA in the cells. In function, we demonstrated that HBXIP enhanced the proliferation of breast cancer cells through Lin28B in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. Therapeutically, HBXIP may serve as a target of breast cancer.

The nucleolus is a stress sensor associated with cell cycle progression and a viral target. However, the role of the nucleolus during hepatitis B virus infection has not been studied. Here we show that under nucleolar stress, the HBx oncoprotein down-regulates p53 and p21(waf1) levels by disrupting the interaction between ribosomal protein L11 and MDM2. Further, HBx inhibited Act D-mediated down-regulation of proliferative factors such as c-Myc and cyclin E and revived RNA pol I-dependent transcription under these conditions. Importantly, HBx also countered the action of anticancer drug Paclitaxel suggesting its possible role in drug resistance. Thus, HBx not only can facilitate cell proliferation under stress conditions but can confer resistance against anticancer drugs.

tumor angiogenesis plays an important role in the development of cancer. Previously, we reported that hepatitis B X-interacting protein (HBXIP) functioned as an oncoprotein in breast cancer. However, the role of HBXIP in angiogenesis in breast cancer remains poorly understood. In the present study, we show that the oncoprotein HBXIP plays crucial roles in the event. We observed that the expression levels of HBXIP were positively correlated with those of fibroblast growth factor 8 (FGF8) or vascular endothelial growth factor (VEGF) in clinical breast cancer tissues. Then, we demonstrated that HBXIP was able to upregulate FGF8 through activation of its promoter involving direct binding to cAMP response element-binding protein (CREB) in breast cancer cells and thereby increased its secretion. Strikingly, we identified another pathway that HBXIP upregulated FGF8 and VEGF through inhibiting miRNA-503, which directly targeted 3 untranslated region of FGF8 or VEGF mRNA in the cells. Moreover, we revealed that HBXIP-induced FGF8 could upregulate VEGF expression through activating phosphoinositide 3-kinase (PI3K)/Akt/hypoxia-inducible factor 1-alpha (HIF1alpha) signaling and increase its secretion. In function, matrigel angiogenesis assay and hemoglobin content analysis uncovered that HBXIP-enhanced FGF8/VEGF boosted tumor angiogenesis and growth in breast cancer in vitro and in vivo in a paracrine/autocrine manner. Thus, we conclude that HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Our finding provides new insights into the mechanism of tumor angiogenesis in breast cancer. Therapeutically, HBXIP may serve as a novel target of tumor angiogenesis.

Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein in hepatocarcinogenesis. Here, we found that the expression levels of HBXIP were positively associated with those of Secretogranin III (SCG3) in clinical hepatocellular carcinoma tissues. We identified that HBXIP up-regulated the expression of SCG3 through modulating both E2F transcription factor 1 (E2F1) and miR-509-3p. HBXIP suppressed miR-509-3p through activating NF-kappaB. In function, we showed that SCG3 increased the proliferation of hepatoma cells and HBXIP enhanced the proliferation of the cells via SCG3 in vitro and in vivo. Thus, we conclude that HBXIP facilitates the proliferation of hepatoma cells through up-regulating SCG3.

BACKGROUND: Hepatitis B virus X protein (HBx) plays crucial roles in hepatocarcinogenesis. However, the underlying mechanism remains elusive. We have reported that HBx is able to up-regulate survivin in hepatocellular carcinoma tissues. The oncopreotein hepatitis B X-interacting protein (HBXIP), a target of miR-520b, is involved in the development of cancer. In this study, we focus on the investigation of hepatocarcinogenesis mediated by HBx. METHODS: The expression of HBx and survivin was examined in the liver tissues of HBx-Tg mice. The effect of HBx/survivin on the growth of LO2-X-S cells was determined by colony formation and transplantation in nude mice. The effect of HBx/survivin on promoter of miR-520b was determined by Western blot analysis, luciferase reporter gene assay, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP), respectively. The expression of HBx, survivin and HBXIP was detected by immunohistochemistry and real-time PCR in clinical HCC tissues, respectively. The DNA demethylation of HBXIP promoter was examined. The functional influence of miR-520b and HBXIP on proliferation of hepatoma cells was analyzed by MTT, colony formation, EdU and transplantation in nude mice in vitro and in vivo. RESULTS: In this study, we provided evidence that HBx up-regulated survivin in the liver cancer tissues of HBx-Tg mice aged 18 M. The engineered LO2 cell lines with survivin and/or HBx were successfully established, termed LO2-X-S. MiR-520b was down-regulated in LO2-X-S cells and clinical HCC tissues. Our data revealed that HBx survivin-dependently down-regulated miR-520b through interacting with Sp1 in the cells. HBXIP was highly expressed in LO2-X-S cells, liver cancer tissues of HBx-Tg mice aged 18 M and clinical HCC tissues (75.17%, 112/149). The expression level of HBXIP was positively associated with those of HBx or survivin in clinical HCC tissues. In addition, we showed that HBx survivin-dependently up-regulated HBXIP through inducing demethylation of HBXIP promoter in LO2-X-S cells and clinical HCC tissues. In function, low level miR-520b and high level HBXIP mediated by HBx with partner survivin contributed to the growth of LO2-X-S cells in vitro and in vivo. CONCLUSION: HBx accelerates hepatocarcinogenesis with partner survivin through modulating tumor suppressor miR-520b and oncoprotein HBXIP.

We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) plays a crucial role in the promotion of migration of breast cancer cells. Lamellipodia and filopodia protrusions play fundamental roles, involving dynamic cytoskeleton reorganization in the metastasis of cancer. Here, we observed that the expression levels of both HBXIP and Calpain small subunit 1 (Capn4) were very high in clinical metastatic lymph nodes of breast tumor. Then, we found that HBXIP was able to up-regulate Capn4 at the levels of promoter, mRNA and protein in breast cancer cells through activation of ERK1/2. Moreover, we showed that HBXIP activated ERK1/2 through up-regulating MEKK2. In function, we revealed that HBXIP increased the filopodia formation through Capn4, resulting in cell migration. Thus, we conclude that the oncoprotein HBXIP enhances the migration of breast cancer through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Therapeutically, HBXIP may serve as a novel target in breast cancer.

We have documented that the oncoprotein hepatitis B X-interacting protein (HBXIP) is able to promote migration of breast cancer cells. A subset of acetylated microtubules that accumulates in the cell leading edge is necessary for cell polarization and directional migration. In this study, we explored the hypothesis that HBXIP contributes to migration of breast cancer cells by supporting microtubule acetylation in breast cancer cells. We found that HBXIP could induce acetylated microtubules accumulating into the leading protrusion in wound-induced directional migration in breast cancer cells by immunofluorescence staining analysis. Interestingly, HBXIP was able to increase the acetylation of alpha-tubulin in the cells by immunofluorescence staining and Western blot analysis. Furthermore, we observed that acetyltransferase GCN5 was involved in the event that HBXIP induced increase of acetylated microtubules and their expansion in protrusions in breast cancer cells by Western blot analysis and immunofluorescence staining. Moreover, GCN5 was required for the HBXIP-enhanced migration of breast cancer cells by wound healing assay. Thus, we conclude that HBXIP promotes the migration of breast cancer cells through modulating microtubule acetylation mediated by GCN5. Therapeutically, HBXIP may serve as a novel target in breast cancer.

The glucose metabolism reprogramming is a hallmark of cancer. The oncoprotein hepatitis B X-interacting protein (HBXIP) functions in the development of breast cancer. In this study, we supposed that HBXIP might be involved in the glucose metabolism reprogramming in breast cancer. We showed that HBXIP led to increases in generation of intracellular glucose and lactate, as well as decreases in generation of reactive oxygen species. expression of synthesis of cytochrome c oxidase 2 (SCO2) and pyruvate dehydrogenase alpha 1 (PDHA1), two factors of metabolic switch from oxidative phosphorylation to aerobic glycolysis, was suppressed by HBXIP. In addition, miR-183/182 and miR-96 directly inhibited the expression of SCO2 and PDHA1 through targeting their mRNA coding sequences (CDSs), respectively. Interestingly, HBXIP elevated the miR-183/96/182 cluster expression through hypoxia-inducible factor 1alpha (HIF1alpha). The stability of HIF1alpha was enhanced by HBXIP through disassociating interaction of von Hippel-Lindau protein (pVHL) with HIF1alpha. Moreover, miR-183 increased the levels of HIF1alpha protein through directly targeting CDS of VHL mRNA, forming a feedback loop of HIF1alpha/miR-183/pVHL/HIF1alpha. In function, HBXIP-elevated miR-183/96/182 cluster enhanced the glucose metabolism reprogramming in vitro. HBXIP-triggered glucose metabolism reprogramming promoted the growth of breast cancer in vivo. Thus, we conclude that the oncoprotein HBXIP enhances glucose metabolism reprogramming through suppressing SCO2 and PDHA1 in breast cancer.