Gene Summary

Gene:TP53INP1; tumor protein p53 inducible nuclear protein 1
Aliases: SIP, Teap, p53DINP1, TP53DINP1, TP53INP1A, TP53INP1B
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:tumor protein p53-inducible nuclear protein 1
Source:NCBIAccessed: 08 August, 2015


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 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 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: TP53INP1 (cancer-related)

Liu F, Kong X, Lv L, Gao J
TGF-β1 acts through miR-155 to down-regulate TP53INP1 in promoting epithelial-mesenchymal transition and cancer stem cell phenotypes.
Cancer Lett. 2015; 359(2):288-98 [PubMed] Related Publications
It has been shown that acquisition of epithelial-mesenchymal transition (EMT) and induction of cancer stem cell (CSC)-like properties contribute to metastasis of cancers in many studies; however, the molecular mechanisms underlying EMT and CSC phenotypes in liver cancer cells remain to be elucidated. MiR-155 is an important microRNA associated with tumour progression. Here, we report that miR-155 regulates not only the epithelial-mesenchymal transition but also the stem-like transition in liver cancer cells. Utilizing quantitative RT-PCR, we found that the expression of miR-155 is positively related to the levels of CD90, CD133 and Oct4 in enriched spheres. Up-regulated miR-155 significantly increases the population of stem-like CSCs among liver cancer cells and the ability to form tumour spheres. Additionally, miR-155 overexpression in cells significantly increases cell motility and invasion, as well as the epithelial-mesenchymal transition process. Conversely, suppression of miR-155 in cells had an opposite effect, which was partially rescued by the down-regulation of TP53INP1. Collectively, miR-155 promotes liver cancer cell EMT and CSCs, in part, via silencing TP53INP1. In addition, we found that TGF-β1 indirectly regulates TP53INP1 expression via miR-155 in liver cancer cells. Taken together, our findings suggest that miR-155 regulates TP53INP1 expression, to induce the epithelial-mesenchymal transition and acquisition of a stem cell phenotype.

Liu F, Kong X, Lv L, Gao J
MiR-155 targets TP53INP1 to regulate liver cancer stem cell acquisition and self-renewal.
FEBS Lett. 2015; 589(4):500-6 [PubMed] Related Publications
In liver cancer, miR-155 up-regulation can regulate cancer-cell invasion. However, whether miR-155 expression is associated with liver cancer stem cells (CSCs) remains unknown. Here, we show that miR-155 expression is up-regulated in tumor spheres. Knock-down of miR-155 resulted in suppression of tumor sphere formation, through a decrease in the proportion of CD90(+) and CD133(+) CSCs and in the expression of Oct4, whereas miR-155 overexpression had the opposite effect. TP53INP1 was determined to be involved in the CSCs-like properties that were regulated by miR-155. Thus, miR-155 may play an important role in promoting the generation of stem cell-like cells and their self-renewal by targeting the gene TP53INP1.

Yuan R, Zhi Q, Zhao H, et al.
Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma.
Tumour Biol. 2015; 36(4):3093-100 [PubMed] Related Publications
Aberrant microRNA (miRNA) expression has been widely recognized to play an extremely important role in several cancers, including hepatocellular carcinoma (HCC). According to the previous studies, abnormal miR-106a expression was closely related to various cancer occurrences. However, the miR-106a expression in HCC remains unclear. In our study, we firstly detected the miR-106a expression levels in 36 pairs of HCC tissues. The results showed that miR-106a expression in HCC tissues was apparently higher than the level in the adjacent tissues. Then, we used quantitative real-time PCR (qPCR) and BSP to analyze miR-106a expression and promoter methylation in HCC cell lines. There came to a conclusion that the methylation status of the miR-106a promoter region was inversely correlated with the expression of miR-106a. After prediction with online software, we further used dual-luciferase reporter gene assay to ensure that TP53INP1 and CDKN1A might be the direct targets of miR-106a. At last, we explored the functions of miR-106a in HCC cells in vitro. Our results manifested that high-miR-106a cell line had stronger invasiveness, faster cell cycle progression, and more resistance to apoptosis compared with the low-miR-106a cell line. Therefore, our study suggested that upregulated expression of miR-106a by its promoter hypomethylation might contribute to the progression of HCC, which might be considered as a potentially effective biomarker and therapeutic approach in the future.

Chaluvally-Raghavan P, Zhang F, Pradeep S, et al.
Copy number gain of hsa-miR-569 at 3q26.2 leads to loss of TP53INP1 and aggressiveness of epithelial cancers.
Cancer Cell. 2014; 26(6):863-79 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Small noncoding miRNAs represent underexplored targets of genomic aberrations and emerging therapeutic targets. The 3q26.2 amplicon is among the most frequent genomic aberrations in multiple cancer lineages including ovarian and breast cancers. We demonstrate that hsa-miR-569 (hereafter designated as miR569), which is overexpressed in a subset of ovarian and breast cancers, at least in part due to the 3q26.2 amplicon, alters cell survival and proliferation. Downregulation of TP53INP1 expression by miR569 is required for the effects of miR569 on survival and proliferation. Targeting miR569 sensitizes ovarian and breast cancer cells overexpressing miR569 to cisplatin by increasing cell death both in vitro and in vivo. Thus targeting miR569 could potentially benefit patients with the 3q26.2 amplicon and subsequent miR569 elevation.

Gao F, Wang W
MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1, forkhead box protein O1 (FOXO1) and FOXO3a.
Mol Med Rep. 2015; 11(2):1200-6 [PubMed] Related Publications
MicroRNAs (miRNAs) are a conserved class of small, endogenous, non protein-coding RNA molecules that are capable of regulating gene expression at post-transcriptional levels and are involved in diverse cellular processes, including cancer pathogenesis. It has previously been reported that miRNA-96 (miR-96) is overexpressed in human colorectal cancer (CRC). However, the underlying mechanism of miR-96 regulation in CRC remains to be elucidated. In the present study, miR-96 was confirmed to be upregulated in CRC tissues by reverse transcription quantitative polymerase chain reaction. MTT assay, colony formation assay and cell cycle analysis revealed that miR-96 overexpression led to increased tumor cell viability, colony formation ability and cell cycle progression. By contrast, inhibition of miR-96 resulted in the suppression of cell proliferation. It was also demonstrated that miR-96 reduced the messenger RNA and protein expression levels of tumor protein p53 inducible nuclear protein 1 (TP53INP1), forkhead box protein O1 (FOXO1) and FOXO3a, which are closely associated with cell proliferation. A luciferase reporter assay indicated that miR-96 inhibited luciferase intensity controlled by the 3'UTRs of TP53INP1, FOXO1 and FOXO3a. In conclusion, the results of the present study demonstrated that miR-96 contributed to CRC cell growth and that TP53INP1, FOXO1 and FOXO3a were direct targets of miR-96, suggesting that miR-96 may have the potential to be used in the development of miRNA‑based therapies for CRC patients.

van Keimpema M, Grüneberg LJ, Mokry M, et al.
FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells.
Blood. 2014; 124(23):3431-40 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
The forkhead transcription factor FOXP1 is involved in B-cell development and function and is generally regarded as an oncogene in activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma, lymphomas relying on constitutive nuclear factor κB (NF-κB) activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B cells and DLBCL cell lines, combined with chromatin immunoprecipitation followed by next-generation sequencing, we established that FOXP1 directly represses a set of 7 proapoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6, and TP53INP1, and AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-κB signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of proapoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-κB activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis.

Mehrotra M, Medeiros LJ, Luthra R, et al.
Identification of putative pathogenic microRNA and its downstream targets in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma.
Hum Pathol. 2014; 45(10):1995-2005 [PubMed] Related Publications
Anaplastic large cell lymphomas (ALCL) are tumors of T/null-cell lineage characterized by uniform CD30 expression. The 2008 World Health Organization classification subdivided ALCLs into 2 groups: anaplastic lymphoma kinase (ALK)-positive (established entity) and ALK-negative (proposed new entity) ALCL. The genetic basis for the pathogenesis of newly categorized ALK- ALCL is poorly understood. In this study, we used microRNA microarray analysis to identify differentially expressed microRNAs in ALK+ and ALK- ALCL. ALK- ALCL showed significantly higher expression of miR-155 (0.888 ± 0.228) compared with ALK+ ALCL (0.0565 ± 0.009) on microarray and by quantitative real-time polymerase chain reaction in ALK- ALCL compared with ALK+ ALCL (P < .05) with a strong correlation between the 2 platforms (R = 0.9, P < .0003). A novel in situ hybridization method allows direct visualization of expression patterns and relative quantitation of miR-155 (mean score, 2.3 versus 1.3; P = .01) for the first time in tissue sections of ALCL. Among computationally predicted targets of miR-155, we identified ZNF652 (r = -0.57, P = .05), BACH1 (r = 0.88, P = .02), RBAK (r = 0.81, P = .05), TRIM32 (r = 0.92, P = .01), E2F2 (r = 0.81, P = .05), and TP53INP1 (r = -0.31, P = .03) as genes whose expression by quantitative real-time polymerase chain reaction correlated significantly with the level of miR-155 in ALCL tumor tissue.

Xiong H, Wang J, Guan H, et al.
SphK1 confers resistance to apoptosis in gastric cancer cells by downregulating Bim via stimulating Akt/FoxO3a signaling.
Oncol Rep. 2014; 32(4):1369-73 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
We previously reported that sphingosine kinase 1 (SphK1), an enzyme that catalyzes the production of sphingosine-1-phosphate (SIP), is upregulated in human gastric cancer and predicts poor clinical outcome. In the present study, we used known differential effects of UV irradiation on human MGC-803 gastric cancer cells to determine their effect on SphK1 activity. Ectopic expression of SphK1 in MGC-803 gastric cancer cells markedly enhanced their resistance to UV irradiation, whereas silencing endogenous SphK1 with shRNAs weakened this ability. Furthermore, these anti-apoptotic effects were significantly associated with decrease of Bim, an apoptosis-related protein. We further demonstrated that SphK1 could downregulate the transcriptional activity of forkhead box O3a (FoxO3a) by inducing its phosphorylation, which was found to be associated with the PI3K/Akt signaling. Taken together, our study supports the theory that SphK1 confers resistance to apoptosis in gastric cancer cells via the Akt/FoxO3a/Bim pathway.

Cramer EM, Shao Y, Wang Y, Yuan Y
miR-190 is upregulated in Epstein-Barr Virus type I latency and modulates cellular mRNAs involved in cell survival and viral reactivation.
Virology. 2014; 464-465:184-95 [PubMed] Related Publications
Epstein-Barr Virus (EBV) is a prevalent human pathogen infecting over 90% of the population. Much of the success of the virus is attributed to its ability to maintain latency. The detailed mechanisms underlying the establishment and maintenance of EBV latency remain poorly understood. A microRNA profiling study revealed differential expression of many cellular miRNAs between types I and III latency cells, suggesting cellular miRNAs may play roles in regulating EBV latency. mir-190 is the most differentially up-regulated miRNA in type I latency cells as compared with type III latency cells and the up-regulation appears to be attributed to EBER RNAs that express in higher levels in type I latency cells than type III cells. With the aide of a lentiviral overexpression system and microarray analysis, several cellular mRNAs are identified as potential targets of mir-190. By targeting TP53INP1, miR-190 enhances cell survival by preventing apoptosis and relieving G0/G1 cell cycle arrest. Additionally, miR-190 down-regulates NR4A3, a cellular immediate-early gene for EBV reactivation, and inhibits the expression of the viral immediate-early gene bzlf1 and viral lytic DNA replication. Taken together, our data revealed a mechanism that EBV utilizes a cellular microRNA to promote host cell survival and prevent virus from entering lytic life cycle for latency maintenance.

Zhang J, Cheng C, Yuan X, et al.
microRNA-155 acts as an oncogene by targeting the tumor protein 53-induced nuclear protein 1 in esophageal squamous cell carcinoma.
Int J Clin Exp Pathol. 2014; 7(2):602-10 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
MicroRNA-155 (miR-155) is overexpressed in many human cancers; however, the function of miR-155 is largely unknown in esophageal squamous cell carcinoma (ESCC). In the present study, we found that miR-155 is dramatically increased in ESCC tissues compared with the paired adjacent normal tissues, which suggested that miR-155 acts as an oncogene in ESCC. We predicted that tumor protein p53-induced nuclear protein 1 (TP53INP1) is a candidate target gene of miR-155 given that miR-155 expression decreased mRNA and protein levels of TP53INP1 as determined by RT-PCR and Western blot analysis. In addition, miR-155 and TP53INP1 showed a negative relation in ESCC tissues. Dual luciferase-based reporter assay indicated direct regulation of TP53INP1 by miR-155. Furthermore, we demonstrated that RNA interference of TP53INP1 increased the proliferation and colonies formation of EC-1 cells. Up-regulation of TP53INP1 abrogated miR-155 induced growth in EC-1 cells and mutation of TP53INP1 in 3'-UTR restored the effects when co-transfected with miR-155. We also indicated that overexpression of miR-155 significantly promoted the proliferation of EC-1 cells in vitro and the development of tumors in nude mice. Taken together, our study reveals that miR-155 acts as an oncogene by targeting TP53INP1 in ESCC.

Qin J, Luo M, Qian H, Chen W
Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1.
Gene. 2014; 538(2):342-7 [PubMed] Related Publications
Chemotherapy plays a crucial role in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of HCC. However, acquisition of cisplatin resistance is common in patients with HCC, and the underlying mechanism of such resistance is not fully understood. In the study, we focused on identifying the role of miRNAs in chemotherapy resistance after cisplatin-based combination chemotherapy. We assayed the expression level of miR-182 after cisplatin-based chemotherapy in patients with advanced HCC, and defined the biological functions by real-time PCR analysis and CCK-8 assay. We found that miR-182 levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-182 levels were also higher in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Upregulated miR-182 significantly increased the cell viability, whereas miR-182 knockdown reduced the cell viability during cisplatin treatment. miR-182 inhibition also partially overcame cisplatin resistance in HepG2-R cell. Furthermore, we found that upregulated miR-182 inhibited the expression of tumor suppressor gene TP53INP1 (tumor protein 53-induced nuclear protein 1) in vitro. In vivo, miR-182 and TP53INP1 expression was negatively correlated. We finally demonstrated that miR-182 increased cisplatin resistance of HCC cell, partly by targeting TP53INP1. These data suggest that miR-182/TP53INP1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

Zhang CM, Zhao J, Deng HY
MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1.
J Biomed Sci. 2013; 20:79 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
BACKGROUND: MiR-155 has emerged as an "oncomiR", which is the most significantly up-regulated miRNA in breast cancer. However, the mechanisms of miR-155 functions as an oncomiR are mainly unknown. In this study, the aims were to investigate the effects of miR-155 on cell proliferation, cell cycle, and cell apoptosis of ERalpha (+) breast cancer cells and to verify whether TP53INP1 (tumor protein 53-induced nuclear protein 1) is a target of miR-155, and tried to explore the mechanisms of miR-155 in this process.
RESULTS: The expression of miR-155 is significantly higher in MCF-7 cells compared with MDA-MB-231 cells. Ectopic expression of TP53INP1 inhibits growth of MCF-7 cells by inducing cell apoptosis and inhibiting cell cycle progression. Overexpression of miR-155 increases cell proliferation and suppress cell apoptosis, whereas abrogating expression of miR-155 suppress cell proliferation and promotes cell apoptosis of MCF-7 cells. In addition, miR-155 negatively regulates TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, and luciferase reporter reveals that TP53INP1 is targeted by miR-155.
CONCLUSIONS: TP53INP1 is the direct target of miR-155. MiR-155, which is overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating target TP53INP1.

Krupar R, Hartl M, Wirsching K, et al.
Comparison of HPV prevalence in HNSCC patients with regard to regional and socioeconomic factors.
Eur Arch Otorhinolaryngol. 2014; 271(6):1737-45 [PubMed] Related Publications
HPV infection is considered as an independent risk factor for head and neck squamous cell carcinomas (HNSCC). Due to highly variable prevalence results in numerous studies, it is, however, difficult to estimate the relevance of HPV infection as risk factor for a specific patient collective. This study aimed to elucidate the disparities of HPV prevalence by analyzing socioeconomically and regionally different patient collectives. Two age, gender, stage and tumor location matched cohorts of 18 private health insured (PHIP) and 16 statutory health insured patients (SIP) suffering from an oropharyngeal squamous cell carcinoma (OSCC) and treated at a university hospital were screened for p16 overexpression and HPV infection by immunohistochemistry and PCR. In addition 85 HNSCC patients of an otolaryngology private practice (PPP) in a rural area were screened for p16 overexpression and positive cases were tested for HPV infection. HPV prevalence was 72.2% in the PHIP collective in comparison to 25.0% (p = 0.015) in the SIP collective with a significantly improved 5-year overall survival (p = 0.003) of the PHIP collective. The total HPV prevalence of PPP group was 7.1% with the highest infection rate in tonsillar carcinomas (33.3%) and a larger percentage of female patients in the HPV positive group (p = 0.037). This study shows that variable HPV infection rates in HNSCC can be caused by the selection of particular patient collectives, which suggest taking socioeconomic and regional factors into account for a decision on HPV testing, if it is not performed on a routine basis.

Wang H, Feng Y, Bao Z, et al.
Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma.
Oncol Rep. 2013; 30(5):2089-96 [PubMed] Related Publications
In order to more thoroughly analyze aberrant DNA methylation in glioma, we applied a large cohort methylation microarray including 119 glioma samples. Six genes, ADCY1, KAZALD1, KLF4, SLMAP, TETRAN and TP53INP1, were screened out through significance analysis of microarray (SAM), survival Cox-regression and certain other pre-set conditions. We focused on the KAZALD1 oncogene. KAZALD1, also known as IGFBP-rP10, belongs to the IGFBP family. We found that KAZALD1 was hypomethylated in high-grade glioma (anaplastic gliomas and glioblastomas) compared to low-grade glioma (astrocytoma, oligodendrocytoma and oligoastrocytoma) using methylation microarrays (p<0.001). Immunohistochemistry (IHC) of 91 glioma samples showed that the KAZALD1 expression scores of high-grade glioma samples were higher compared to the scores of low-grade gliomas (p<0.001). In high-grade gliomas, overall survival (OS) was shorter for patients with KAZALD1 hypomethylation or overexpression compared to those without. Decreased KAZALD1 expression in glioma inhibited cell proliferation and invasion both in vitro and in vivo. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that KAZALD1 promoter hypomethylation is an important prognostic biomarker in glioma. KAZALD1 promotes glioma malignant progression through invasion and proliferation.

Zhang Y, Yang J, Cui X, et al.
A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth.
EMBO Mol Med. 2013; 5(9):1322-34 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.

Shiozaki A, Iitaka D, Ichikawa D, et al.
xCT, component of cysteine/glutamate transporter, as an independent prognostic factor in human esophageal squamous cell carcinoma.
J Gastroenterol. 2014; 49(5):853-63 [PubMed] Related Publications
BACKGROUND: xCT is a component of the cysteine/glutamate transporter, which plays a key role in glutathione synthesis. The objectives of the present study were to investigate the role of xCT in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC).
METHODS: xCT expression in human ESCC cell lines was analyzed by Western blotting and immunofluorescent staining. Knockdown experiments were conducted with xCT siRNA, and the effect on cell cycle was analyzed. The cells' gene expression profiles were analyzed by microarray analysis. An immunohistochemical analysis of 70 primary tumor samples obtained from ESCC patients that had undergone esophagectomy was performed.
RESULTS: xCT was highly expressed in TE13 and KYSE170 cells. In these cells, the knockdown of xCT using siRNA inhibited G1-S phase progression. Microarray analysis identified 1652 genes whose expression levels in TE13 cells were altered by the knockdown of xCT. Pathway analysis showed that the top-ranked canonical pathway was the G1/S checkpoint regulation pathway, which involves TP53INP1, CDKN1A, CyclinD1/cdk4, and E2F5. Immunohistochemical staining showed that xCT is mainly found in the nuclei of carcinoma cells, and that its expression is an independent prognostic factor.
CONCLUSIONS: These observations suggest that the expression of xCT in ESCC cells might affect the G1/S checkpoint and impact on the prognosis of ESCC patients. As a result, we have a deeper understanding of the role played by xCT as a mediator and/or biomarker in ESCC.

Zhang C, Zhao J, Deng H
17β-estradiol up-regulates miR-155 expression and reduces TP53INP1 expression in MCF-7 breast cancer cells.
Mol Cell Biochem. 2013; 379(1-2):201-11 [PubMed] Related Publications
In estrogen responsive breast cancer cells, estradiol (E2) is a key regulator of cell proliferation and survival. MiR-155 has emerged as an "oncomiR", which is the most significantly up-regulated miRNA in breast cancer. Moreover, miR-155 is higher in ERα (+) breast tumors than ERα (-), but no one has examined whether E2 regulates miR-155 expression in MCF-7 cells. In this study, the aim was to explore whether miR-155 involved in E2 regulated expression of estrogen responsive genes. We evaluated miR-155 expression in human breast cancer cells by real-time PCR, finding out miR-155 was overexpressed in MCF-7 cells compared with MDA-MB-231 cells. Treatment with E2 in MCF-7 cells increased miR-155 expression, promoting proliferation and decreasing apoptosis, similarly, transfection of miR-155m to MCF-7 cells gave the similar results. In contrast, inhibited miR-155 expression by transfection with miR-155 inhibitors reduced proliferation and promoted apoptosis of MCF-7 cells. Moreover, TP53INP1 is one of the targets of miR-155. E2 negatively regulated TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, whereas transfection with miR-155 inhibitors increased TP53INP1, cleaved-caspase-3, -8, -9, and p21 protein level. These results demonstrated that E2 promoted breast cancer development and progression possibly through increasing the expression of miR-155, which was overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating TP53INP1.

Chen X, Zheng P, Xue Z, et al.
CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2.
Apoptosis. 2013; 18(7):861-9 [PubMed] Related Publications
Our former report indicates that calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is over-expressed in the SGC7901/ADR cell line. However, the potential role of CacyBP/SIP in the development of multidrug resistance (MDR) of pancreatic cancer is still uncertain. In this paper, we investigated the role of CacyBP/SIP in MDR of pancreatic cancer cells and its possible underlying mechanisms, and found that CacyBP/SIP was over-expressed in the Gemcitabine induced MDR pancreatic cancer cell PC-3/Gem compared with its parental cell PC-3. Up-regulation of CacyBP/SIP expression could enhance resistance of chemotherapy drugs on PC-3 cells and inhibit Adriamycin-induced apoptosis accompanied by decreased accumulation of intracellular Adriamycin. Furthermore, CacyBP/SIP could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene. In addition, the decrease of CacyBP/SIP expression using RNA interference or P-gp inhibitor could partially reverse CacyBP/SIP-mediated MDR. In brief, our study demonstrated that CacyBP/SIP could enhance the MDR phenotype of pancreatic cancer cells by increasing the expression of P-gp and Bcl-2, thus inhibiting apoptosis of pancreatic cancer cell.

Wang M, Gu H, Qian H, et al.
miR-17-5p/20a are important markers for gastric cancer and murine double minute 2 participates in their functional regulation.
Eur J Cancer. 2013; 49(8):2010-21 [PubMed] Related Publications
AIM: To investigate the potential roles and mechanisms of miR-17-5p/20a in human gastric cancer development and progression.
METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine miR-17-5p/20a expression profiles in 110 gastric cancer tissues. microRNAs' (miRNAs) mimics and inhibitors were used to reveal their function in gastric cancer. Antagomirs were applied to treating gastric cancer cell derived xenograft in vivo. Western blot and luciferase assays were performed to uncover the targets and mechanisms of miR-17-5p/20a.
RESULTS: miR-17-5p/20a levels were upregulated in human gastric cancer tissues. Overexpression of miR-17-5p/20a promoted gastric cancer cell cycle progression and inhibited cell apoptosis, whereas knockdown of miR-17-5p/20a resulted in cell cycle arrest and increased apoptosis. p21 and tumour protein p53-induced nuclear protein 1 (TP53INP1) were validated as the targets of miR-17-5p/20a. Antagomirs against miR-17-5p/20a significantly inhibited gastric cancer growth via upregulation of p21 and TP53INP1 in a mouse xenograft model. The negative relationship between miR-17-5p/20a and TP53INP1 was observed in patient gastric cancer tissues. Murine double minute 2 (MDM2) was found to be involved in miRNA regulation and function. Targeted inhibition of MDM2 in a miRNA mimic-transfected gastric cancer cell line abolished miR-17-5p/20a function and inhibition of p21 expression. MDM2 restoration by pCMV-MDM2 rescued the functionality.
CONCLUSIONS: Our findings indicate that miR-17-5p/20a promote gastric cancer cell proliferation and inhibit cell apoptosis via post-transcriptional modulation of p21 and TP53INP1. They may be promising therapeutic markers for gastric cancer. MDM2 contributes to miR-17-5p/20a function and inhibition of p21 in gastric cancer, and may be a novel mechanism underlying the oncogenic roles of miR-17-5p/20a.

Bubnov V, Moskalev E, Petrovskiy Y, et al.
Hypermethylation of TUSC5 genes in breast cancer tissue.
Exp Oncol. 2012; 34(4):370-2 [PubMed] Related Publications
AIM: Breast cancer (BC) is one of the most common forms of cancer amongst females. Early diagnosis, prognosis and therapy plays crucial role in the survival of patients with breast cancer. The study was aimed on identification of potential markers for early BC diagnostics by means of genome-wide comparative analysis of gene expression in cancer and normal tissue of breast.
METHODS: The analysis of gene expression in 15 invasive adenocarcinoma specimens and 15 normal breast tissue was conducted using the full-genome microarrays Sentrix HumanWD-6V3 BeadChip (Illumina). Methylation of TP53INK1 and TUSС5 promoters was interrogated by the combined bisulfite restriction analysis (COBRA).
RESULTS: Analysis of gene expression in the samples of breast adenocarcinoma revealed abnormal expression of more than 2,300 genes. While genes TFF1, S100P, ERBB2, TOP2A, CDF15, HOOK1, DNAJC12, CORO2A were up-regulated in cancer, decreased expression was found for genes TUSC5, SFRP1, PPPQR1B, NTRK4, TIMP4, BARD1, AKR1C2, TP53INK1 and others. Analysis of DNA methylation of TUSC5 by COBRA revealed higher levels of exon 1 methylation (11/12) in samples of breast cancer, whereas the gene was essentially unmethylated in matched normal appearing tissue of breast (2/12). TP53INK1 gene was methylated neither in cancer nor in normalcy.
CONCLUSION: A total of 149 genes exhibited the highest difference in expression in cancer versus normal appearing tissue of breast. Most prominent down-regulated candidates, TUSC5 and TP53INK1, were reported for the first time in breast cancer and may be considered as potential markers of the disease. Aberrant DNA hypermethylation of TUSC5 suggests epigenetic mechanism of cancer associated down-regulation.

Saito Y, Suzuki H, Tsugawa H, et al.
Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication.
PLoS One. 2012; 7(11):e47396 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
microRNAs (miRNAs) are small non-coding RNAs that can function as endogenous silencers of target genes and play critical roles in human malignancies. To investigate the molecular pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the miRNA expression profile was analyzed. miRNA microarray analysis with tissue specimens from gastric MALT lymphomas and surrounding non-tumor mucosae revealed that a hematopoietic-specific miRNA miR-142 and an oncogenic miRNA miR-155 were overexpressed in MALT lymphoma lesions. The expression levels of miR-142-5p and miR-155 were significantly increased in MALT lymphomas which do not respond to Helicobacter pylori (H. pylori) eradication. The expression levels of miR-142-5p and miR-155 were associated with the clinical courses of gastric MALT lymphoma cases. Overexpression of miR-142-5p and miR-155 was also observed in Helicobacter heilmannii-infected C57BL/6 mice, an animal model of gastric MALT lymphoma. In addition, miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their target. The results of this study indicate that overexpression of miR-142-5p and miR-155 plays a critical role in the pathogenesis of gastric MALT lymphoma. These miRNAs might have potential application as therapeutic targets and novel biomarkers for gastric MALT lymphoma.

Zong A, Zhao T, Zhang Y, et al.
Anti-metastatic and anti-angiogenic activities of sulfated polysaccharide of Sepiella maindroni ink.
Carbohydr Polym. 2013; 91(1):403-9 [PubMed] Related Publications
A previous study demonstrated that SIP-SII, a sulfated Sepiella maindroni ink polysaccharide, suppressed the invasion and migration of cancer cells via the inhibition of the proteolytic activity of matrix metalloproteinase-2 (MMP-2). Therefore, this study investigated the anti-metastatic effect of SIP-SII in vivo. SIP-SII (15 and 30 mg/kg d) markedly decreased B16F10 pulmonary metastasis in mice models by 85.9% and 88.0%, respectively. Immunohistochemistry showed that SIP-SII decreased the expression of the intercellular adhesion molecule 1 (ICAM-1) and basic fibroblast growth factor (bFGF) in lung metastasis nodules. In addition, SIP-SII inhibited neovascularization in chick chorioallantoic membrane assay at 0.08-2 mg/mL. In the in vitro experiments, SIP-SII (0.8-500 μg/mL) significantly decreased the protein and mRNA expression of ICAM-1 and bFGF in SKOV3 and EA.hy926 cells, respectively. These results suggested that SIP-SII might suppress melanoma metastasis via the inhibition of the tumor adhesion mediated by ICAM-1 and the angiogenesis mediated by bFGF, as well as resulting in depression of the invasion and migration of carcinoma cells.

John-Aryankalayil M, Palayoor ST, Makinde AY, et al.
Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells.
Radiat Res. 2012; 178(3):105-17 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single-dose radiation. To understand the role of miRNA in regulation of radiation-induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by microarray. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17-92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity.

Wei Q, Li YX, Liu M, et al.
MiR-17-5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells.
IUBMB Life. 2012; 64(8):697-704 [PubMed] Related Publications
MicroRNAs are a class of small endogenous noncoding RNAs that function as post-transcriptional regulators. Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a p53 target gene and is a major player in the stress response. Here, we identified TP53INP1 as a target of miR-17-5p. miR-17-5p suppressed cell growth and promoted apoptosis of cervical cancer cells, whereas the effects of TP53INP1 were opposite, and ectopic expression of TP53INP1 counteracted the suppression of cell growth caused by miR-17-5p. The same correlations between miR-17-5p and TP53INP1 were observed in cervical cancer tissues. Together, these results indicated that miR-17-5p functions as a tumor suppressor in cervical cancer cells by targeting TP53INP1.

Bousquet M, Nguyen D, Chen C, et al.
MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA.
Haematologica. 2012; 97(11):1713-21 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
BACKGROUND: We previously described a t(2;11)(p21;q23) chromosomal translocation found in patients with myelodysplasia or acute myeloid leukemia that leads to over-expression of the microRNA miR-125b, and we showed that transplantation of mice with murine stem/progenitor cells overexpressing miR-125b is able to induce leukemia. In this study, we investigated the mechanism of myeloid transformation by miR-125b.
DESIGN AND METHODS: To investigate the consequences of miR-125b over-expression on myeloid differentiation, apoptosis and proliferation, we used the NB4 and HL60 human promyelocytic cell lines and the 32Dclone3 murine promyelocytic cell line. To test whether miR-125b is able to transform myeloid cells, we used the non-tumorigenic and interleukin-3-dependent 32Dclone3 cell line over-expressing miR-125b, in xenograft experiments in nude mice and in conditions of interleukin-3 deprivation. To identify new miR-125b targets, we compared, by RNA-sequencing, the transcriptome of cell lines that do or do not over-express miR-125b.
RESULTS: We showed that miR-125b over-expression blocks apoptosis and myeloid differentiation and enhances proliferation in both species. More importantly, we demonstrated that miR-125b is able to transform the 32Dclone3 cell line by conferring growth independence from interleukin-3; xenograft experiments showed that these cells form tumors in nude mice. Using RNA-sequencing and quantitative real-time polymerase chain reaction experiments, we identified multiple miR-125b targets. We demonstrated that ABTB1, an anti-proliferative factor, is a new direct target of miR-125b and we confirmed that CBFB, a transcription factor involved in hematopoiesis, is also targeted by miR-125b. MiR-125b controls apoptosis by down-regulating genes involved in the p53 pathway including BAK1 and TP53INP1.
CONCLUSIONS: This study demonstrates that in a myeloid context, miR-125b is an oncomiR able to transform cell lines. miR-125b blocks myeloid differentiation in part by targeting CBFB, blocks apoptosis through down-regulation of multiple genes involved in the p53 pathway, and confers a proliferative advantage to human and mouse myeloid cell lines in part by targeting ABTB1.

Bomben R, Gobessi S, Dal Bo M, et al.
The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes.
Leukemia. 2012; 26(7):1584-93 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) cells from clinically aggressive cases have a greater capacity to respond to external microenvironmental stimuli, including those transduced through Toll-like-receptor-9 (TLR9). Concomitant microRNA and gene expression profiling in purified CLL cells (n=17) expressing either unmutated (UM) or mutated (M) IGHV genes selected microRNAs from the miR-17∼92 family as significantly upregulated and in part responsible for modifications in the gene expression profile of UM CLL cells stimulated with the TLR9 agonist CpG. Notably, the stable and sustained upregulation of miR-17∼92 microRNAs by CpG was preceded by a transient induction of the proto-oncogene MYC. The enforced expression of miR-17, a major member from this family, reduced the expression of the tumor suppressor genes E2F5, TP53INP1, TRIM8 and ZBTB4, and protected cells from serum-free-induced apoptosis (P ≤ 0.05). Consistently, transfection with miR-17∼92 family antagomiRs reduced Bromo-deoxy-uridine incorporation in CpG-stimulated UM CLL cells. Finally, miR-17 expression levels, evaluated in 83 CLL samples, were significantly higher in UM (P=0.03) and ZAP-70(high) (P=0.02) cases. Altogether, these data reveal a role for microRNAs of the miR-17∼92 family in regulating pro-survival and growth-promoting responses of CLL cells to TLR9 triggering. Overall, targeting of this pathway may represent a novel therapeutic option for management of aggressive CLL.

Ning X, Sun S, Zhang K, et al.
S100A6 protein negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation and tumorigenesis.
PLoS One. 2012; 7(1):e30185 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Calcyclin-binding protein (CacyBP/SIP), identified on the basis of its ability to interact with S100 proteins in a calcium-dependent manner, was previously found to inhibit the proliferation and tumorigenesis of gastric cancer cells in our laboratory. Importantly, the effects of S100 proteins on the biological behavior of CacyBP/SIP in gastric cancer remain unclear. Herein, we report the construction of eukaryotic expression vectors for wild-type CacyBP/SIP and a truncated mutant lacking the S100 protein binding domain (CacyBP/SIPΔS100). The expressions of the wild-type and truncated recombinant proteins were demonstrated by transfection of MKN45 gastric cancer cells. Co-immunoprecipitation assays demonstrated interaction between S100A6 and wild-type CacyBP/SIP in MKN45 cells. Removal of the S100 protein binding domain dramatically reduced the affinity of CacyBP/SIP for S100 proteins as indicated by reduced co-immunoprecipitation of S100A6 by CacyBP/SIPΔS100. The MTT assay, FACS assay, clonogenic assay and tumor xenograft experiment were performed to assess the effect of CacyBP/SIP on cell growth and tumorigenesis in vitro and in vivo. Overexpression of CacyBP/SIP inhibited the proliferation and tumorigenesis of MKN45 gastric cancer cells; the proliferation and tumorigenesis rates were even further reduced by the expression of CacyBP/SIPΔS100. We also showed that S100 proteins negatively regulate CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation, through an effect on β-catenin protein expression and transcriptional activation of Tcf/LEF. Although the underlying mechanism of action requires further investigation, this study provides new insight into the interaction between S100 proteins and CacyBP/SIP, which might enrich our knowledge of S100 proteins and be helpful for our understanding of the development of gastric cancer.

Liu W, Li Z, Luo Q, et al.
The elevated expression of osteopontin and vascular endothelial growth factor in sinonasal inverted papilloma and its relationship with clinical severity.
Am J Rhinol Allergy. 2011 Sep-Oct; 25(5):313-7 [PubMed] Related Publications
BACKGROUND: Osteopontin (OPN) is involved in cell survival, immunity, and tumor progression. The overexpression of OPN has been proposed as a biomarker of progression and metastasis for several tumor types, but it is still unclear whether it is up-regulated in sinonasal inverted papilloma (SIP).
METHODS: We enrolled 33 subjects with SIP and 15 normal controls to determine the importance of OPN and vascular endothelial growth factor (VEGF) in SIP. Using immunohistochemistry, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, we examined the distribution, mRNA expression, and protein levels, respectively, of OPN and VEGF. We then correlated these values with clinical severity.
RESULTS: The immunostaining levels for OPN and VEGF were significantly increased in SIP tissues compared with control tissues (p < 0.05), as were their mRNA expression and protein levels (p < 0.05). The correlation between OPN and VEGF expression and the clinical stage of SIP was significant (p < 0.05).
CONCLUSION: Our findings indicate that OPN and VEGF were both overexpressed in the analyzed SIP tissues and were associated with clinical severity, suggesting that the OPN-VEGF axis might contribute to tumor progression by enhancing angiogenesis. Therefore, OPN may serve as a potential therapeutic target for preventing SIP progression and recurrence.

Yamamoto Y, Yoshioka Y, Minoura K, et al.
An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells.
Mol Cancer. 2011; 10:135 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
BACKGROUND: Acquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance.
RESULTS: Through genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR.
CONCLUSION: These findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.

Horiguchi K, Sakamoto K, Koinuma D, et al.
TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP.
Oncogene. 2012; 31(26):3190-201 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-β-induced EMT, and found that TGF-β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-β-induced EMT and the progression of breast cancers.

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