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Lin Yue,
Leilei Li,
Fangfang Liu, Nan Hu,
Weiying Zhang,
Xiao Bai,
Yinghui Li,
Yingyi Zhang,
Li Fu,
Xiaodong Zhang,
Lihong Ye
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ABSTRACT: Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein and plays critical roles in the development of cancer. In the present study, we report that HBXIP activates LIM-only protein 4 (LMO4), a transcriptional coregulatory protein, in promotion of cell proliferation. We observed that the 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 (EMSA) 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 (co-IP), 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 (MTT), 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 conclude 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 active transcription in the development of cancer.
Carcinogenesis 01/2013; · 5.70 Impact Factor
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ABSTRACT: Methods for predicting outcome for patients with oligodendrogliomas and anaplastic oligodendrogliomas (AOs) are limited. Hypoxia-inducible factor-1α (HIF-1α) controls many proteins involved in glycolysis and angiogenesis including VEGF, Glut-1, and CA-IX. We examined whether expression of HIF-1α and other hypoxia-regulated molecules (HRM) can predict overall (OS) and progression-free (PFS) survival. We correlated these data with more established biomarkers and a published preoperative scoring system. We prospectively collected tissue samples and followed outcomes of 50 patients with oligodendrogliomas and 32 with AOs. Tumor tissues were stained for measures of proliferative index, microvascular density, IDH-1 mutational status, and HRMs. We retrospectively analyzed preoperative imaging and clinical data based on the UCSF Scoring System (good prognostic indicators: Karnofsky Performance Scale (KPS) score > 80, age < 50 years, tumor diameter < 4 cm, noneloquent tumor location) and correlated these with immunohistochemical markers, 1p19q chromosomal status, and compared both with patient PFS and OS. Mean follow-up was 85.6 ± 41.4 months. HRMs showed higher expression in AOs than in oligodendrogliomas. Both 1p19q codeletion and IDH-1 mutation predict outcome of patients with both oligodendroglioma and AO. The UCSF score is a strong predictor for oligodendrogliomas patient outcome and is strengthened by IDH-1 and 1p19q status. Glut-1 may be useful in predicting PFS in AOs. Proliferation index >5 for oligodendrogliomas and KPS ≤ 80 for AOs predict a worse prognosis. Immunohistochemical markers of HRMs show a significantly higher expression in anaplastic variants of oligodendrogliomas and may contribute to the prediction of survival in these patients.
Journal of Neuro-Oncology 03/2012; 108(3):459-68. · 3.21 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the contributions of impaired cytochrome P450 and breast cancer resistance protein (BCRP) activity and expression to drug pharmacokinetics under diabetic conditions. Diabetes was induced in rats with the intraperitoneal administration of streptozocin. Glibenclamide (GLB), a substrate of BCRP, served as a model drug. The pharmacokinetics of orally administered GLB (10 mg/kg) were studied. The results showed that diabetes mellitus significantly increased exposure (area under the curve and peak concentration) to GLB after oral administration. Data from hepatic microsomes suggested impairment of GLB metabolism in diabetic rats. GLB metabolism in hepatic microsomes was significantly inhibited by a selective inhibitor (sulfaphenazole) of CYP2C11 and an anti-CYP2C11 antibody. Western blotting further indicated the contribution of impaired CYP2C11 expression to the impairment of GLB metabolism. Excretion data showed that ∼72% of the orally administered dose was excreted in the feces of normal rats, which indicates an important role for intestinal BCRP. Diabetes significantly decreased the recovery from feces, which was only 40% of the orally administered dose. Results from in situ, single-pass, intestinal perfusion experiments revealed that diabetes significantly increased the apparent effective permeability and decreased the efflux of GLB through the intestine; this suggests impairment of intestinal BCRP function, which may play a role in the increased exposure to orally administered GLB in diabetic rats. Insulin treatment partly or completely reversed the changes in diabetic rats. All results yielded the conclusion that impaired hepatic CYP2C11 and intestinal BCRP expression and activity induced by diabetes contributed to the increased exposure of orally administered GLB.
Drug metabolism and disposition: the biological fate of chemicals 03/2012; 40(6):1104-12. · 3.74 Impact Factor
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Christian C Abnet,
Zhaoming Wang,
Xin Song, Nan Hu,
Fu-You Zhou,
Neal D Freedman,
Xue-Min Li,
Kai Yu,
Xiao-Ou Shu,
Jian-Min Yuan, [......],
Wan-Cai Yang,
Jun-Yan Hong,
Liang Wang,
Song-Liang Qiu,
Alisa M Goldstein,
Zhi-Qing Yuan,
Stephen J Chanock,
Xue-Jun Zhang,
Philip R Taylor,
Li-Dong Wang
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ABSTRACT: Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
Human Molecular Genetics 02/2012; 21(9):2132-41. · 7.64 Impact Factor
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Yi Wu,
Na Luo,
Li-Wen Tan,
Bing-Ji Fang,
Ying Li,
Bing Xie,
Hao-Tong Xu, Nan Hu,
Wei-Ping Yang,
Wei Wu,
Wouter H Lamers,
Shao-Xiang Zhang
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ABSTRACT: The structures of superior mediastinum and their spatial relationships are complex and difficult to master. This study aimed to compare visualization of the superior mediastinum based on computed tomography (CT) images and on the thin sections of the Chinese visible human (CVH) data set to provide a sectional anatomical basis for diagnostic imaging of superior mediastinal pathology. CVH sections of the mediastinum of a 35-year old male were compared with plain and enhanced CT images of a 45-year old male without apparent abnormalities in the upper chest. In addition, a three-dimensional model based on the CVH sections was compared with a model based on CT images. Although CT imaging is noninvasive and can be carried out in many individuals, its weakness is clearly the visualization of small soft tissue structures. In this respect, the sectional anatomical approach of the CVH images is complementary, as it visualizes these small soft tissue structures due to the higher resolution in the plain of sectioning and the color of the different structures in the section. Three-dimensional surface and volume rendering of reconstructions of the CVH data set can help medical students and less experienced thoracic surgeons to familiarize themselves with the topographic anatomy of the superior mediastinal structures and their spatial relationships, and thus with interpreting CT images of patients. Clin. Anat., 2012. © 2012 Wiley Periodicals, Inc.
Clinical Anatomy 02/2012; · 1.29 Impact Factor
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Wenjing Cui,
Yu Zhao,
Changliang Shan,
Guangyao Kong, Nan Hu,
Yiwen Zhang,
Shuai Zhang,
Weiying Zhang,
Yingyi Zhang,
Xiaodong Zhang,
Lihong Ye
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ABSTRACT: Hepatitis B X-interacting protein (HBXIP) is able to enhance migration of breast cancer cells. However, the role of HBXIP in regulation of complement-dependent cytotoxicity (CDC) in breast cancer is not understood. Here, we report that HBXIP contributes to protecting breast cancer cells from CDC by upregulating membrane-bound complement regulatory protein (mCRPs), including CD46, CD55 and CD59. We found that HBXIP upregulated mCRPs through activating p-ERK1/2/NF-κB. Interestingly, the knockdown of CD59 was able to block the HBXIP-enhanced breast tumor growth in animal. Thus, we conclude that HBXIP upregulates CD46, CD55 and CD59 through p-ERK1/2/NF-κB signaling to protect breast cancer from CDC.
FEBS letters 01/2012; 586(6):766-71. · 3.54 Impact Factor
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Qing Miao,
Xiao-Peng Shi,
Ming-Xiang Ye,
Jin Zhang,
Shan Miao,
Si-Wang Wang,
Bo Li,
Xiu-Xiu Jiang,
Song Zhang, Nan Hu,
Juan Li,
Jian Zhang
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ABSTRACT: Hypoxic pulmonary hypertension is a life-threatening emergency if untreated. Consistent pulmonary hypertension also leads to arteries and ventricular remodeling. The clinical therapeutic strategy for pulmonary hypertension and the corresponding remodeling mainly interacts with NO, angiotensin II (Ang II) and elevated endothelin (ET) targets. In the present study, we evaluated the effects of polydatin on hypoxia-induced pulmonary hypertension. It was observed that polydatin attenuated hypoxic pulmonary hypertension, reversed remodeling, and regulated NO, Ang II, ET contents in the serum and lung samples. However, forced activation of PKC signaling by its selective activator thymeleatoxin (THX) could abate the effects of polydatain. These results suggest that polydatin might be a promising candidate for hypoxic pulmonary treatment through interaction with PKC mechanisms.
International Journal of Molecular Sciences 01/2012; 13(6):7776-87. · 2.60 Impact Factor
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Wusheng Yan,
Joanna H Shih,
Jaime Rodriguez-Canales,
Michael A Tangrea,
Kris Ylaya,
Jason Hipp,
Audrey Player, Nan Hu,
Alisa M Goldstein,
Philip R Taylor,
Michael R Emmert-Buck,
Heidi S Erickson
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ABSTRACT: Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets.
As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels.
These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type.
BMC Research Notes 01/2012; 5:73.
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ABSTRACT: Genistein, a major phytoestrogen of soy, is considered a potential drug for the prevention and treatment of post-menopausal osteoporosis. Mounting evidence suggested a positive correlation between genistein consumption and bone health both in vivo and in vitro. Earlier studies have revealed that genistein acted as a natural estrogen analogue which activated estrogen receptor and exerted anti-osteoporotic effect. However, it remains unclear whether PTH, the most crucial hormone that regulates mineral homeostasis, participates in the process of genistein-mediated bone protection. In the present study, we compared the therapeutic effects between genistein and nilestriol and investigated whether PTH and its specific receptor PTHR1 altered in response to genistein-containing diet in the animal model of ovariectomy. Our results showed that genistein administration significantly improved femoral mechanical properties and alleviates femoral turnover. Genistein at all doses (4.5 mg/kg, 9.0 mg/kg and 18.0 mg/kg per day, respectively) exerted improved bending strength and b-ALP limiting effects than nilestriol in the present study. However, genistein administration did not exert superior effects on bone protection than nilestriol. We also observed circulating PTH restoration in ovariectomized rats receiving genistein at the dose of 18 mg/kg per day. Meanwhile, PTHR1 abnormalities were attenuated in the presence of genistein as confirmed by RT-PCR, Western blot and immunohistochemistry. These findings strongly support the idea that besides serving as an estrogen, genistein could interact with PTH/PTHR1, causing a superior mineral restoring effect than nilestriol on certain circumstance. In conclusion, our study reported for the first time that the anti-osteoporotic effect of genistein is partly PTH/PTHR1-dependent. Genistein might be a potential option in the prevention and treatment of post-menopausal osteoporosis with good tolerance, more clinical benefits and few undesirable side effects.
International Journal of Molecular Sciences 01/2012; 13(1):56-70. · 2.60 Impact Factor
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ABSTRACT: To investigate the changes in drug sensitivity of miR-122 transfected BEL-7402/5-FU cells. MiR-122 and negative miRNA expression vectors were constructed and stably transfected into BEL-7402/5-FU cells. Real-time RT-PCR was used to detect the level of miR-122, Bcl-XL, Bcl-2 and P53 mRNA. Western Blotting was used to detect Bcl-2, Bcl-XL and P53 protein expression. Drug sensitivity of the cells to 5-fluorouracil (5-FU) was analyzed with MTT and flow cytometry. Compared with negative miRNA transfectants or untreated cells, mRNA and protein expression level of Bcl-2, Bcl-XL in stable miR-122 transfectants were decreased. Accordingly, P53 protein expression showed a significant up-regulation; MTT results showed that after incubation with 5-FU, miR-122 transfectants had higher cell inhibitory rates than negative miRNA or untreated cells; flow cytometry results demonstrated that apoptosis rate increased in miR-122 transfected cells, compared with negative miRNA or untreated cells. After addition of 5-FU (10 and 100 micromol/I), miR-122 transfected cells showed higher apoptosis rate than negative miRNA or untreated cells. MiR-122 can specifically down-regulate the expression of Bcl-2 and Bcl-XL, and increase P53 activity in BEL-7402/5-FU cells, which increased cells spontaneous apoptosis and sensitize cells to 5-FU. Therefore, MiR-122 can be used as a potential therapy agent against human hepatoblastoma.
Pharmazie 12/2011; 66(12):975-81. · 1.01 Impact Factor
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ABSTRACT: To investigate the endogenous signaling pathways associated with high proliferation potential of breast cancer cells.
Breast cancer cell lines LM-MCF-7 and MCF-7 with high and low proliferation capability were used. The promoter activity of fatty acid synthase (FASN) was examined using luciferase reporter gene assay. The expression level of FASN mRNA was measured using RT-PCR and real time PCR, respectively. The level of leukotriene B4 (LTB4) was determined with ELISA. The expression levels of 5-lipoxygenase (5-LOX) was analyzed using RT-PCR and Western blot, respectively. 5-Bromo-20-deoxyuridine (BrdU) incorporation assay was used to study the proliferation of LM-MCF-7 and MCF-7 cells.
The promoter activity of FASN was significantly higher in LM-MCF-7 cells than MCF-7 cells. Treatment of LM-MCF-7 cells with ERK1/2 inhibitor PD98059 (30-50 μmol/L) or LOX inhibitor NDGA (25 μmol/L) abolished the activation of FASN. Moreover, treatment of LM-MCF-7 cells with the specific 5-LOX inhibitor MK-886 (20-40 μmol/L) or 5-LOX siRNA (50-100 nmol/L) decreased the promoter activity of FASN. The level of LTB4, the final metabolite produced by 5-LOX, was significantly higher in LM-MCF-7 cells than MCF-7 cells. Administration of exogenous LTB4 (1-10 nmol/L) was able to stimulate the promoter activity of FASN in MCF-7 cells. Treatment of LM-MCF-7 cells with the FASN inhibitor cerulenin (10 μmol/L) reduced all the levels of p-ERK1/2, 5-LOX, and LTB4. Treatment of LM-MCF-7 cells with cerulenin, PD98059, or MK-886 abolished the proliferation. Administration of exogenous LTB4 (10 nmol/L) significantly increased BrdU incorporation in MCF-7 cells.
THESE results suggest a novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN contributes to the sustaining growth of breast cancer LM-MCF-7 cells.
Acta Pharmacologica Sinica 06/2011; 32(7):921-9. · 1.95 Impact Factor
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Nan Hu,
Jianli Zhang,
Wenjing Cui,
Guangyao Kong,
Shuai Zhang,
Lin Yue,
Xiao Bai,
Zhao Zhang,
Weiying Zhang,
Xiaodong Zhang,
Lihong Ye
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ABSTRACT: MicroRNAs play important roles in tumor metastasis. Recently, we reported that the level of miR-520b is inversely related
to the metastatic potential of breast cancer cells. In this study, we investigated the role of miR-520b in breast cancer cell
migration. We found that miR-520b suppressed the migration of breast cancer cells with high metastatic potential, including
MDA-MB-231 and LM-MCF-7 cells, although the inhibition of miR-520b enhanced the migration of low metastatic potential MCF-7
cells. We further discovered that miR-520b directly targets the 3′-untranslated region (3′UTR) of either hepatitis B X-interacting
protein (HBXIP) or interleukin-8 (IL-8), which has been reported to contribute to cell migration. Surprisingly, tissue array assays showed that 75% (38:49) and
94% (36:38) of breast cancer tissues and metastatic lymph tissues, respectively, were positive for HBXIP expression. Moreover,
overexpression of HBXIP was able to promote the migration of MCF-7 cells. Interestingly, HBXIP was able to regulate IL-8 transcription
by NF-κB, suggesting that the two target genes of miR-520b are functionally connected. In addition, we found that miR-520b
could indirectly regulate IL-8 transcription by targeting HBXIP. Thus, we conclude that miR-520b is involved in regulating breast cancer cell migration by targeting HBXIP and IL-8 via a network in which HBXIP promotes migration by stimulating NF-κB-mediated IL-8 expression. These studies point to HBXIP
as a potential therapeutic target for breast cancer.
Journal of Biological Chemistry 04/2011; 286(15):13714-13722. · 4.77 Impact Factor
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Nan Hu,
Jianli Zhang,
Wenjing Cui,
Guangyao Kong,
Shuai Zhang,
Lin Yue,
Xiao Bai,
Zhao Zhang,
Weiying Zhang,
Xiaodong Zhang,
Lihong Ye
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ABSTRACT: MicroRNAs play important roles in tumor metastasis. Recently, we reported that the level of miR-520b is inversely related to the metastatic potential of breast cancer cells. In this study, we investigated the role of miR-520b in breast cancer cell migration. We found that miR-520b suppressed the migration of breast cancer cells with high metastatic potential, including MDA-MB-231 and LM-MCF-7 cells, although the inhibition of miR-520b enhanced the migration of low metastatic potential MCF-7 cells. We further discovered that miR-520b directly targets the 3'-untranslated region (3'UTR) of either hepatitis B X-interacting protein (HBXIP) or interleukin-8 (IL-8), which has been reported to contribute to cell migration. Surprisingly, tissue array assays showed that 75% (38:49) and 94% (36:38) of breast cancer tissues and metastatic lymph tissues, respectively, were positive for HBXIP expression. Moreover, overexpression of HBXIP was able to promote the migration of MCF-7 cells. Interestingly, HBXIP was able to regulate IL-8 transcription by NF-κB, suggesting that the two target genes of miR-520b are functionally connected. In addition, we found that miR-520b could indirectly regulate IL-8 transcription by targeting HBXIP. Thus, we conclude that miR-520b is involved in regulating breast cancer cell migration by targeting HBXIP and IL-8 via a network in which HBXIP promotes migration by stimulating NF-κB-mediated IL-8 expression. These studies point to HBXIP as a potential therapeutic target for breast cancer.
Journal of Biological Chemistry 02/2011; 286(15):13714-22. · 4.77 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs), non-coding RNAs that function as post-transcriptional gene regulators, play a pivotal role in cancer development. In the present study, we elucidated the roles of miR-520b and miR-520e in breast cancer cells. We examined the expression levels of miR-520b and miR-520e in the immortalized breast cell line, HBL-100, and in three breast cancer cell lines: MCF-7, LM-MCF-7 and MDA-MB-231. We show the expression levels of miR-520b and miR-520e in the breast cancer cell lines were lower than that in the HBL-100 cells. Furthermore, the breast cancer cell lines showed less sensitivity to complement-dependent cytotoxicity (CDC). We found that overexpression of miR-520b and miR-520e increases the sensitivity of the breast cancer cells to CDC, whereas further suppression of miR-520b and miR-520e decreases the sensitivity of the breast cancer cells to CDC. We then demonstrate that miR-520b and miR-520e are able to directly target the 3'untranslated regions (3'UTR) of the membrane-bound complement regulatory protein CD46; suggesting that miR-520b and miR-520e down-regulate CD46 at post-transcriptional level. Enzyme-linked immunosorbent assay (ELISA) showed that overexpression of miR-520b and miR-520e results in the increased expression of C3b, which is mediated by downregulated CD46. These results suggest that miRNA-520b and miR-520e mediated down-regulation of CD46 induces opsonization of cancer cells via an alternative pathway resulting in complement activation. Thus, we conclude that miR-520b and miR-520e contribute to CDC in breast cancer cells via directly targeting the 3'UTR of CD46.
Cancer biology & therapy 08/2010; 10(3):232-41. · 2.64 Impact Factor
