[show abstract][hide abstract] ABSTRACT: Background
Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined.
We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFRα1, GFRα3 and Syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma.
The expression of GFRα1 and GFRα3, but not SDC3, was significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFRα1 and GFRα3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Co-expression of ARTN with either GFRα1 or GFRα3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFRα1 and GFRα3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma.
The expression of GFRα1 and/or GFRα3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma.
[show abstract][hide abstract] ABSTRACT: Animals born with a deficiency in the cell surface receptor for growth hormone (GH) have a significantly reduced risk of developing cancer. Conversely, increased expression levels of GH and the GH receptor (GHR) are detectable in a variety of different human cancers. Here we discuss recent literature contributing to our understanding of the field.
In addition to animal evidence, studies of individuals with Laron syndrome suggest that congenital GHR deficiency may also protect humans against cancer. GH expression in certain malignancies is correlated with clinicohistopathological parameters and may contribute the therapeutic resistance. Other recent studies have identified novel aspects of the GH signal transduction pathway, including receptor crosstalk and the involvement of microRNA in endocrine regulation of GH.
Substantial evidence suggests the GH/insulin-like growth factor-1 axis initiates and promotes progression of cancer. However, important questions remain unanswered regarding the therapeutic utility of GH or GHR antagonism in cancer. Further clinical studies regarding the clinical association of GH expression with human malignancies and translational studies investigating GHR antagonism in animal models of human cancer are critical.
Current opinion in endocrinology, diabetes, and obesity 08/2013; 20(4):307-313.
[show abstract][hide abstract] ABSTRACT: ARTEMIN (ARTN) has been reported to promote a TWIST1 dependent epithelial to mesenchymal transition of estrogen receptor negative mammary carcinoma (ER-MC) cells associated with metastasis and poor survival outcome. We therefore examined a potential role of ARTN in the promotion of the cancer stem cell (CSC) like phenotype in mammary carcinoma cells. Acquired resistance of ER-MC cells to either ionizing radiation (IR) or paclitaxel was accompanied by increased ARTN expression. Small interfering RNA (siRNA) mediated depletion of ARTN in either IR or paclitaxel resistant ER-MC cells restored cell sensitivity to IR or paclitaxel. Expression of ARTN was enriched in ER-MC cells grown in mammospheric compared to monolayer culture and was also enriched, along with BMI1, TWIST1 and DVL1, in mammospheric and ALDH1+ populations. ARTN promoted mammospheric growth and self renewal of ER-MC cells and increased the ALDH1+ population, whereas siRNA mediated depletion of ARTN diminished these CSC-like cell behaviours. Furthermore, increased ARTN expression was significantly correlated with ALDH1 expression in ER-MC cohort of patients. Forced expression of ARTN also dramatically enhanced tumor initiating capacity of ER-MC cells in xenograft models at low inoculum. ARTN promotion of the CSC-like cell phenotype was mediated by TWIST1 regulation of BCL-2 expression. ARTN also enhanced mammosphere formation and the ALDH1+ population in estrogen receptor positive mammary carcinoma (ER+MC) cells. Increased expression of ARTN, and the functional consequences thereof, may be one common adaptive mechanism used by mammary carcinoma cells to promote cell survival and renewal in hostile tumor micro-environments.
Journal of Biological Chemistry 10/2012; · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: The neurotrophic factor ARTEMIN (ARTN) has been reported to possess a role in mammary carcinoma progression and metastasis. Herein, we report that ARTN modulates endothelial cell behaviour and promotes angiogenesis in ER-mammary carcinoma (ER-MC). Human microvascular endothelial cells (HMEC-1) do not express ARTN but respond to exogenously added, and paracrine ARTN secreted by ER-MC cells. ARTN promoted endothelial cell proliferation, migration, invasion and 3D matrigel tube formation. Angiogenic behaviour promoted by ARTN secreted by ER-MC cells was mediated by AKT with resultant increased TWIST1 and subsequently VEGF-A expression. In a patient cohort of ER-MC, ARTN positively correlated with VEGF-A expression as measured by Spearman's rank correlation analysis. In xenograft experiments, ER-MC cells with forced expression of ARTN produced tumors with increased VEGF-A expression and increased microvessel density (CD31 and CD34) compared to tumors formed by control cells. Functional inhibition of ARTN by siRNA decreased the angiogenic effects of ER-MC cells. Bevacizumab (a humanized monoclonal anti-VEGF-A antibody) partially inhibited the ARTN mediated angiogenic effects of ER-MC cells and combined inhibition of ARTN and VEGF-A by the same resulted in further significant decrease in the angiogenic effects of ER-MC cells. Thus, ARTN stimulates de novo tumor angiogenesis mediated in part by VEGF-A. ARTN therefore co-ordinately regulates multiple aspects of tumor growth and metastasis.
PLoS ONE 01/2012; 7(11):e50098. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: miRNAs, endogenous oligonucleotide RNAs, play an important role in mammary gland carcinogenesis and tumor progression. Detection of their expression and investigation of their functions could lead to discovery of novel biomarkers for breast cancer.
In situ hybridization was used to detect miR-133a expression in formalin-fixed paraffin-embedded breast surgical specimens from 26 benign, 34 pericancerously normal and 90 cancerous tissues. qRT-PCR was performed to assess miR-133a levels in 6 breast cell lines and 10 benign and 18 cancerous fresh breast tissue specimens. Cell viability, migration, and invasion assays were used to determine the role of miR-133a in regulation of breast cancer cell growth, migration, and invasion, respectively. Luciferase assay was performed to assess miR-133a binding to FSCN1 gene.
Expression of miR-133a was reduced from normal through benign to cancerous breast tissues. Expression of miR-133a was also low in breast cancer cell lines. The reduced miR-133a expression was associated with lymph nodes metastasis, high clinical stages, and shorter relapse-free survivals of patients with breast cancer. Furthermore, transfection of miR-133a oligonucleotides slightly inhibited growth but significantly decreased migration and invasion capacity of breast cancer cells, compared with negative controls, whereas knockdown of miR-133a expression induced breast cancer cell migration and invasion. In addition, we identified a putative miR-133a binding site in the 3'-untranslated region (UTR) of Fascin1 (FSCN1) gene using an online bioinformatical tool. We found that miR-133a transfection significantly reduced expression of FSCN1 mRNA and protein. The luciferase reporter assay confirmed that FSCN1 was the direct target gene of miR-133a.
miR-133a expression was lost in breast cancer tissues, loss of which was associated with lymph nodes metastasis, high clinical stages and shorter relapse-free survivals of patients with breast cancer. Functionally, miR-133a can suppress tumor cell invasion and migration and targeted the expression of FSCN1. Future study will verify whether detection of miR-133a expression can served as a novel biomarker for breast cancer progression and patient prognosis.
[show abstract][hide abstract] ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood.
Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver.
Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC.
Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.
[show abstract][hide abstract] ABSTRACT: ARTEMIN (ARTN) is an estrogen regulated growth factor, the expression of which promotes resistance to antiestrogen therapies and predicts poorer survival outcome of patients with estrogen receptor (ER) positive mammary carcinoma (ER+MC) treated with tamoxifen. ARTN is also expressed in ER negative mammary carcinoma (ER-MC). Herein, we determined the role of ARTN in ER-MC and defined the mechanism of action producing poor patient prognosis.
We modulated the expression of ARTN in two ER- (mesenchymal/claudin-low) mammary carcinoma cell lines (BT549 and MDA-MB-231) by forced expression or small interfering RNA (siRNA) mediated depletion. The effects of modulation of ARTN expression were examined by various in vitro measures of oncogenicity, including the expression of TWIST1 messenger RNA (mRNA) and protein. In vitro results were correlated to xenograft studies in immunodeficient mice. Co-expression of ARTN and TWIST1 and their association to poor survival outcome were examined in a cohort of patients with ER-MC. Pathway analysis was performed by pharmacological inhibition of phosphorylation of AKT (pAKT-Ser 473) or modulation of TWIST1 expression.
ARTN expression resulted in ER-MC cells with enhanced mesenchymal characteristics, including increased invasion and a gene expression profile consistent with enhanced mesenchymal phenotype. ARTN stimulated ER-MC cell anchorage independent and 3D matrigel growth, endothelial cell adhesion and transmigration of ER-MC cells through an endothelial cell barrier. Forced expression of ARTN produced a larger, locally invasive tumour mass with tumour emboli that produced distant metastasis. ARTN regulated TWIST1 expression in ER-MC cells and ARTN expression was significantly correlated to TWIST1 expression in a panel of mammary carcinoma cell lines and in a cohort of patients with ER-MC. Low expression of both ARTN and TWIST1 predicted 100% relapse free and overall survival in patients with ER-MC, whereas high expression of both ARTN and TWIST1 was associated with a poor survival outcome. ARTN stimulated an increase in TWIST1 expression via increased AKT activity. siRNA mediated depletion of TWIST1 abrogated ARTN stimulated cellular behaviour associated with metastasis, and forced expression of TWIST1 abrogated the functional effects of ARTN depletion.
ARTN and TWIST1 synergize to produce a worse outcome in ER-MC and combined inhibition of ARTN and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) may therefore provide a novel therapeutic strategy in this subtype of mammary carcinoma.
Breast cancer research: BCR 11/2011; 13(6):R112. · 5.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cutaneous malignant melanoma is one of the most common and aggressive forms of human cancers and has a poor prognosis. Activation of signal transducer and activator of transcription 3 (STAT3) has been found in several human cancers and is thought to correlate aggressive disease and poor response. In this study, we investigated the clinical role of STAT3 and its natural inhibitor, suppressor of cytokine signaling 3 (SOCS3), in human cutaneous melanoma development and progression. Immunohistochemical analysis of pSTAT3, SOCS3, matrix metalloproteinase (MMP)-2, and MMP-9 expression was performed on 90 primary melanomas and 43 common melanocytic nevi specimens. The expression of STAT3 mRNA was further detected by in-situ hybridization in the same cohort of patients. The association of STAT3 mRNA, pSTAT3, and SOCS3 protein expression with clinicopathological parameters and patient survival was analyzed. Altered expression of STAT3 mRNA, pSTAT3, and SOCS3 protein was observed in melanoma specimens, compared with benign melanocytic nevi. High expression of pSTAT3 was correlated to large tumor diameter, depth of tumor invasion, tumor lymph node metastasis, MMP-2 and MMP-9 expression, and poor patient survival. Decreased expression of SOCS3 was correlated to depth of tumor invasion, tumor lymph node metastasis, the expression of MMP-2, MMP-9, and pSTAT3, and poor patient survival. Moreover, the expression of pSTAT3 was conversely correlated to SOCS3 expression in melanoma. Our results indicate that deregulated expression of pSTAT3 and SOCS3 might possess potential roles in the development and progression of human cutaneous melanoma.
Melanoma research 08/2011; 21(6):483-90. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evidence suggests that human GH (hGH) and human prolactin (hPRL) possess an autocrine or paracrine oncogenic role in mammary and endometrial carcinoma. However, especially for hGH, the prognostic relevance of tumor expression of these hormones is not well defined.
We investigated the potential association of tumor mRNA and protein expression of hGH and hPRL with the clinicopathological features of mammary and endometrial carcinoma. The prognostic relevance of the individual or combined expression of hGH and hPRL in mammary and endometrial carcinoma was also determined.
The expression of hGH and hPRL was analyzed in histopathological samples of mammary and endometrial carcinoma, and the respective normal tissues, by in situ hybridization and immunohistochemistry. Kaplan-Meier and Cox regression analysis was performed to examine the association of tumor hGH and hPRL expression with relapse-free survival and overall survival of patients.
hGH expression was significantly associated with lymph node metastasis, tumor stage, human epidermal growth factor receptor-2 status, and proliferative index in mammary carcinoma and with International Federation of Gynecology and Obstetrics grade, myometrial invasion, and ovarian metastases in endometrial carcinoma. hPRL expression was associated with lymph node metastasis, tumor grade, and tumor stage in mammary carcinoma and with International Federation of Gynecology and Obstetrics stage and myometrial invasion in endometrial carcinoma. Both hGH and hPRL expression, individually and combined, are associated with worse relapse-free survival and overall survival in patients with mammary or endometrial carcinoma.
Tumor expression of both hGH or hPRL in mammary or endometrial carcinoma is associated with a large and significant difference in survival outcome for patients with these tumors.
The Journal of clinical endocrinology and metabolism 08/2011; 96(10):E1619-29. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Empirical evidence suggests that autocrine human GH (hGH) may possess a proliferative and oncogenic role in human mammary carcinoma. However, this concept is largely derived from studies using cultured human mammary carcinoma cell (HMCC) lines.
We investigated the expression and functionality of hGH and the hGH receptor in isolated cultures of primary HMCC. Design: Epithelial cell adhesion molecule-positive primary HMCC were isolated from surgical biopsies of patients with mammary carcinoma and cultured in vitro. Expression of hGH and hGH receptor was determined by RT-PCR, immunofluorescence microscopy, and ELISA. The proliferative response of the cultured primary HMCC to hGH stimulation or hGH inhibition with a hGH antagonist was determined.
One hundred percent of cultured primary HMCC expressed the hGH receptor, and 52% expressed hGH at the mRNA level. hGH-positive primary HMCC produced hGH protein within the cell and secreted hGH to the media. Both hGH-negative and hGH-positive HMCC responded to hGH stimulation with large increases in cell number. hGH-positive HMCC responded to inhibition of hGH by a hGH antagonist with a decrease in cell number, whereas hGH-negative HMCC did not.
Primary HMCC proliferate in response to hGH, and the proliferation of hGH-positive HMCC is inhibited by hGH antagonism. Inhibition of hGH in patients with mammary carcinoma may therefore limit tumor growth.
The Journal of clinical endocrinology and metabolism 07/2011; 96(9):E1418-26. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Different microRNAs have been shown to have oncogenic and tumor-suppressive functions in human cancers. Detection of their expression may lead to identifying novel markers for breast cancer.
The authors detected miR-340 expression in 4 human breast cell lines and then focused on its role in regulation of tumor cell growth, migration, and invasion and target gene expression. They then analyzed miR-340 expression in benign and cancerous breast tissue specimens.
Endogenous miR-340 expression was down-regulated in the more aggressive breast cancer cell lines, which was confirmed in breast cancer tissue specimens by using quantitative real-time polymerase chain reaction. Further studies showed that induction of miR-340 expression was able to suppress tumor cell migration and invasion, whereas knockdown of miR-340 expression induced breast cancer cell migration and invasion. At the gene level, the authors identified c-Met as a direct miR-340 target to mediate cell migration and invasion through regulation of MMP-2 and MMP-9 expression. Ex vivo, loss of miR-340 expression was associated with lymph node metastasis, high tumor histological grade, clinical stage, and shorter overall survival of breast cancer as well as increased c-Met expression in breast cancer tissue specimens.
miR-340 may play an important role in breast cancer progression, suggesting that miR-340 should be further evaluated as a novel biomarker for breast cancer metastasis and prognosis, and potentially a therapeutic target.
Cancer 07/2011; 117(13):2842-52. · 5.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: HER-2 plays an important role in the development and progression of ovarian carcinoma. A number of monoclonal antibodies (MAbs) and engineered antibody fragments (such as scFvs) against the subdomain II or IV of HER-2 extracellular domain (ECD) have been developed. We investigated the effect of chA21, an engineered anti-HER-2 antibody that bind primarily to subdomain I, on ovarian carcinoma cell invasion in vitro, and explored its possible mechanisms.
Growth inhibition of SK-OV-3 cells was assessed using a Methyl thiazolyl tetrazolium (MTT) assay. The invasion ability of SK-OV-3 was determined by a Transwell invasion assay. The expression of matrix metalloproteinase-2 (MMP-2) and its tissue inhibitors (TIMP-2) was detected by immunocytochemical staining, and the expression of p38 and the phosphorylation of p38 were assayed by both immunocytochemistry and Western blot.
After treatment with chA21, the invasion of human ovarian cancer SK-OV-3 cells was inhibited in dose- and time-dependent manners. Simultaneously the expression of p38, phospho-p38, MMP-2 and the MMP-2/TIMP-2 ratio decreased, while TIMP-2 expression increased. Additionally, the decrease in phospho-p38 was much greater than that of p38.
chA21 may inhibit SK-OV-3 cell invasion via the signal transduction pathway involving MMP-2, TIMP-2, p38 and the activation of p38MAPK.
Chinese Journal of Cancer Research 06/2011; 23(2):147-152. · 0.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: Altered expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and suppressor of cytokine signaling 3 (SOCS3) has been implicated in various types of human cancers. However, the clinical role of pSTAT3 and SOCS3 in hepatocellular carcinoma (HCC) is not well established. Immunohistochemical analysis of pSTAT3, SOCS3, Ki67 and VEGF expression was performed on tissue microarrays from 138 HCC patients. The expression of STAT3 mRNA was further detected by in situ hybridization. The association of pSTAT3 and SOCS3 expression with clinicopathological factors and patient survival was analyzed. Altered expression of pSTAT3 and SOCS3 was observed in HCC specimens, compared to adjacent non-tumor tissue. Increased expression of pSTAT3 was correlated with large tumor size, higher clinical stage, Ki67 and VEGF expression, as well as poor patient survival. Decreased expression of SOCS3 was correlated with the expression of Ki67, VEGF and pSTAT3, and poor patient survival. Moreover, the expression of pSTAT3 was conversely correlated with SOCS3 expression in HCC. Our results indicate that deregulated expression of pSTAT3 and SOCS3 may play roles in the development and progression of HCC. PSTAT3 and SOCS3 should be further evaluated as potential novel biomarkers for HCC prognosis.
Experimental and therapeutic medicine 01/2011; 2(4):647-653. · 0.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the clinicopathological characteristics and possible causes of solitary necrotic nodule of the liver (SNN), two cases of SNN of the liver were studied with clinicopathological data, immunohistochemistry, and histochemistry staining. The patients had no specific symptoms, with negative results for the serum tumor markers. CT and ultrasound all showed low-density lesion. Morphologically, there was isolate, single necrosis tubercle of the liver. It was composed of a central necrotic core and a peripheral fibrotic capsule with inflammatory cells, including histiocytes, plasma cells, lymphocytes, and so forth. The staining result of PAS, acid-fast, and iron was all negative, and AG + VG staining showed that the outline of reticular fibers and collagen was intact. Vimtin was positive for necrotic tissue and surrounding fibrous tissue. CD34 and CD68 was both positive for case 1. CK was negative in case 2 but positive for a few residual cells in case 1. SNN of the liver is a rare nonmalignant disease with a good prognosis. Hemangioma and fatty liver might be ones of the causes of SNN.
[show abstract][hide abstract] ABSTRACT: MicroRNAs (miRNAs) play an important role in the regulation of cell growth, differentiation, apoptosis, and carcinogenesis. Detection of their expression may lead to identifying novel markers for breast cancer.
We profiled miRNA expression in three breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) and then focused on one miRNA, miR-339-5p, for its role in regulation of tumor cell growth, migration, and invasion and target gene expression. We then analyzed miR-339-5p expression in benign and cancerous breast tissue specimens.
A number of miRNAs were differentially expressed in these cancer cell lines. Real-time PCR indicated that miR-339-5p expression was downregulated in the aggressive cell lines MDA-MB-468 and MDA-MB-231 and in breast cancer tissues compared with benign tissues. Transfection of miR-339-5p oligonucleotides reduced cancer cell growth only slightly but significantly decreased tumor cell migration and invasion capacity compared with controls. Real-time PCR analysis showed that BCL-6, a potential target gene of miR-339-5p, was downregulated in MDA-MB-231 cells by miR-339-5p transfection. Furthermore, the reduced miR-339-5p expression was associated with an increase in metastasis to lymph nodes and with high clinical stages. Kaplan-Meier analyses found that the patients with miR-339-5p expression had better overall and relapse-free survivals compared with those without miR-339-5p expression. Cox proportional hazards analyses showed that miR-339-5p expression was an independent prognostic factor for breast cancer patients.
MiR-339-5p may play an important role in breast cancer progression, suggesting that miR-339-5p should be further evaluated as a biomarker for predicting the survival of breast cancer patients.
[show abstract][hide abstract] ABSTRACT: We herein show that Artemin (ARTN), one of the glial cell line-derived neurotrophic factor family of ligands, promotes progression of human non-small cell lung carcinoma (NSCLC). Oncomine data indicate that expression of components of the ARTN signaling pathway (ARTN, GFRA3, and RET) is increased in neoplastic compared with normal lung tissues; increased expression of ARTN in NSCLC also predicted metastasis to lymph nodes and a higher grade in certain NSCLC subtypes. Forced expression of ARTN stimulated survival, anchorage-independent, and three-dimensional Matrigel growth of NSCLC cell lines. ARTN increased BCL2 expression by transcriptional upregulation, and inhibition of BCL2 abrogated the oncogenic properties of ARTN in NSCLC cells. Forced expression of ARTN also enhanced migration and invasion of NSCLC cells. Forced expression of ARTN in H1299 cells additionally resulted in larger xenograft tumors, which were highly proliferative, invasive, and metastatic. Concordantly, either small interfering RNA-mediated depletion or functional inhibition of endogenous ARTN with antibodies reduced oncogenicity and invasiveness of NSCLC cells. ARTN therefore mediates progression of NSCLC and may be a potential therapeutic target for NSCLC.
Molecular Cancer Therapeutics 06/2010; 9(6):1697-708. · 5.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Here, we provide evidence for a functional role of artemin (ARTN) in progression of endometrial carcinoma (EC). Increased ARTN protein expression was observed in EC compared with normal endometrial tissue, and ARTN protein expression in EC was significantly associated with higher tumor grade and invasiveness. Forced expression of ARTN in EC cells significantly increased total cell number as a result of enhanced cell cycle progression and cell survival. In addition, forced expression of ARTN significantly enhanced anchorage-independent growth and invasiveness of EC cells. Moreover, forced expression of ARTN increased tumor size in xenograft models and produced highly proliferative, poorly differentiated, and invasive tumors. The ARTN-stimulated increases in oncogenicity and invasion were mediated by increased expression and activity of AKT1. Small interfering RNA-mediated depletion or antibody inhibition of ARTN significantly reduced oncogenicity and invasion of EC cells. Thus, inhibition of ARTN may be considered as a potential therapeutic strategy to retard progression of EC.
[show abstract][hide abstract] ABSTRACT: Membranous (M) cell of the human palatine tonsil is an antigen entry site for mucosal infection, but its location is obscure in histological sections. Recently, a microarray analysis has demonstrated that clusterin, annexin A5, CD44, MMP14, and beta-tubulin are candidate genes of M cell marker in mice. Among these genes, we here describe class II beta-tubulin as a new marker for human tonsillar M cells and follicular dendritic cells (FDCs), and present its usefulness for diagnosis of angioimmunoblastic T-cell lymphomas (AILTs).
Immunohistochemistry and Western blotting for class II beta-tubulin were performed using 81 cases of lymphoid, gastrointestinal and thyroid tissues, and an FDC cell line, respectively. Double immunostaining with clusterin and class II beta-tubulin were carried out.
Class II beta-tubulin localized the M cells and FDCs in the palatine tonsils (10/10, 100%) and adenoids (10/10, 100%). It was colocalized with clusterin in the palatine tonsils. However, class II beta-tubulin staining did not identify intestinal M cells in the intestines. Immunoblot analysis revealed that class II beta-tubulin expression was upregulated in HK cells, a normal FDC cell line. Class II beta-tubulin immunostaining highlighted hyperplastic FDC meshworks in all AILTs (14/14, 100%).
Class II beta-tubulin is a specific histochemical marker for human tonsillar M cells and FDCs. Thus, class II beta-tubulin immunostaining may be useful to identify tonsillar M cells and to diagnose FDC proliferative lesions such as AILT.
Journal of Oral Pathology and Medicine 02/2010; 39(7):533-9. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have previously reported that artemin (ARTN) stimulates the oncogenicity and invasiveness of endometrial carcinoma cells. Herein, we demonstrate that ARTN modulates the sensitivity of endometrial carcinoma cells to agents used to treat late-stage endometrial carcinoma. Forced expression of ARTN in endometrial carcinoma cells decreased sensitivity to doxorubicin and paclitaxel. Accordingly, depletion of ARTN by small interfering RNA or functional inhibition of ARTN with antibodies significantly increased sensitivity of endometrial carcinoma cells to doxorubicin and paclitaxel. Forced expression of ARTN in endometrial carcinoma cells abrogated doxorubicin-induced G(2)-M arrest and paclitaxel-induced apoptosis. ARTN increased CD24 expression in endometrial carcinoma cells by transcriptional up-regulation, and CD24 was partially correlated to ARTN expression in endometrial carcinoma. Forced expression of CD24 in endometrial carcinoma cells stimulated cell proliferation and oncogenicity, enhanced cell invasion, and decreased sensitivity to doxorubicin and paclitaxel. Depletion of CD24 in endometrial carcinoma cells abrogated ARTN-stimulated resistance to doxorubicin and paclitaxel. ARTN-stimulated resistance to doxorubicin and paclitaxel in endometrial carcinoma cells is therefore mediated by the specific regulation of CD24. Functional inhibition of ARTN may therefore be considered as an adjuvant therapeutic approach to improve the response of endometrial carcinoma to specific chemotherapeutic agents.
[show abstract][hide abstract] ABSTRACT: To investigate the expression of MMP-2, TIMP-2, TGF-beta1 and TGF-betaRI and the relationship among them in breast cancer.
The protein expression of MMP-2, TIMP-2, TGF-beta1 and TGF-betaRI was detected on tissue chips by S-P immunohistochemical staining in 160 cases of breast carcinoma.
The positive rates of TGF-beta1, TGF-beta1 mRNA, MMP-2, MMP-9, TIMP-1 and TIMP-2 expression were 73.7%, 56.2%, 96.9%, 95.0%, 87.5% and 89.4%, respectively. Axillary lymph node metastasis and TNM staging (P < 0.01 and P < 0.01, respectively) were positively correlated to the expression of TGF-beta1. Relase-free survival of TGF-beta1 positive group was lower than that of TGF-beta1 negative group (P = 0.023). The expression of MMP-2 or MMP-9 was positively correlated to that of TGF-beta1 (r = 0.170, P < 0.05; r = 0.221, P < 0.01) and was negatively correlated to that of TGF-beta1 mRNA (r = -0.126, P > 0.05;r = 0.019, P > 0.05).
The expression of TGF-beta1 may be closely correlated with the invasion and metastasis of breast cancer. TGF-beta1-induced invasiveness and metastasis of breast cancer cells are mediated by MMP-2 and MMP-9.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 09/2009; 31(9):679-82.