Effects of DNA methylation on galectin-3 expression in pituitary tumors

Galectin-3 (Gal-3), a beta-galactoside-binding protein is expressed in a specific cell-type manner in pituitary tumors. Here we questioned the mechanism of Gal-3 expression in pituitary tumors, by using methylation-specific PCR and DNA sequence analyses to analyze the methylation status of the promoter region of the LGALS3 gene. DNA analysis of a human pituitary tumor, breast carcinoma cell lines, and thyroid carcinoma cell lines showed that in cells expressing Gal-3 protein, the LGALS3 gene was unmethylated, whereas in Gal-3 null cells, the promoter of the LGALS3 gene was methylated. Treatment of cells with 30 mumol/L 5-aza-2'-deoxycytidine induced Gal-3 mRNA and protein expression. Among pituitary tumors, 30% (7/23), mainly in follicle-stimulating hormone/luteinizing hormone-producing (38%) and null cell (57%) adenomas, the promoter of the LGALS3 was found to be methylated and silenced, although prolactin- and adrenocorticotropic hormone-producing tumors, which were unmethylated, expressed the Gal-3 protein. These results show for the first time that Gal-3 expression is regulated in part by promoter methylation in pituitary as well as in other tumors. Because it is functionally involved in cancer progression and metastasis, Gal-3 may serve as a possible therapeutic target in the treatment of pituitary tumors.     

Differential expression of galectin-1 and galectin-3 in benign and malignant salivary gland neoplasms

Galectins are a family of non-integrin beta-galactosidase-binding lectins. Altered expression of galectins has been associated with neoplastic transformation and progression in several human tumors. In this study, we examined the distribution patterns of galectin-1 and galectin-3 in normal (n=45), benign (n=16), and malignant (n=49) salivary gland specimens using immunohistochemistry to determine their diagnostic and/or biological implications in salivary gland tumorigenesis. In normal salivary glands, galectin-3 expression was limited to ductal cells, and galectin-1 was usually faintly detected in ductal cells and strongly positive in myoepithelial cells. In benign tumors, galectin-3 maintained the ductal localization, but galectin-1 showed variable expression in ductal and myoepithelial cells. In malignant tumors, most of the polymorphous low-grade adenocarcinomas and carcinoma ex-pleomorphic adenomas expressed both galectins, whereas adenoid cystic and acinic cell carcinomas showed dramatically reduced galectin-3 expression and heterogeneous galactin-1 staining. Our data demonstrated altered localization and expression of galectin-3, and to lesser extent, galectin-1 in salivary gland carcinomas. These findings may assist in the differential diagnosis of some salivary gland malignancies, especially when using small and limited fine-needle aspiration materials.     

Ubiquitous expression of galectin-3 mRNA in benign and malignant thyroid tumors

We measured the relative expression levels of galectin-3 mRNA to beta-actin mRNA in normal thyroid tissues, thyroid tumor tissues and thyroid-derived fibroblasts. Galectin-3 mRNA was expressed ubiquitously in both benign and malignant thyroid tumors. Although a significant increase in its expression was observed in papillary carcinomas, no significant difference was observed between follicular carcinomas and adenomas. In contrast to the previous optimistic reports using immunohistochemical analysis of the galectin-3 protein expression, these results demonstrate that galectin-3 mRNA may not be a suitable target for molecular-based diagnosis of thyroid carcinomas.     

Evaluation of galectin-8 expression in thyroid tumors

The expression of galectin-8 (gal-8) has been shown to be altered during neoplastic transformation of certain cell types. This is the first study aimed to analyze the expression of this protein in normal and pathological human thyroid tissue. A total of 41 archival thyroid tissue samples (5 follicular adenomas, 31 papillary carcinomas, 5 follicular carcinomas) together with 36 adjacent hyperplastic or normal thyroid tissues were analyzed by immunohistochemistry. Galectin-8 was expressed in the majority of papillary carcinomas (27/31; 87%). Positive but weaker staining was also found in some of the follicular thyroid carcinomas (2/5; 40%) and adenomas (2/5; 40%). This protein was not detectable in five normal thyroid tissue samples, whereas hyperplastic areas adjacent to tumor were weakly positive in 9 out of 31cases (29%). High gal-8 immunostaining in papillary thyroid carcinoma indicates that gal-8 may potentially serve as a marker of papillary thyroid carcinoma. However, it does not seem to be helpful in the differential diagnostics of follicular carcinoma and adenoma. Further studies are required to determine biological functions and molecular mechanisms underlying the increased expression of gal-8 protein in thyroid lesions, particularly, in papillary thyroid carcinoma.     

Cyclooxygenase-2 expression in human pituitary tumors

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a role in progression of colon, breast, pancreas, and lung carcinomas. The authors investigated COX-2 expression in pituitary tumors. METHODS: Expression of COX-2 was evaluated in 164 surgically removed human pituitary tumors. Correlation of COX-2 with MIB-1, a cell proliferation marker, as well as angiogenesis, patient age, gender, tumor type, size, invasiveness, and metastatic potential was investigated. RESULTS: Cyclooxygenase-2 immunoreactivity was confined to the cytoplasm of tumor cells, whereas the nuclei were unlabeled. Few normal peritumoral adenohypophysial cells showed slight COX-2 cytoplasmic immunoreactivity. The staining intensity and the percentage of immunopositive cells were higher in tumors. Most pituitary tumors (96%) were COX-2-immunopositive. Expression was strong in 60 (44%), moderate in 39 (28%), and weak in 32 (24%). Male gonadotroph adenomas and null cell adenomas showed a high level of COX-2 expression. Growth hormone-producing adenomas, prolactin-producing adenomas, thyrotropic hormone-producing adenomas, female gonadotroph adenomas, silent adrenocorticotropic hormone-producing adenomas, and silent subtype 3 adenomas had a low level of COX-2 expression. Significant correlation was demonstrated with patient age, but not with tumor size, invasiveness, and MIB-1 labeling indices. Expression was medium to high in 76% of macroadenomas and in only 45% of microadenomas. Strong correlations were noted with angiogenesis markers, such as microvessel density and surface density. CONCLUSIONS: Correlation with angiogenesis suggests that COX-2 may be involved in the regulation of angiogenesis in pituitary tumors. Phamacologic inhibition of COX-2 activity might suppress angiogenesis in pituitary tumors and may provide a novel approach for medical therapy.     

Differential expression of folate receptor in pituitary adenomas

Pituitary adenomas cause significant morbidity caused by compression of regional structures or the inappropriate expression of pituitary hormones. However, little is known about the molecular changes that contribute to the development of these tumors. To investigate these changes, we recently used cDNA microarray analysis to identify several genes with altered expression patterns in pituitary adenomas. The folate receptor (FRalpha) was significantly overexpressed in clinically nonfunctional (NF) adenomas but not in functional adenomas (adrenocorticorticotropic hormone, growth hormone, and prolactin). FRalpha is a high affinity folate transporter that is overexpressed by other tumors and could provide a growth advantage to cells that express it. Analysis of FRalpha expression by Western blotting confirmed that FRalpha protein was specifically overexpressed in NF tumors. The FRalpha was capable of binding folates from measurements of [(3)H] folic acid binding, indicating that the overexpressed receptor was properly folded and may mediate vitamin uptake. Comparison of protein and specific [(3)H] folic acid binding levels in subtypes of NF adenomas suggested that the immunohistochemically negative adenomas produced more properly folded FRalpha than adenomas that stained positively for anterior pituitary hormones. Finally, immunohistochemistry demonstrated that FRalpha was specifically expressed in NF adenoma cells. These results demonstrate that overexpression of FRalpha mRNA by NF pituitary adenomas results in production of properly folded FRalpha protein, may mediate vitamin transport, and could potentially facilitate the growth of these tumors.     

半乳糖凝集素-3及骨桥蛋白在食管癌中的表达及其意义

目的 研究半乳糖凝集素-3(Gal-3)、骨桥蛋白(OPN)在食管癌中的表达情况及其临床意义.方法 选取2006年至2008年接受手术治疗的食管癌患者37例,男28例,女9例,年龄41～82岁.应用荧光PCR及ELISA方法分别检测食管癌组织、癌旁组织及正常食管组织Gal-3 mRNA、OPN mRNA和血浆中Gal-3、OPN的水平,并结合术后随访,对其表达差异进行分析.结果 37例食管癌患者的肿瘤组织与癌旁组织及正常食管组织中Gal-3 mRNA相对表达值差异有统计学意义(F=11.934,P<0.05).三者之间OPN mRNA相对表达值差异有统计学意义(F=4.269,P<0.05).不同分期患者的食管癌组织Gal-3mRNA和OPN mRNA表达差异有统计学意义(F=3.216,P<0.05),而与患者的年龄、性别和肿瘤病理性质无关.复发组血浆中Gal-3和OPN水平及癌组织中的Gal-3 mRNA和OPN mRNA表达均高于未复发组(P相似文献   

半乳糖凝集素-3及骨桥蛋白在食管癌中的表达及其意义

目的 研究半乳糖凝集素-3(Gal-3)、骨桥蛋白(OPN)在食管癌中的表达情况及其临床意义.方法 选取2006年至2008年接受手术治疗的食管癌患者37例,男28例,女9例,年龄41～82岁.应用荧光PCR及ELISA方法分别检测食管癌组织、癌旁组织及正常食管组织Gal-3 mRNA、OPN mRNA和血浆中Gal-3、OPN的水平,并结合术后随访,对其表达差异进行分析.结果 37例食管癌患者的肿瘤组织与癌旁组织及正常食管组织中Gal-3 mRNA相对表达值差异有统计学意义(F=11.934,P<0.05).三者之间OPN mRNA相对表达值差异有统计学意义(F=4.269,P<0.05).不同分期患者的食管癌组织Gal-3mRNA和OPN mRNA表达差异有统计学意义(F=3.216,P<0.05),而与患者的年龄、性别和肿瘤病理性质无关.复发组血浆中Gal-3和OPN水平及癌组织中的Gal-3 mRNA和OPN mRNA表达均高于未复发组(P相似文献   

半乳糖凝集素-3及骨桥蛋白在食管癌中的表达及其意义

 目的　研究半乳糖凝集素-3（Gal-3）、骨桥蛋白（OPN）在食管癌中的表达情况及其临床意义。方法　选取2006年至2008年接受手术治疗的食管癌患者37例,男28例,女9例,年龄41～82岁。应用荧光PCR及ELISA方法分别检测食管癌组织、癌旁组织及正常食管组织Gal-3 mRNA、OPN mRNA和血浆中Gal-3、OPN的水平,并结合术后随访,对其表达差异进行分析。结果　37例食管癌患者的肿瘤组织与癌旁组织及正常食管组织中Gal-3 mRNA相对表达值差异有统计学意义（F＝11.934,P＜0.05）。三者之间OPN mRNA相对表达值差异有统计学意义（F＝4.269,P＜0.05）。不同分期患者的食管癌组织Gal-3 mRNA和OPN mRNA表达差异有统计学意义（F=3.216,P＜0.05）,而与患者的年龄、性别和肿瘤病理性质无关。复发组血浆中Gal-3和OPN水平及癌组织中的Gal-3 mRNA和OPN mRNA表达均高于未复发组（P＜0.05）。结论　食管癌组织中Gal-3 mRNA和OPN mRNA的差异表达可能与食管癌的发生、发展和转移有关。术前外周血Gal-3和OPN检测可能成为判定食管癌术前微转移的重要指标之一。     

Association of galectin-3 expression with melanoma progression and prognosis

AimsGalectin-3 plays an important role in adhesion, proliferation, differentiation, angiogenesis and metastasis in multiple tumours. To investigate the role of galectin-3 in melanoma pathogenesis we examined the expression of galectin-3 in melanocytic lesions and analysed the correlation between galectin-3 expression and clinicopathologic factors including patient survival and BRAF mutation status.MethodsWe evaluated the expression of galectin-3 in 53 cases of benign naevi, 31 cases of dysplastic naevi, 59 in-situ melanomas, 314 cases of primary melanoma and 69 metastatic melanomas using tissue microarray and immunohistochemistry.ResultsMarked differences in expression of galectin-3 were seen between different categories of melanocytic lesions (ANOVA p < 0.0001). An increase in expression of galectin-3 between benign naevi and thin primary melanomas and a progressive decrease in expression between thin primary melanomas and thicker melanomas or metastatic melanomas was seen. Strong galectin-3 expression was associated with improved overall survival (p = 0.002 and p = 0.0002 for cytoplasmic and nuclear expression, respectively) and melanoma-specific survival (p = 0.017 and p = 0.003 for cytoplasmic and nuclear expression, respectively). A multifactorial Cox regression analysis suggested that galectin-3 expression was an independent prognostic marker for overall survival in melanoma (risk ratio 0.73, 95% CI 0.547–0.970, p = 0.031 for cytoplasmic expression and risk ratio 0.76, 95% CI 0.587–0.985, p = 0.036 for nuclear expression). No association between galectin-3 expression and BRAF mutation status was observed.ConclusionThis study suggests that galectin-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanoma.     

Relationship between galectin-3 expression and TRAIL sensitivity in breast cancer

Evaluation of: Mazurek N, Byrd JC, Sun Y, Ueno S, Bresalier RS. A galectin-3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells. Cancer DOI: 10.1002/cncr.26078 (2011) (Epub ahead of print).

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors expressed on cancer cells and induces apoptosis. Triple-negative breast cancer cell lines are more sensitive to TRAIL or TRAIL-death receptor agonistic monoclonal antibody-induced apoptosis compared with HER-2/neu-overexpressing or luminal cell lines. The paper under evaluation sought to determine whether the His64/Pro64 polymorphism of galectin-3, which is associated with breast cancer incidence, affects sensitivity to TRAIL. None of five breast cancer cell lines homozygous for Pro64 galectin-3 were sensitive to TRAIL, but two out of two homozygous His64 cell lines and one out of two heterozygous His64 cell lines were sensitive. Transfection of galectin-3 null BT549 breast cancer cells with His64 galectin-3 rendered them sensitive to TRAIL, while Pro64 galectin-3-transfected cells remained resistant to TRAIL. This article highlights that galectin-3 receptor expression and genotype may be useful markers in predicting TRAIL or agonistic antibody sensitivity of breast cancer patients.     

Relationship between galectin-3 expression and TRAIL sensitivity in breast cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors expressed on cancer cells and induces apoptosis. Triple-negative breast cancer cell lines are more sensitive to TRAIL or TRAIL-death receptor agonistic monoclonal antibody-induced apoptosis compared with HER-2/neu-overexpressing or luminal cell lines. The paper under evaluation sought to determine whether the His64/Pro64 polymorphism of galectin-3, which is associated with breast cancer incidence, affects sensitivity to TRAIL. None of five breast cancer cell lines homozygous for Pro64 galectin-3 were sensitive to TRAIL, but two out of two homozygous His64 cell lines and one out of two heterozygous His64 cell lines were sensitive. Transfection of galectin-3 null BT549 breast cancer cells with His64 galectin-3 rendered them sensitive to TRAIL, while Pro64 galectin-3-transfected cells remained resistant to TRAIL. This article highlights that galectin-3 receptor expression and genotype may be useful markers in predicting TRAIL or agonistic antibody sensitivity of breast cancer patients.     

Involvement of galectin-3 expression in colorectal cancer progression and metastasis.

Galectin-3 is a beta-galactoside-specific lectin that binds to laminin sugar-sites and is involved in tumor malignancy. Galectin-3 expression in relation to primary tumor and liver metastasis of colorectal cancer was examined to determined its involvement in cancer progression and metastasis. Immunohistochemical staining of galectin-3 was performed on 117 primary lesions and 15 liver metastases of colorectal cancer using TIB166 monoclonal antibody. The expression of galectin-3 was evaluated by grading the intensity of the staining as either negative, weakly positive, or strongly positive. Normal mucosa of all patients were strongly positive for galectin-3, but the staining in these tissues was still significantly less than in the primary lesions of the cancer (31.6%). Galectin-3 expression in the primary lesions was significantly increased, correlating with the progression of clinical stage (p=0. 0224), liver metastasis (p<0.0001), venous invasion (p=0.0048), and lymph node metastasis (p=0.0289). Liver metastatic lesions also showed up-regulated levels of galectin-3 compared to the primary lesions (p=0.0030). The group showing strongly positive galectin-3 had a significantly poorer prognosis than the negative/weakly positive group in terms of disease-free survival (p=0.0224). The strong expression of galectin-3 in colorectal cancer correlates with cancer progression, liver metastasis, and poor prognosis for patients.     

Interleukin-6 and interleukin-6 receptor gene expression in pituitary tumors

Summary Interleukin-6 (IL-6) is a multifunctional cytokine which plays a role in the stimulation, inhibition, differentiation, and regulation of cell growth. IL-6 has been shown to act as an autocrine growth factor in several tumors, and is expressed by a variety of tumors. IL-6 also exhibits a regulatory role in the hypothalamopituitary axis. It is produced by both the hypothalamus and the pituitary, and it induces the secretion of anterior pituitary hormones. Because of the regulatory role of IL-6 in tumor growth and its involvement in the pituitary, we decided to evaluate IL-6 and IL-6 receptor expression in pituitary tumors. For this purpose we utilized complimentary cDNA probes specific for the IL-6 and IL-6 receptor mRNA, as well as monoclonal anti-IL-6 antibodies for immunohistochemical analysis.Our results show that the IL-6 gene is expressed in the normal pituitary tissue. However, the non-functioning and functioning pituitary tumors such as the prolactin and growth hormone secreting tumors express increased levels of the IL-6 gene. The IL-6 receptor gene was only expressed in the prolactin secreting and non-functioning pituitary tumors. These results show that the IL-6 and IL-6 receptor gene expression is enhanced in pituitary tumors, thus suggesting a possible role of IL-6 in the pathogenesis of these tumors.     

Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3

Galectin-3, a multifunctional lectin, is involved during cancer progression. Previous observations showed that both cytosolic expression and nuclear exclusion of galectin-3 in human prostate cancer cells were associated to progression of the disease. In this study, we examined the biological roles of galectin-3 when expressed either in the nucleus or in the cytosol. LNCaP, a galectin-3-negative human prostate cancer cell line, was used to generate transfectants expressing galectin-3 either in the nucleus or in the cytosol. No changes in cell morphology, proliferation, attachment to laminin-1 or androgen dependency were observed. Cytoplasmic galectin-3 induced significantly increased Matrigel invasion, anchorage-independent growth and in vivo tumor growth and angiogenesis, and decreased inducible apoptosis. Surprisingly, nuclear galectin-3 affected these parameters in an opposite fashion with an overall antitumoral activity. Thus, our study demonstrates that galectin-3 exerts opposite biological activities according to its cellular localization: nuclear galectin-3 plays antitumor functions and cytoplasmic galectin-3 promotes tumor progression.     

Decreased expression of galectin-3 in basal cell carcinoma of the skin.

Galectins are beta-galactoside-binding lectins that play multiple roles during tumor progression. Previous work conducted in our laboratory has demonstrated decreased galectin-3 expression in carcinomas from colon, breast, ovary and endometrium, compared to the corresponding normal tissues. In this study, we examined the pattern of galectin-3 expression by immunohistochemistry in a group of 10 basal cell carcinomas of the skin. In the surrounding normal skin, galectin-3 immunostaining was found predominantly in the middle epidermis (spine layer) and eccrine sweat glands. Compared to the normal epidermal cells, basal carcinoma cells observed in all 10 samples examined presented with significantly decreased galectin-3 immunostaining. These data further demonstrates that galectin-3 is down-regulated in a variety of human cancers, including basal cell carcinoma.     

Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas.

PURPOSE: Galectin-3, a member of the beta-galactoside-binding lectin family, has multiple biological functions including cell-cell interactions and cell-extracellular matrix adhesion, cellular proliferation, cellular differentiation, and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings and patient prognosis in ductal adenocarcinoma of the pancreas. EXPERIMENTAL DESIGN: We examined galectin-3 expression in 104 surgically resected pancreatic ductal adenocarcinoma cases with stages I through IV using immunohistochemistry and investigated the relationship of it to overall survival. RESULTS: Patients were divided into two groups: a low expression group, where <60% of tumor cells were positive; and a high expression group, where > or =60% of tumor cells were positive. Cases in the low expression group had a significant tendency to be at later stages, to have distant metastasis, and to have less differentiated tumors, compared with cases in the high expression group (P = 0.001 for stage, P = 0.001 for metastasis, and P = 0.006 for differentiation). Postoperative overall survival was worse in the low galectin-3 expression group than in the high galectin-3 expression group (P = 0.004). Multivariate analysis showed that the risk ratio of prognosis was 2.06 among patients in the low galectin-3 expression group compared with the high galectin-3 expression group (P = 0.006). CONCLUSIONS: Decreased expression of galectin-3 was associated with advanced stage, tumor de-differentiation, and metastasis in ductal adenocarcinoma of the pancreas. Galectin-3 expression might be a useful prognostic marker for survival in ductal adenocarcinoma of the pancreas.     

早期胃癌组织Galectin-3表达与淋巴结微转移关系的探讨

目的:研究早期胃癌组织中半乳凝素3(Galectin-3)表达水平与淋巴结微转移的关系。方法:采用免疫组化技术检测56例早期胃癌患者胃癌组织Galectin-3的表达水平,采用淋巴结组织HE染色和角蛋白AE1/AE3表达检测判断淋巴结微转移情况分析Galectin-3表达水平与淋巴结微转移的关系。结果:56例早期胃癌患者中,7例患者13枚淋巴结发现AE1/AE3阳性细胞,总阳性率12.5%(7/56),淋巴结总转移率11.67%(14/120);Galectin-3免疫反应在不同病理亚型早期胃癌组织中程度不同,随着分化程度降低而增强,有淋巴结转移或微转移的早期胃癌组织中Galectin-3表达比无淋巴结转移或微转移的早期胃癌组织中Galec-tin-3表达明显增强。结论:胃癌组织Galec-tin-3高表达有较高的淋巴结转移风险,这对判断预后和指导治疗有重要意义。     

Suppression of galectin-3 expression enhances apoptosis and chemosensitivity in liver fluke-associated cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with high resistance to anticancer drugs. This is probably in part due to enhanced resistance to apoptosis. We have previously shown that galectin-3 (Gal-3), a β-galactoside-binding lectin, is highly expressed in CCA tissues. In this study, we demonstrated further that Gal-3 plays a direct role in anti-apoptosis regardless of the apoptotic insults. The anti-apoptotic activity and chemoresistance of CCA cells were related to Gal-3 expression level. Suppression of Gal-3 expression with siRNA stimulated apoptosis. siGal-3-K626 transiently depleted Gal-3 expression to the baseline and dramatically induced apoptosis, while siGal-3-K402 suppressed Gal-3 expression by 50% and provoked cell apoptosis, but only under apoptotic insults (hypoxic conditions or short UV radiation). These actions were reversed in Gal-3 overexpressing CCA cells. The correlation between the degree of anti-apoptotic activity and the level of endogenous Gal-3 was demonstrated. Suppression of Gal-3 expression in CCA cells with siGal-3-K402 significantly enhanced apoptosis induced by cisplatin or 5-fluorouracil by approximately 10 times, whereas overexpression of Gal-3 led to an increased resistance to drugs. In summary, the present study showed that the cellular level of Gal-3 might contribute to the anti-apoptotic activity and chemoresistance of CCA cells. Hence, Gal-3 expression level in cancer cells or tissues may be a marker for predicting chemotherapeutic response, and Gal-3 may be a specific gene-targeting therapy option for treating CCA. ( Cancer Sci 2009; 00: 000–000)