Expression of MAGE-A3 in intrahepatic cholangiocarcinoma and its precursor lesions

MAGE-A3 antigen is known to be neo-expressed in a large proportion of tumors but not detectable in normal tissues, and could be a target antigen recognized by autologous cytotoxic T lymphocytes. In the present study, the expression of MAGE-A3 at protein and mRNA levels was examined in intrahepatic cholangiocarcinoma (ICC) and its precursor lesions. Carcinomatous and dysplastic biliary cells expressed MAGE-A3 in their cytoplasm diffusely, although there was no MAGE-A3 expression in normal and hyperplastic biliary cells. MAGE-A3 was expressed in one of 10 cases (10%) of low-grade dysplasia, four of 13 (31%) cases of high-grade dysplasia/in situ carcinoma, and 32 of 68 invasive ICC cases (47%), respectively. The MAGE-A3 mRNA expression pattern was similar to that of MAGE-A3 protein. The incidence and intensity of MAGE-A3 expression increased along the progression of biliary neoplasia (P < 0.05). There was no correlation between MAGE-3 expression and histological differentiation or anatomical locations of invasive ICC. MAGE-A3 is a promising target molecule for the specific immunotherapy of ICC.     

Expression of galectin-1 and galectin-3 in renal cell carcinoma; immunohistochemical study

Background and aimsGalectins comprise a large family of calcium independent lectins. Galectin-1 and galectin-3 contribute to neoplastic transformation, angiogenesis, and tumor metastasis in some cancers. This study aimed at studying the immunohistochemical expression of both galectin-1 and galectin-3 in renal cell carcinoma (RCC) variants and detecting the possible association of galectins with various clinicopathological parameters.Materials and methodsSections from 67 formalin-fixed paraffin-embedded tissue blocks of RCC variants were stained with galectin-1 and galectin-3. Expression was assessed in tumor tissue and adjacent renal parenchyma and was correlated with clinicopathological criteria.ResultsIn apparently normal renal parenchyma adjacent to tumor tissue, galectin-1 was expressed in 27 (40.2%) of specimens in renal tubules and glomeruli, while 34 (50.7%) of specimens showed galectin-3 expression in renal tubules sparing glomeruli. In tumor tissue, galectin-1 showed high expression in 47 (70.1%) and low expression in 20 (29.9%) of specimens. Galectin-3 had high expression in 15 (22.4%) and low expression in 52 (77.6%) of specimens. Significant association was detected between expression of galectin-1 and galectin-3 and the type of RCC (P = 0.032) and (P = 0.006), respectively. Significant inverse association was detected between the expression of galectin-3 and the presence of tumor haemorrhage and necrosis (P = 0.014) and (P = 0.039), respectively.ConclusionGalectin-1 and galectin-3 are overexpressed in RCC with different percentage in different subtypes. Galactin-1expression is more in tumor tissue than surrounding renal parenchyma suggesting that it has a carcinogenic role. Galectin-1 and galectin-3 overexpression in chromophobe RCC suggests that they may have diagnostic role.     

Expression pattern of galectin-1 and galectin-3 in rat testes and epididymis during postnatal development

Galectins are a family of lectins-binding beta-galactosides involved in a variety of extracellular and intracellular processes, thereby contributing to homeostasis, cell adhesion, cellular turnover, and immunity. This study aimed to determine the localization and expression of galectin-1 (Gal-1) and galectin-3 (Gal-3) in the testis and epididymis of rats at postnatal [(prepubertal (day 5), pubertal (day 20), postpubertal (day 50) and mature (day 70)] periods by using immunohistochemistry and Western blotting. Gal-1 and Gal-3 were differentially expressed in different types of cells in the testis and epididymis during postnatal development. While we detected Gal-1 expression in some spermatogenic cells and Leydig cells in the testis, not in the epididymal epithelium, Gal-3 was expressed in Sertoli cells, peritubular myoid cells, Leydig cells, smooth muscles and interstitial CD68-positive macrophages. Epithelial cells of the corpus and cauda epididymis showed an intense Gal-3 expression. Gal-1 expression was higher in the testis than in the epididymis on days 50 and 70. The expression of Gal-3 in the testis increased from the prepubertal to mature period. While the expression difference of Gal-3 was not statistically significant in the testis and epididymis until puberty, Gal-3 expression in the postpubertal and mature periods was higher in the epididymis. The expression of Gal-3 in the corpus and cauda epididymis was higher than that in the caput epididymis. In conclusion, our findings suggest that puberty has potential regulatory effect on the expression of galectins in testis and epididymis of rats. Gal-1 and 3 may play a role in the development of the reproductive system and the preservation of the immune-privileged environment in the testis, due to their pro-apoptotic and anti-apoptotic functions. The presence of intense expression of Gal-3 in the corpus and cauda epididymis may contribute to the maturation and storage of spermatozoa.     

Prognostic significance of NQO1 expression in intrahepatic cholangiocarcinoma

This study aimed to evaluate the association between the immunohistochemical expression of NAD(P) H:quinone oxidoreductase-1 (NQO1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in resected specimens of intrahepatic cholangiocarcinoma (ICC) and to elucidate the prognostic value of NQO1 and Nrf2 expression. A retrospective analysis was conducted of 34 consecutive patients who underwent surgical resection for ICC. Immunohistochemistry of the resected specimens was conducted using each of the following primary monoclonal antibodies against NQO1 and Nrf2. Of the 34 patients, 23 were classified as having tumors with NQO1-positive expression and 11 had tumors with loss of NQO1 expression, whereas 22 patients had tumors with Nrf2-positive expression and 12 had tumors with loss of Nrf2 expression. NQO1 expression showed a positive association with Nrf2 expression (p=0.005). Loss of NQO1 expression was more frequent in tumor specimens that were moderately or poorly differentiated (11/26; 42%) than in well-differentiated tumors (0/8; 0%; p=0.034). Post-resection survival was significantly worse in patients with tumors with loss of NQO1 expression than in patients with NQO1-positive tumors (cumulative 5 -year survival rate of 0% and 51%, respectively; p=0.005). Nrf2 expression was not associated with survival after resection (p=0.287). The Cox proportional hazards regression analysis revealed that lymph node involvement (p<0.001) and loss of NQO1 expression (p<0.001) had an independent adverse effect on survival. Loss of NQO1 expression reflects dedifferentiation and thus indicates a poor prognosis for patients undergoing resection for ICC.     

Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in intrahepatic cholangiocarcinoma

Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in cholangiocarcinoma was examined by immunohistochemistry. In the developing hilar bile ducts, tenascin was expressed in the mesenchyme around the epithelial cells migrating from the ductal plate into the mesenchyme at 10–14 weeks of gestation. Tenascin was also expressed in the mesenchyme around newly formed hilar bile ducts at 15-20 weeks of gestation, but its expression disappeared after 21 weeks of gestation. Type IV collagen and laminin were expressed around the ductal plate, around epithelial cells migrating from the ductal plate into the mesenchyme, and around newly formed hilar bile ducts, and their expression was present throughout fetal life. By contrast, in the development of peripheral bile ducts, tenascin expression was not found. Type IV collagen and laminin were identified around the ductal plate, migrating epithelial cells and peripheral bile ducts. In cholangiocarcinoma, tenascin and type IV collagen were expressed in the stroma, but laminin was not identified. These findings suggest that tenascin may play a role in hilar bile duct development and that type IV collagen and laminin may play a role in both hilar and peripheral bile duct development. Expression of tenascin and type IV collagen in the stroma of cholangiocarcinoma may be the result of malignant transformation of intrahepatic biliary epithelium; tenascin in peritumoral stroma may stimulate carcinoma cell proliferation and growth in cholangiocarcinoma.     

Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases.     

Expression of cytokeratin 19, HBME-1 and galectin-3 in neoplastic and nonneoplastic thyroid lesions

In this study, 105 cases of thyroid lesions were evaluated to assess the role of HBME-1, cytokeratin-19 (CK-19), galectin-3 in distinguishing benign from malignant thyroid lesions. Thirty-seven papillary, 10 follicular, 6 medullary, 1 mixed medullary follicular cell carcinoma, 3 poorly differentiated carcinoma, 18 adenomatous nodular hyperplasia, 30 follicular adenoma cases were included in the study. Immunohistochemical staining was performed with HBME-1, CK-19, galectin-3 on cross-sections derived from selected paraffin blocks. Benign and malignant lesions were compared in terms of intensity, percentage and type of staining with CK-19, HBME-1 and galectin-3, and a statistically significant difference (p < 0.05) was found. The percentage and intensity of staining was higher in malignant lesions. Especially, strong and diffuse expressions of CK19, HBME-1 and galectin-3 were observed in papillary carcinomas. Membranous (luminal) staining was seen more frequently in malignant lesions; cytoplasmic staining in benign lesions. It was concluded that these markers could assist in the diagnosis of thyroid lesions with cellular properties suspicious for the diagnosis of papillary carcinoma and without capsule and vessel invasion. They may be used especially in cases where the follicular variant of papillary carcinoma, follicular adenoma and follicular carcinoma are confused with each other and follicular adenoma cannot be differentiated from follicular carcinoma.     

Galectin-1 and galectin-3 in chronic pancreatitis

Galectin-1 and galectin-3 have important functions in cell-cell interactions, cell adhesion to extracellular matrix, the organization of extracellular matrix, and tissue remodeling. To assess their potential role in chronic pancreatitis (CP), we examined their expression by Northern blot analysis, in situ hybridization, immunohistochemistry, and Western blot analysis in normal and CP pancreatic tissues. Northern blot analysis revealed a 4.5-fold increase of galectin-1 mRNA (p < 0.01) and a 3.8-fold increase of galectin-3 mRNA (p < 0.01) in CP samples compared with normal controls. In situ hybridization analysis of normal pancreas indicated low abundance of galectin-1 mRNA in fibroblasts, whereas galectin-3 mRNA was moderately present in ductal cells. CP samples exhibited moderate to intense galectin-1 mRNA signals in fibroblasts, whereas galectin-3 mRNA signals were intense in the cells of ductular complexes and weak in the degenerating acinar cells. In addition, intense galectin-1 and galectin-3 mRNA signals were present in nerves of normal and CP samples. Immunohistochemistry showed a distribution pattern of galectin-1 and galectin-3 similar to that described for in situ hybridization. Relative quantification of galectin-1 and galectin-3 protein by immunoblotting revealed an increase of 3.2-fold and 3.0-fold, respectively, in CP compared with normal controls. There was a significant correlation between galectin-1 and fibrosis and between galectin-3 and fibrosis and the density of ductular complexes. Up-regulation of galectin-1 in fibroblasts and galectin-3 in ductular complexes suggests a role of these lectins in tissue remodeling in CP. Galectin-1 might participate in ECM changes, whereas galectin-3 seems to be involved in both ECM changes and ductular complex formation.     

Microsatellite alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

A series of 20 hepatocellular carcinomas and 8 intrahepatic cholangiocarcinomas was screened from the Korean population for microsatellite alterations, including a loss of heterozygosity and replication errors using nine microsatellite markers containing several genes. The microsatellite results and our previous comparative genomic hybridization results of two tumors were compared at each locus, and the correlations between these and clinicopathologic variables were examined. The most characteristic findings were found at 13q. Replication errors were prevalent at D13S160 (13q21.2 approximately q31) and D13S292(13q12). The incidence of loss of heterozygosity, however, was higher at D13S153 (13q14.1 approximately q14.3) and D13S265(13q31 approximately q32). In contrast, there were higher deletion frequencies observed in hepatocellular carcinoma (HCC) and higher amplification frequencies observed in intrahepatic cholangiocarcinoma at 13q in our previous comparative genomic hybridization (CGH) study. Higher frequencies of replication errors were observed at D16S408 (13q12 approximately q21) and D16S504(13q23 approximately q24) in the HCC. This study found that significant differences in the patterns of genetic instability of microsatellites were dependent on the chromosomal loci. It is believed that certain genes at altered CGH regions, which are relevant to the development and/or progression of these cancers, are activated by different mutation mechanisms.     

Allelotype analysis of intrahepatic cholangiocarcinoma.

To identify the chromosomal loci of allelic loss in intrahepatic cholangiocarcinoma (ICC), we performed an allelotype study of 36 ICCs using 55 genome-wide microsatellite markers. Loss of heterozygosity was found most frequently on 8p (65.6%), 17p (64.7%), and 9p (64.5%), followed by 18q (54.2%), 1p (48.5%), 3p (44.8%), 9q (42.1%), 14q (41.7%), 6q (41.7%), and 1q (40.6%). The fractional allelic loss (FAL) values ranged from 0 to 0.731 (mean, 0.322). Analysis of the relationship between FAL values and clinicopathologic parameters disclosed significantly higher FAL values in moderately to poorly differentiated ICCs than in well-differentiated ones (P < .05). In summary, this study defined for the first time the overall number of chromosomes having allelic loss and the chromosomal arms and/or regions potentially involved in the development of ICC.     

细胞角蛋白19、galectin-3、HBME-1在甲状腺病变上的表达及鉴别诊断意义

目的 研究细胞角蛋白(CK)19、galectin(Gal)-3、HBME-1在甲状腺不同病变表达的特点及鉴别诊断中的应用价值。方法 应用免疫组织化学EnVision法检测了21例结节性甲状腺肿(结甲)、14例毒性甲状腺肿(甲亢)、15例甲状腺滤泡性腺瘤(腺瘤)、13例滤泡性癌、13例滤泡型乳头状癌及48例经典型乳头状癌中单克隆抗体CK19、Gal-3、HBME-1的表达。结果 甲状腺病变中3种标记表达均位于细胞质;CK19、Gal-3、HBME-1的表达在甲状腺良性病变(结甲、甲亢、腺瘤)大多为弱阳性或阴性,而滤泡性癌阳性明显增加、乳头状癌(滤泡型及经典型)大多为中、强阳性,3种标记在甲状腺不同病变的阳性表达率结甲为52．4％(11／21)、9．5％(2／21)、19．0％(4／21),甲亢为50．0％(7／14)、7．1％(1／14)、7．1％(1／14),腺瘤为60％(9／15)、13．3％(2／15)、13．3％(2／15),滤泡性癌为76．9％(10／13)、61．5％(8／13)、53．8％(7／13),滤泡型乳头状癌为：100％(13／13)、84．6％(11／13)、92．3％(12／13),经典型乳头状癌为100％(48／48)、93．8％(45／48)、95．8％(46／48);在甲状腺良性病变(结甲、甲亢、腺瘤)与恶性病变(滤泡性癌、乳头状癌)间3种标记差异均有显著性(P均=0．000);同时3种标记在滤泡样病变即腺瘤、滤泡性癌和滤泡型乳头状癌间亦有显著差异(CK19：P=0．038,Gal-3：P=0．001,HBME-1：P=0．000)。结甲有9例,甲亢有7例,腺瘤有6例3种标记均不表达,滤泡性癌仅有1例,而乳头状癌(滤泡型及经典型)没有病例3种标记均不表达,同一病例有2种以上阳性表达在结甲、甲亢、腺瘤、滤泡性癌、滤泡型乳头状癌和经典型乳头状癌中分别为14．2％(3／21)、21．4％(3／14)、20．0％(3／15)、69．2％(9／13)、92．3％(12／13)、100．0%(48／48),在甲状腺良性病变与恶性病变间以及滤泡样病变间差异亦有显著性(P=0．000)。结论 CK19、Gal-3、HBME-1的检测尤其是联合检测对甲状腺病变的诊断、鉴别诊断具有较高的实用价值。     

肝内及肝外胆管癌表达下调microRNAs表达谱的鉴定

目的筛选并鉴定肝内及肝外胆管癌组织表达下调的miRNAs,进行初步的功能研究。方法利用miRNA-基因芯片方法筛选肝内、肝外胆管癌组织特异表达下调或共同表达下调的miRNAs,选择real-time PCR方法进行验证;根据肝内及肝外胆管癌不同的下调miRNAs表达谱,选择差异明显且具有代表性的miRNAs,利用miRNA特异模拟物转染胆管癌细胞系QBC939,利用MTT试剂盒分析细胞增殖变化,研究表达下调miRNAs与胆管癌细胞增殖的关系。结果表达分析显示,肝外胆管癌组织特异表达下调的miRNAs共25个,肝内胆管癌组织特异表达下调的miRNAs共15个,在肝内及肝外胆管癌组织均表达下调的miRNAs共6个。在胆管癌细胞系QBC939中分别过表达miR-181a、miR-596、miR-492以及miR-602可以明显抑制细胞增殖。结论肝内及肝外胆管癌具有不同的miRNAs表达谱,表达下调的miRNAs可以明显抑制胆管癌细胞增殖。     

E-cadherin gene mutations in human intrahepatic cholangiocarcinoma

Deletions or mutations of the E-cadherin gene may result in reduced cell adhesiveness. In particular, conservative point mutations within the N-terminal calcium-binding pocket (including exons 7, 8, and 9) are frequently detected in several cancers and are enough to abolish cell-cell adhesion. There have been no studies on E-cadherin gene mutations in human intrahepatic cholangiocarcinoma (ICC). Human ICCs were therefore investigated for E-cadherin gene mutations within exons 7, 8, and 9. In addition, the relationships were analysed between their mutations and the immunohistochemical expression of E-cadherin, histological grade, and clinicopathological parameters. The E-cadherin gene was analysed in 34 tumours by nested polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) followed by DNA sequencing. In four of the 34 cases (11.8%), tumour-restricted mobility shifts were observed; two cases harboured a single shift, one case presented two different mobility shifts, and one case presented three different mobility shifts within exons 7 and 8, encoding extracellular domains of E-cadherin. Polymorphism as previously reported was not identified and all seven new DNA alterations were not present in genomic DNA of non-tumour origin. The E-cadherin gene mutations correlated significantly with down-regulated E-cadherin protein expression and high ICC histological grade. These data suggest that E-cadherin gene mutations in ICC are associated with reduced cell adhesiveness and high histological grade.     

The role of thymidine phosphorylase and thrombospondin-1 in angiogenesis and progression of intrahepatic cholangiocarcinoma

Thymidine phosphorylase (TP), an important regulator of angiogenesis, is correlated with progression, metastasis, and prognosis in various types of tumor. In contrast, both positive and negative effects of thrombospondin-1 (TSP-1) on angiogenesis have been reported. In the present study, we examined the expression of TP and TSP-1 in carcinoma cells in 67 primary intrahepatic cholangiocarcinomas (ICCs) immunohistochemically and its correlation with angiogenesis, clinicopathological features, and prognosis. Twenty-six (38.8%) cases were classified as exhibiting positive TP expression. TP expression showed a significant correlation with vascular invasion, lymphatic permeation, perineural invasion, and lymph node metastasis. Thirty-four (50.7%) cases were classified as exhibiting positive TSP-1 expression. TSP-1 expression was significantly correlated with only lymphatic permeation. The microvessel count in positive TP expression cases was significantly higher than that in negative cases. In contrast, the microvessel count in negative TSP-1 expression cases was significantly higher than that in positive cases. Survival in patients who were positive for both TP and TSP-1 expression was significantly poor. Our results suggest that the increased TP expression and decreased TSP-1 expression contribute to angiogenesis, but that the role of angiogenesis in ICC is not closely related to tumor aggressiveness. The TP and TSP-1 expression in ICC may enhance tumor aggressiveness.     

Differential expression of galectin-1 and galectin-3 in thyroid tumors. Potential diagnostic implications.

Carcinoma of the thyroid gland, the most frequently diagnosed endocrine malignancy, is often associated with early regional metastases. With the exception of papillary carcinoma, distinguishing benign from malignant thyroid neoplasms in the absence of metastatic disease is difficult. Recently, the vertebrate lectins galectin-1 and galectin-3 have been implicated in the regulation of cellular growth, differentiation, and malignant transformation of a variety of tissues. To determine whether these galectins have a role in thyroid neoplasia, we analyzed 32 specimens from thyroid malignancies (16 papillary, 7 follicular, 8 medullary carcinomas, and 1 metastasis to lymph node), 10 benign thyroid adenomas, 1 nodular goiter, and 33 specimens from adjacent normal thyroid tissue for the expression of galectin-1 and galectin-3 with immunohistochemical and immunoblotting techniques utilizing anti-galectin antibodies. All thyroid malignancies of epithelial origin (ie, papillary and follicular carcinomas) and a metastatic lymph node from a papillary carcinoma expressed high levels of both galectin-1 and galectin-3. The medullary thyroid carcinomas, which are of parafollicular C cell origin, showed a weaker and variable expression of these galectins. In contrast, neither benign thyroid adenomas nor adjacent normal thyroid tissue expressed galectin-1 or galectin-3. These results suggest that galectin-1 and galectin-3 may be associated with malignant transformation of thyroid epithelium and may potentially serve as markers for distinguishing benign thyroid adenomas from differentiated thyroid carcinomas.     

Genetic alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

In the following study, we used comparative genomic hybridization (CGH) to screen and compare for genetic alterations of hepatocellular carcinoma (HCC) and intrahepatic choalgiocarcinoma (ICC). The studies showed distinctive features of genetic alterations between the two tumors. Characteristic abnormal changes for HCC were 1q gain and loss of 4q, 10q and 13q regions. In contrast, gains of 5p, 7p, 13q and 20q were more predominant in ICC. Losses of 16q, 17p, and 18q, and gain of 8q region showed a similar high frequency of incidence in both tumors. The most striking and different findings were 1q amplification in HCC and 20q gain in ICC. Our data indicate that ICC shows the pattern of genetic alterations similar to pancreatic and colorectal cancers. This suggests that the genetic alterations in tumorigenesis show a similar pattern depending on the origin of cells, not the organ.     

Galecin-3在膜联蛋白A7表达抑制的HeLa细胞中的表达变化

目的探讨膜联蛋白A7(ANXA7)表达抑制的HeLa细胞galectin-3(gal-3)的表达改变。方法将细胞分为实验组、阴性对照组和空白对照组。采用RNA干扰技术将靶向ANXA7的siRNA和阴性对照siRNA脂质体2000转染法分别转染宫颈癌细胞系HeLa细胞,空白对照组不予任何处理。转染48h后采用Western blotting法和RT-PCR法分别在蛋白水平和mRNA水平进行抑制效果的鉴定。Western blotting和实时定量PCR法分别检测ANXA7表达抑制的HeLa细胞中galectin-3的表达改变。结果靶向ANXA7的siRNA可显著抑制ANXA7的表达;当ANXA7表达受抑后,galectin-3在HeLa细胞中的表达显著下降,与阴性对照组和空白对照组相比,差异有显著性(P0.05)。结论 ANXA7表达抑制的宫颈癌细胞系HeLa细胞中galectin-3的表达显著下调,这可能是ANXA7表达受抑的细胞行为学发生改变的机制之一。     

Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression

Aquaporin-1 (AQP-1) has been found to be important in bile formation across cell membranes of the biliary epithelium, and thus it has been suggested that AQP-1 is involved in the pathogenesis of hepatobiliary disease. To clarify the role of AQP-1 in the development of intrahepatic cholangiocarcinoma, we determined AQP-1 expression in the normal bile duct, 21 cases of biliary dysplasia, and in 112 cases of intrahepatic cholangiocarcinoma by immunohistochemical analysis. Mucus core protein 5AC expression, a poor prognostic marker of intrahepatic cholangiocarcinoma, was also assessed in intrahepatic cholangiocarcinoma cases. High (>50%) expression of AQP-1 was detected in 16% (9/58) of the normal large bile ducts examined, and in 48% (10/21) of the biliary dysplasia samples originating from large bile ducts. High (>50%), low (40 mm) and poorly differentiated histology were significantly more prevalent in the negative AQP-1 group than in the high AQP-1 group. Low or negative AQP-1 expression was associated with positive lymph node metastasis (P=.0001). AQP-1 expression was found to inversely correlate with that of mucus core protein 5AC, and their distributions tended to be complementary. The low and negative AQP-1 expression was an independent prognostic factor by multivariate survival analysis. We concluded that AQP-1 is up-regulated in biliary dysplasia, as compared with in the normal large bile duct, and down-regulation of AQP-1 is associated with mucin production and aggressive progression of intrahepatic cholangiocarcinoma.