Expression of MUC1 and MUC4 and Its Prognostic Significance in Non-Small Cell Lung Carcinoma

권건영,전지민,이혜원,박지영,정혜라,황일선,권선영,최미선,강유나,김상표,이상숙,최원일 대한병리학회 2010 Journal of Pathology and Translational Medicine Vol.44 No.4

Background : Mucin (MUC)1 and MUC4 (MUC1, 4) are high molecular weight glycoproteins expressed in normal and malignant epithelial cells, and these expressions are related to the prognosis of some carcinomas. In non-small cell lung carcinoma (NSCLC), the relationship between MUC1, 4 expressions and their prognostic significance is not well known. We evaluated these relationships in a series of NSCLC: 1) between MUC1, 4 expression levels and histologic subtypes, and 2) between high expression of MUC1, 4 and their prognostic significance. Methods : We performed immunohistochemical staining for MUC1, 4 in paraffin-embedded tissues from 165 NSCLC cases arranged in a tissue microarray. Results : We found a significant correlation between MUC1, 4 expressions and NSCLC histologic subtypes (p < 0.05). High MUC1 expression was characteristic of adenocarcinoma. Low MUC1, 4 expressions were characteristic of squamous cell carcinoma. In adenocarcinoma, we found significant association between diffuse MUC1 expression and short patient survival (p = 0.005). In squamous cell carcinoma, diffuse MUC4 expression showed long patient survival trend (p = 0.128). Conclusions : MUC1, 4 expression levels were significantly correlated with NSCLC histologic subtypes. Diffuse MUC1 expression was significantly associated with shortened survival in NSCLC patients, especially in adenocarcinoma.

Airborne particulate matter increases MUC5AC expression by downregulating Claudin-1 expression in human airway cells

( Sang-su Kim ),( Cheol Hong Kim ),( Ji Wook Kim ),( Hsi Chiang Kung ),( Tae Woo Park ),( Yu Som Shin ),( Ju Deok Kim ),( Siejeong Ryu ),( Wang-joon Kim ),( Yung Hyun Choi ),( Kyoung Seob Song ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.10

CLB_2.0, a constituent of PM, induces secretion of multiple cytokines and chemokines that regulate airway inflammation. Specifically, IL-6 upregulates CLB_2.0-induced MUC5AC and MUC1 expression. Interestingly, of the tight junction proteins examined, claudin-1 expression was inhibited by CLB_2.0. While the overexpression of claudin-1 decreased CLB_2.0-induced MUC5AC expression, it increased the expression of the anti-inflammatory mucin, MUC1. CLB_2.0-induced IL-6 secretion was mediated by ROS. The ROS scavenger N-acetylcysteine inhibited CLB_2.0-induced IL-6 secretion, thereby decreasing the CLB_2.0-induced MUC5AC expression, whereas CLB_2.0-induced MUC1 expression increased. CLB_2.0 activated the ERK1/2 MAPK via a ROS-dependent pathway. ERK1/2 downregulated the claudin-1 and MUC1 expressions, whereas it dramatically increased CLB_2.0-induced MUC5AC expression. These findings suggest that CLB_2.0-induced ERK1/2 activation acts as a switch for regulating inflammatory conditions though a ROS-dependent pathway. Our data also suggest that secreted IL-6 regulates CLB_2.0-induced MUC5AC and MUC1 expression via ROS-mediated downregulation of claudin-1 expression to maintain mucus homeostasis in the airway. [BMB Reports 2017; 50(10): 516-521]

MUC1 from the Mucin Family as Potential Tools in Breast Cancer Immunotherapy

박흥규,U Hyoung Seo 한국유방암학회 2009 Journal of breast cancer Vol.12 No.3

Many breast cancer patients develop minimal residual disease that becomes resistance to treatments, and finally are faced with relapse and progression of disease. Currently, immunotherapy has become a potential therapy in treating minimal residual disease and preventing cancer occurrence. Cancer vaccines provide a unique therapeutic modality in that they initiate a dynamic process of activating the host’s own immune system. A lot of tumor specific antigens as a target of immune system were identified and some have been applied for cancer vaccine. Mucin 1 (MUC1) oncoprotein, which is overexpressed in breast cancer in contrast with normal mammary tissue, is one of the first tumor antigens shown to be a target for human tumor-specific T cells and thus a valid target for immunotherapy. MUC1 is a high-molecular-weight glycoprotein rich in serine and threonine residues that are O-glycosylated. MUC1 is expressed on glandular epithelia and on epithelial tumors. But, tumor MUC1 differs from normal MUC1 by modified glycan side chains. Over-expression and aberrant glycosylation of MUC1 antigen by epithelial tumors results in endogenous antibody responses in cancer patients to MUC1 antigen. This finding has led to the identification of MUC1 derived peptide epitopes that induce T-cell responses. MUC1 based clinical trials have used peptides, protein, DNA, pulsed dendritic cells, or glycopeptide. This review will summarize the potential utility of breast cancer immunotherapy of MUC1, as well as the structure and function.

Associations between the Expression of Mucins (MUC1, MUC2, MUC5AC, and MUC6) and Clinicopathologic Parameters of Human Breast Ductal Carcinomas

도성임,김경은,김동훈,채승완,박용래,박찬흔,손진희 한국유방암학회 2013 Journal of breast cancer Vol.16 No.2

Purpose: Mucins are members of the glycoprotein family expressed in benign and malignant epithelial cells. The aim of this study is to evaluate the relationships between the expression of mucins in breast ductal carcinoma and clinicopathologic parameters. Methods: We constructed tumor microarrays based on 240 cases of invasive ductal carcinoma and 40 cases of ductal carcinoma in situ (DCIS) using formalin fixed, paraffin embedded tissues. We examined the expressions of MUC1, MUC2, MUC 5AC, and MUC6 by immunohistochemistry. Results: MUC1 demonstrated cytoplasmic, membranous, apical, and combinative expressions. Other mucins demonstrated cytoplasmic expression. In invasive ductal carcinoma, MUC1, MUC2, MUC5AC, and MUC6 were expressed in 93.6%, 6.2%, 4.8%, and 12.4% of cases, respectively; these rates were slightly, but not significantly, higher than observed in cases of DCIS. MUC1 expression was associated with estrogen receptor (ER) expression and negative MUC1 expression was associated with triple negativity. MUC6 expression was correlated with higher histologic grade, lymphatic invasion, lymph node metastasis, and HER2 positivity. No associations with any other clinicopathologic parameters were observed. Conclusion: Most invasive ductal carcinomas of the breast express MUC1, and this expression is associated with ER expression. MUC6 expression is correlated with some clinicopathologic parameters that are indicators of poor prognosis. To evaluate the role of MUC6 as a potential biomarker, further studies are warranted.

Expression of MUC1 and MUC4 in Gallbladder Adenocarcinoma

김수미,허방,오선주 대한병리학회 2012 Journal of Pathology and Translational Medicine Vol.46 No.5

Background: Recent reports have indicated that overexpression of mucin (MUC) 1 and/or MUC4 correlates with the occurrence and progression of extra-hepatobiliary malignancy. In this study, we investigated the expression of MUC1 and MUC4 and their prognostic significance in gallbladder adenocarcinoma. Methods: We examined 54 surgical gallbladder adenocarcinoma samples by immunohistochemistry for MUC1 and MUC4 expression. Staining was evaluated as a sum score of extent and intensity, dividing the samples into low and high expression groups. Results: The low expression group for both MUC1 and MUC4 was 10 samples (18.5%), and the high expression group was 44 samples (81.5%). High MUC1 expression was significantly correlated with more differentiated tumors (p=0.033), whereas high expression of MUC4 correlated with negative nodal status (p=0.012). Other pathological features were not correlated with MUC expression. Multivariate cox regression analysis showed that neither MUC1 nor MUC4 expression correlated with survival. Conclusions: Although there were some correlations found, a prognostic role for either MUC1 or MUC4 expression in gallbladder carcinoma was not identified in this study. Further investigation is required.

호흡기 상피 암세포에서 PKC-ERK/p38-COX-2-PGE2의 활성화를 통한 Interleukin-1β에 의한 MUC5AC 점액유전자의 발현과 점액 생성

김용대,배창훈,우현재 대한이비인후과학회 2003 대한이비인후과학회지 두경부외과학 Vol.46 No.1

Background and Objectives:Mucus hypersecretion is a major problem in inflamatory airway disease. Interleukin-1β (β) has been implicated in the pathogenesis of inflammatory airway diseases. This study was designed to investigate the signal transduction mechanism and the relationship between cycloxygenase-2 (COX-2) expression and the IL-1β-mediated MUC5AC secretion. Materials and Method:In cultured human airway NCI-H292 epithelial cells, the IL-1β-mediated MUC5AC gene expression and mucin secretion were analyzed by reverse transcription-polymerase chain reaction and imunoasay. To identify the signal transduction pathway of the IL-1β-mediated MUC5AC expresion, we used specific inhibitors. Results:IL-1β in-duced COX-2 and MUC5AC expresion at the mRNA and protein levels. Mucin secretion was blocked by NS398 and resve-ratrol, selective COX-2 inhibitors. Prostaglandin E2 (PGE2) directly induced MUC5AC expresion at both mRNA and protein levels in a dose-dependent manner. Cells activated by IL-1β showed increased extracellular-regulated protein kinase (ERK) 1/2 β-induced MUC5AC gene expresion and mucin secretion were blocked by PD98059, the MEK/ ERK inhibitor and SB203580, the p38 inhibitor. Furthermore, inhibition of both mitogen-activated protein kinases (MAPKs) reduced the IL-1β-induced COX-2 expresion and PGE2 synthesis. Ro31-8220, the PKC inhibitors prevented the IL-1β-induced COX-2 expresion and mucin secretion. Also Ro31-8220 inhibited the IL-1β-mediated MAPKs phosphorylation. Conclusion:IL-1βp38-COX-2-PGE2 in the human airway NCI-H292 epithelial cels. (Korean J Otolaryngol 203 ;46 :27-34)

Common Genetic Variants of PSCA, MUC1 and PLCE1 Genes are not Associated with Colorectal Cancer

Kupcinskas, Juozas,Gyvyte, Ugne,Bruzaite, Indre,Leja, Marcis,Kupcinskaite-Noreikiene, Rita,Pauzas, Henrikas,Tamelis, Algimantas,Jonaitis, Laimas,Skieceviciene, Jurgita,Kiudelis, Gediminas Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Background: Polymorphisms of genes encoding PSCA, PLCE1 and MUC1 have been associated with the risk of different cancers in genome wide association studies (GWAS). Up to date there are limited data on the role of these genetic alterations in colorectal cancer (CRC) development. The aim of this study was to evaluate potential associations between single nucleotide polymorphisms (SNPs) of genes encoding PSCA, PLCE1 and MUC1 and the presence of CRC in European populations. Materials and Methods: Gene polymorphisms were analyzed in 574 European subjects (controls: n=382; CRC: n=192). PSCA C>T (rs2294008), PSCA G>A (rs2976392), MUC1 A>G (rs4072037) and PLCE1 A>G (rs2274223) SNPs were genotyped by RT-PCR. Results: The distribution of genotypes for all four SNPs was in line with the Hardy-Weinberg equilibrium (rs2294008, P=0.153; rs2976392, P=0.269; rs4072037, P=0.609; rs2274223, P=0.858). The distribution of genotypes and alleles of PSCA C>T, PSCA G>A, MUC1 A>G and PLCE1 A>G SNPs was similar among controls and CRC patient groups (P>0.05). GG genotype of MUC1 SNP was more frequent in CRC patients (24.0%) than in controls (20.2%); however, this association failed to reach significance (OR-1.45, P=0.15). Overall, in the present study SNPs of PSCA (rs2294008, rs2976392), MUC1 (rs4072037) and PLCE1 (rs2274223) genes were not associated with the presence of CRC. Conclusions: Gene polymorphisms of PSCA, PLCE1 and MUC1 genes are not associated with the presence of CRC in European subjects.

사람 호흡기 상피세포에서 Ginsenoside RB1이 TGF-β1로 유도된 MUC4/5AC 점액 유전자의 발현과 상피-중간엽 전이에 미치는 효과

최태영,김준희,조수연,이상재,나형균,최윤석,송시연,김용대,배창훈 대한이비인후과학회 2021 대한이비인후과학회지 두경부외과학 Vol.64 No.4

Background and Objectives Ginsenoside Rb1 is the main metabolite of Panax ginseng. Itis known to have many beneficial properties including anti-inflammatory, antitumoral and antioxidanteffects. However, the therapeutic effects of ginenoside Rb1 on inflammatory airwaydiseases have not been elucidated. Therefore, we investigated the effects of ginsenoside Rb1 onthe TGF-β1-induced mucin gene expression and epithelial-mesenchymal transition (EMT) inhuman airway epithelial cells. Materials and Method We evaluated the effects of ginsenoside Rb1 on the changes of MUC4,MUC5AC, occludin, claudin 4, claudin 18, neural (N)-cadherin, and epithelial (E)-cadherin expressionby TGF-β1 in NCI-H292 cells using reverse, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and western blot. Results TGF-β1 significantly increased MUC4/5AC expression. Rb1 inhibited TGF-β1- inducedMUC4/5AC expression. In addition, TGF-β1 significantly attenuated occludin, claudin 18,and E-cadherin expressions but induced claudin 4 and N-cadherin expressions. On the otherhand, Rb1 reversed changes in the TGF-β1- mediated expressions of cell junction molecules. Conclusion These results suggest that ginsenoside Rb1 attenuates TGF-β1-induced MUC4/5AC expressions and EMT in the human airway epithelial cells. These findings are importantdata demonstrating the potential of ginsenoside Rb1 as a therapeutic agent for inflammatoryairway diseases

식도의 원주상피 피복 점막에서 점액유전자 발현 및 세포증식능에 대한 연구

최석채 ( Suck Chei Choi ),김용성 ( Yong Sung Kim ),김기훈 ( Ki Hoon Kim ),김헌수 ( Hun Soo Kim ),조향정 ( Hyang Jeong Jo ),윤기중 ( Ki Jung Yun ) 대한소화기기능성질환·운동학회 2007 Journal of Neurogastroenterology and Motility (JNM Vol.13 No.1

목적 : 바렛식도는 지속적인 위식도역류 등으로 원위부 식도에 정상적으로 존재하는 편평상피세포 대신에 배상세포를 포함하는 장형 원주세포로 식도 점막이 피복되는 것을 말한다. 그리고 이형성을 거쳐 선암종으로 진행할 수 있기 때문에 이형성 이전 단계인 바렛식도의 발암과정에 대한 연구가 필요하다. 이에 바렛식도와 배상세포를 포함하지 않은 원주세포만 있는 식도를 대조군으로 하여 점액유전자 및 세포증식능에 대해 비교 연구하였다. 대상 및 방법 : 임상 및 내시경적으로 바렛식도가 의심되어 원위부 식도에서 생검한 환자들 중에서 배상세포가 있어 조직학적으로 바렛식도로 증명된 25명의 환자와 배상세포가 없었던 환자들 중에서 무작위로 선택한 30예를 대조군으로 하였다. 생검 당시의 나이와 성별 그리고 MUC1, MUC2, Ki-67에 대한 면역조직화학적 염색을 시행하였다. 결과 : 바렛식도의 평균 나이 및 남자 비율은 각각 65.3±10.1세, 76.0%이였고, 대조군의 평균 나이 및 남자 비율은 각각 53.0±14.8세, 60.0%로 바렛식도의 나이가 대조군식도보다 의의있게 높았다. MUC1은 바렛식도 및 대조군 모두에서 100% 발현되었고, MUC2 발현율은 바렛식도 및 대조군에서 각각 92%, 20%이었다. Ki-67 발현율은 바렛식도 및 대조군에서 각각 80.0%, 70.0%이였고, Ki-67 발현 강도의 평균은 바렛식도 1.20±0.76, 대조군 0.77±0.57로 발현 강도에서 바렛식도가 의의있게 높았다. 결론 : 바렛식도는 원주세포만 있는 식도에서 보다 좀더 지속적인 위식도역류 등의 자극으로 생긴다. 그리고 MUC2는 주로 바렛식도에서 발현되고 세포증식능은 바렛식도에서 좀더 높으며 이는 MUC2 발현과 관련될 수 있다고 생각된다. Background/Aims: Barrett`s esophagus is characterized by the presence of metaplastic columnar epithelium with goblet cells in the distal esophagus. Barrett`s esophagus progresses through low grade dysplasia and high grade dysplasia to adenocarcinoma. We studied the patient age, the mucin gene and the proliferation activity of biopsy-proven Barrett`s esophagus and simple columnar epithelium-lined esophagus. Methods: To evaluate the mucin gene expression and proliferation activity, twenty five cases of Barrett`s esophagus and thirty cases of control esophagus were examined immunohistochemically with using the monoclonal antibodies to MUC1, MUC2 and Ki-67. Results: The Barrett`s esophagus patients were older (mean: 65.3±10.1 years) than the control patients (mean: 53.0±14.8 years). The MUC1 expression was 100% in both Barrett`s esophagus and the control esophagus. An MUC2 expression was observed in 92.0% of the Barrett`s esophagus and 20.0% of the control esophagus. The rate and intensity of the Ki-67 expression was higher in the Barrett`s esophagus (80.0%, 1.20±0.76) than that in the control esophagus (70.0%, 0.77±0.57). Conclusions: Barrett`s esophagus is a metaplastic lesion due to the more long-standing gastroesophageal reflux than that in a simple columnar epithelium-lined esophagus. The cause of increased proliferation activity in Barrett`s esophagus may be related to the MUC2 expression. (Kor J Neurogastroenterol Motil 2007;13:21-25)

호흡기 상피세포에서 IL-1b에 의해 유발되는 MUC2/MUC5AC 유전자 발현 및 점액분비에 있어서 Budesonide의 억제작용

김용대,조중석,장근영,신재흔,송시연,윤석근 대한이비인후과학회 2002 대한이비인후과학회지 두경부외과학 Vol.45 No.9

Background and Objectives:Mucus hypersecretion is a hallmark of many respiratory inflammatory diseases such as asthma, bronchitis and sinusitis. While the current therapeutic pharmacological approaches to reducing mucus hypersecretion are limited, clinical studies have suggested that glucocorticoids reduce mucus secretion in patients with airway disease. However, the effect of glucocorticoids on mucus hypersecretion is not clear. Recently, we observed that IL-1β induces MUC2 gene expression and mucin secretion in a previous experiment. This study was designed to investigate the effects of budesonide on the IL-1β-mediated MUC2/5AC genes expression and mucin secretion. Materials and Method:We observed the steady state mRNA level of MUC2/5AC genes using RT-PCR and mucin protein using immunoassay method in cultured human airway NCI-H292 epithelial cells. Results:Budesonide attenuated IL-1β-mediated MUC2/5AC gene expression as well as mucin secretion. The attenuated effect of budesonide was in a dose-dependent pattern. This attenuated effect of budesonide was blocked by glucocorticoid receptor antagonist, RU-486. Conclusion:This result suggests that budesonide suppresses the IL-1β-mediated MUC2/5AC genes expression and mucin secretion via blockage of glucocorticoid receptor. (Korean J Otolaryngol 2002;45:873-7)