MUC16 facilitates cervical cancer progression via JAK2/STAT3 phosphorylation‑mediated cyclooxygenase‑2 expression

Hui Shen,Meng Guo,Lu Wang,Xinyue Cui 한국유전학회 2020 Genes & Genomics Vol.42 No.2

Objectives MUC16 (mucin 16, also known as CA-125, cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) has been predicted as tumor biomarker for therapy. We determined to investigate effects and regulatory mechanism of MUC16 on cervical tumorigenesis. Methods Expression levels of MUC16 in cervical cancer cell lines was analyzed via qRT-PCR (quantitative real-time polymerase chain reaction). Knockdown of MUC16 was conducted via shRNA (Short hairpin RNA) transfection. MTT and colony formation assays were used to investigate effect of MUC16 on cell proliferation. Wound healing assay was utilized to detect migration and transwell assay to detect invasion. The underlying mechanism was demonstrated via western blot analysis. Results MUC16 was elevated in cervical cancer cell lines. MUC16 knockdown inhibited cell proliferation, invasion and migration. Gain- and loss-of functional assays revealed that over-expression of MUC16 activated Janus Kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) via phosphorylation, thus facilitating cyclooxygenase-2 (COX-2) expression, while knockdown of MUC16 demonstrated the reverse effect on JAK2/STAT3 activation and COX-2 expression. Moreover, inhibition of JAK2/STAT3 attenuated the regulation of MUC16 on COX-2. Conclusions MUC16 enhanced proliferation and invasion of cervical cancer cells via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression, suggesting the potential therapeutic target ability of MUC16 to treat cervical cancer.

AP2α is essential for MUC8 gene expression in human airway epithelial cells

Moon, Uk Yeol,Kim, Chang-Hoon,Choi, Jae Young,Kim, Yoon-Ju,Choi, Yeon Ho,Yoon, Ho-Geun,Kim, Hyeyoung,Yoon, Joo-Heon Wiley Subscription Services, Inc., A Wiley Company 2010 Journal of cellular biochemistry Vol.110 No.6

<P>Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein-2alpha (AP2α) in human nasal polyp epithelium. We hypothesized that AP2α overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12-myristate 13-acetate (PMA) treatment of the airway epithelial cell line NCI-H292 increases MUC8 gene and AP2α expression. In this study, we sought to determine which signal pathway is involved in PMA-induced MUC8 gene expression. The results show that the protein kinase C and mitogen-activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO-31-8220 or PKC siRNA significantly suppress AP2α as well as MUC8 gene expression in PMA-treated cells. To verify the role of AP2α, we specifically knocked down AP2α expression with siRNA. A significant AP2α knock-down inhibited PMA-induced MUC8 gene expression. While dominant negative AP2α decreased PMA-induced MUC8 gene expression, overexpressing wildtype AP2α increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2α in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2α activation in human airway epithelial cells. J. Cell. Biochem. 110: 1386–1398, 2010. © 2010 Wiley-Liss, Inc.</P>

위선암에서 MUC2 및 MUC5AC 발현의 임상적 의의

박승배(Sung Bae Park),김대중(Dae Joong Kim),김용석(Yong Seok Kim),김범규(Beom Gyu Kim),지경천(Kyung Choun Chi),임현묵(Hyun Muck Lim),노재형(Jae Hyung Noh),손태성(Tae Sung Sohn),김성(Sung Kim) 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.74 No.3

Purpose: We examined the clinical significance of MUC2 and MUC5AC gene expression in gastric adeno-carcinoma tissues. Methods: Two hundred specimens were obtained from gastric carcinoma patients who underwent gastric cancer operations at Samsung Medical Center between January 2001 and January 2005. MUC2 and MUC5AC expression were examined immunohistochemically, and correlated with clinicopathologic features and prognostic significance. Results: MUC2 expression was positive in 88 tissues (44.0%) and MUC5AC expression was positive in 125 tissues (62.5%). MUC2 expression was associated with cancer advancement, lymph node metastasis, T classification, distant metastasis, and endolymphatic invasion. Loss of MUC5AC expression was significantly related to cancer advancement, lymph node metastasis, advanced T stage, and distant metastasis. MUC2 expression was usually negative in early gastric cancer (78%), but usually positive in advanced gastric cancer (66%). MUC5AC was usually positive in early gastric cancer (74%). The prognosis of the MUC2(-) group was significantly better than the MUC2(+) group (P<0.001). There was no relationship with MUC5AC expression and survival. Multivariate analysis showed that T classification, lymph node metastasis, distant metastasis, endolymphatic invasion, and MUC2 expression were independent prognostic factors, but MUC5AC expression was not. Conclusion: MUC2 and MUC5AC expression correlated with several clinicopathologic parameters (cancer advancement, lymph node metastasis, advanced T classification, distant metastasis). MUC2 expression was a significant independent prognostic factor and positive MUC2 expression suggested poor prognosis. MUC2 expression may have prognostic significance in gastric adeno-carcinomas.

MUC2 Expression Is Correlated with Tumor Differentiation and Inhibits Tumor Invasion in Gastric Carcinomas: A Systematic Review and Meta-analysis

표정수,손진희,강구현,김동훈,김경은,도인구,김동현 대한병리학회 2015 Journal of Pathology and Translational Medicine Vol.49 No.3

Background: While MUC2 is expressed in intestinal metaplasia and malignant lesions, the clinicopathological significance of MUC2 expression is not fully elucidated in gastric carcinoma (GC). Methods: The present study investigated the correlation between MUC2 expression and clinicopathological parameters in 167 human GCs. In addition, to confirm the clinicopathological significance of MUC2 expression, we performed a systematic review and meta-analysis in 1,832 GCs. Results: MUC2 expression was found in 58 of 167 GCs (34.7%). MUC2-expressing GC showed lower primary tumor (T), regional lymph node (N), and tumor node metastasis (TNM) stages compared with GCs without MUC2 expression (p = .001, p = .001, and p = .011, respectively). However, MUC2 expression was not correlated with Lauren’s classification and tumor differentiation. In meta-analysis, MUC2 expression was significantly correlated with differentiation and lower tumor stage (odds ratio [OR], 1.303; 95% confidence interval [CI], 1.020 to 1.664; p = .034 and OR, 1.352; 95% CI, 1.055 to 1.734; p = .017, respectively) but not with Lauren’s classification, pN stage, or pTNM stage. Conclusions: MUC2 expression was correlated with a lower tumor depth and lower lymph node metastasis in our study; the meta-analysis showed a correlation of MUC2 expression with tumor differentiation and lower tumor depth.

인체 호흡기상피세포에서 Interleukin-1β에 의한 MUC2 유전자 및 단백 발현

김용대,권은진,조중석,이재억,우현재,최경종,송시연,윤석근,백석환 대한이비인후과학회 2002 대한이비인후과학회지 두경부외과학 Vol.45 No.1

Background and Objectives:Mucin secretion is regulated by the mucin genes (MUC) in the respiratory, gastrointestinal and reproductive system. Inflammation induces mucin hypersecretion in the human body. This study demonstrates the efects of IL-1βMaterials and Method:Analysis of MUC2 gene was done by RT-PCR and the protein analysis was done by a flow cyto-metric analysis and an immunoasay method using cultured human airway epithelial cells, and NCI-H292 cells. Results:The expresion of MUC2 mRNA and protein induced by IL-1β increased in a dose-and time-dependent maner. The maxi-mum mRNA level of the MUC2 gene was approximately 3-fold, compared to that of the control cell. The IL-1β-mediated MUC2 protein started at 6 hours of exposure to IL-1β (20 ng/ml) and the maximum level was 12 hours. The MUC2 protein data of flow cytometric analysis coresponded to that of immunoassay analysis. The expresion of MUC2 gene was suppr-esed by actinomycin D, but not attenuated by cycloheximide. Conclusion:These results suggest that the IL-1β-mediated MUC2 gene and protein expresion were increased in a dose- and time-dependent pattern and regulated by transcriptional step. (Korean J Otolaryngol 2002;45:35-40)

Rare minisatellite alleles of MUC2-MS8 influence susceptibility to rectal carcinoma

Seol So-Young,Yang Gi-Eun,Cho Yoon,Kim Min Chan,Choi Hong-Jo,Choi Yung Hyun,임선희 한국유전학회 2021 Genes & Genomics Vol.43 No.12

Background Previously, we identifed eight novel minisatellites in the MUC2, of which allelic variants in MUC2-MS6 were examined to infuence susceptibility to gastric cancer. However, studies on the susceptibility to gastrointestinal cancer of other minisatellites in the MUC2 region still remain unprogressive. Objective In this study, we investigated whether polymorphic variations in the MUC2-MS8 region are related to susceptibility to gastrointestinal cancer. Methods We assessed the association between MUC2-MS8 and gastrointestinal cancers by a case–control study with 1229 controls, 486 gastric cancer cases, 220 colon cancer cases and 278 rectal cancer cases. To investigate whether intronic minisatellites afect gene expression, various minisatellites were inserted into the luciferase-reporter vector and their expression levels were examined. We also examined the length of MUC2-MS8 alleles in blood and cancer tissue matching samples of 107 gastric cancer patients, 125 colon cancer patients, and 85 rectal cancer patients, and investigated whether the repeat sequence afects genome instability. Results A statistically signifcant association was identifed between rare MUC2-MS8 alleles and the occurrence of rectal cancer: odds ratio (OR), 6.66; 95% confdence interval (CI), 1.11–39.96; and P=0.0165. In the younger group (age,<55), rare alleles were signifcant associated with an increased risk of rectal cancer (odds ratio, 24.93 and P=0.0001). Suppression of expression was found in the reporter vector inserted with minisatellites, and loss of heterozygosity (LOH) of the MUC2- MS8 region was confrmed in cancer tissues of gastrointestinal cancer patients (0.8–5.9%). Conclusion Our results suggest that the rare alleles of MUC2-MS8 could be used to identify the risk of rectal cancer and that this repeat region is related to genomic instability.

위상피 이형성 병변과 장형 위암종에서 MUC1, MUC2 및 MUC5AC의 발현

김선택(Sung Taek Kim),한상영(Sang Young Han),최석렬(Seok Reyol Choi),김종성(Jong Seong Kim),정진숙(Jin Sook Jeong) 대한소화기학회 2000 대한소화기학회지 Vol.36 No.3

Background/Aims: The transition from intestinal metaplasia to adenocarcinoma is characterized by qualitative and quantitative alterations of mucin core peptides. The purposes of this study were to evaluate expression of mucin core peptides known as prognostic factors in gastric cancer and to investigate their usefulness in assessment of the progression from gastric epithelial dysplasia to intestinal-type gastric carcinoma. Methods: Immunohistochemical studies of 3 antigens associated with alteration of mucin glycoprotein (MUC1, MUC2, MUC5AC) were performed for 63 gastric carcinoma tissues (EGC: 23 cases, AGC: 40 cases) and 54 gastric epithelial dysplasia tissues obtained from January 1997 to December 1997 in Dong-A University Hospital. Results: Expressions of MUC1, MUC2 and MUC5AC peptides were significantly increased. Distribution and density of them were also significantly increased in progression from gastric dysplasia to advanced intestinal-type gastric cancer (p=0.001). The incidence of lymph node metastasis was significantly increased according to the increase in expression of MUC2 and MUC5AC peptides. The expression of MUC2 and MUC5AC peptides and extensive staining pattern of MUC1, MUC2 and MUC5AC peptides were more increased in carcinomas with deep invasion. Conclusions: These results suggest that the alterations in expression of the mucin peptides may be correlated with prognostic factors and can predict progression from gastric epithelial dysplasia to intestinal-type gastric cancer. (Kor J Gastroenterol 2000;36:348 - 360)

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)

Mometasone Furoate Suppresses PMA-Induced MUC-5AC and MUC-2 Production in Human Airway Epithelial Cells

( Orapan Poachanukoon ),( Sittichai Koontongkaew ),( Paopanga Monthanapisut ),( Napaporn Pattanacharoenchai ) 대한결핵 및 호흡기학회 2017 Tuberculosis and Respiratory Diseases Vol.80 No.1

Background: Mucus hypersecretion from airway epithelium is a characteristic feature of airway inflammatory diseases. Tumor necrosis factor α (TNF-α) regulates mucin synthesis. Glucocorticoids including mometasone fuorate (MF) have been used to attenuate airway inflammation. However, effects of MF on mucin production have not been reported. Methods: Effects of MF and budesonide (BUD) on the phorbol-12-myristate-13-acetate (PMA)-induction of mucin and TNF-α in human airway epithelial cells (NCI-H292) were investigated in the present study. Confluent NCI-H292 cells were pretreated with PMA (200 nM) for 2 hours. Subsequently, the cells were stimulated with MF (1-500 ng/mL) or BUD (21.5 ng/mL) for 8 hours. Dexamethasone (1 μg/mL) was used as the positive control. Real-time polymerase chain reaction was used to determine MUC2 and MUC5AC mRNA levels. The level of total mucin, MUC2, MUC5AC, and TNF-α in culture supernatants were measured using enzyme-linked immunosorbent assay. Results: MF and BUD significantly suppressed MUC2 and MUC5AC gene expression in PMA-stimulated NCI-H292 cells. The inhibitory effects of the two steroid drugs were also observed in the production of total mucin, MUC2 and MUC5AC proteins, and TNF-α. Conclusion: Our findings demonstrated that MF and BUD attenuated mucin and TNF-α production in PMA-induced human airway epithelial cells.

Expression and Regulation of Transcription Factor FoxA2 in Chronic Rhinosinusitis With and Without Nasal Polyps

Qing Luo,Jia Zhang,Hongtian Wang,Fenghong Chen,Xi Luo,Beiping Miao,Xingmei Wu,Renqiang Ma,Xiangqian Luo,Geng Xu,Jianbo Shi,Huabin Li 대한천식알레르기학회 2015 Allergy, Asthma & Immunology Research Vol.7 No.5

Purpose: Chronic rhinosinusitis (CRS) is characterized by the excessive production of mucus. However, the molecular mechanism underlying mucin overproduction in CRS with or without nasal polyps (CRSwNP and CRSsNP, respectively) is poorly understood. This study was conducted to assess the importance of the transcription factor FoxA2 in mucin production and to investigate the targeting of FoxA2 as a potential therapeutic strategy for mucus hypersecretion in CRS patients. Methods: We enrolled 15 CRSwNP patients, 15 CRSsNP patients, and 10 normal controls in this study. The expression levels of FoxA2, MUC5AC, and MUC5B in inflamed and healthy nasal tissues were examined via immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, and the levels of several proinflammatory cytokines in nasal secretions were measured via FlowCytomix analysis. In addition, the expression of MUC5AC and FoxA2 was determined in polyp-derived epithelial cells and NCI-H292 cells after in vitro stimulation. Results: FoxA2 was significantly down-regulated, and MUC5AC and MUC5B were significantly up-regulated in both the CRSwNP and CRSsNP patients compared to the controls (P<0.05), and the protein level of FoxA2 was negatively associated with the IL-6 level in the CRS patients (P<0.05). IL-6 significantly increased MUC5AC expression but inhibited FoxA2 expression in vitro (P<0.05). Transfection with a FoxA2 expression plasmid significantly decreased MUC5AC promoter activity (P<0.05) and inhibited IL-6-induced MUC5AC production (P<0.05). In addition, clarithromycin significantly alleviated IL-6-induced FoxA2 suppression and decreased MUC5AC expression in vitro (P<0.05). Conclusions: Our findings suggest that FoxA2 may be considered a therapeutic target for the modulation of mucus hypersecretion in CRS patients.