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Iyer MK, Shi C, Eckhoff AM, Fletcher A, Nussbaum DP, Allen PJ. Digital spatial profiling of intraductal papillary mucinous neoplasms: Toward a molecular framework for risk stratification. SCIENCE ADVANCES 2023; 9:eade4582. [PMID: 36930707 PMCID: PMC10022906 DOI: 10.1126/sciadv.ade4582] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.
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Affiliation(s)
| | - Chanjuan Shi
- Department of Pathology, Duke University, Durham, NC, USA
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2
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Kaur S, Jain M, Batra SK. Liquid Biopsy for Identification of High-Risk Cystic Lesions of Pancreas. Gastroenterology 2021; 160:1016-1018. [PMID: 33385429 DOI: 10.1053/j.gastro.2020.12.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 12/28/2020] [Indexed: 12/02/2022]
Affiliation(s)
- Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology and, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
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Detlefsen S, Jakobsen M, Nielsen MFB, Klöppel G, Mortensen MB. Expression of CD117, CK17, CK20, MUC4, villin and mismatch repair deficiency in pancreatic intraductal papillary mucinous neoplasm. Pathol Res Pract 2020; 217:153312. [PMID: 33341087 DOI: 10.1016/j.prp.2020.153312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 12/28/2022]
Abstract
Among pancreatic intraductal papillary neoplasms, gastric, intestinal, and pancreatobiliary intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN) have been defined, differing regarding association with invasive carcinoma and prognosis. Immunohistochemistry (IHC) can help in the distinction of these neoplasms, but a proportion is unclassifiable using recommended markers. Hence, additional markers useful for the typing of pancreatic intraductal papillary neoplasms are needed. The reported frequencies of the different types of IPMNs in surgical series vary to some extent, and such data based on Danish patients are currently lacking. Besides, the role of mismatch repair (MMR) deficiency in these neoplasms has not been fully elucidated. We aimed to evaluate the frequency of different types of pancreatic intraductal papillary neoplasms in a Danish cohort. Furthermore, we aimed to examine the utility of CD117, CK17, CK20, MUC4, and villin as markers for their distinction, in addition to the recommended markers MUC1, MUC2, MUC5AC, MUC6 and CDX2, and to evaluate the frequency of MMR deficiency. We typed 40 consecutively resected pancreatic intraductal papillary neoplasms according to the WHO criteria from 2019. IHC for CD117, CDX2, CK17, CK20, MLH1, MSH2, MSH6, MUC1 (H23), MUC1 (Ma695), MUC2, MUC4, MUC5AC, MUC6, PMS2, and villin was performed and evaluated using a five-tiered semiquantitative scale. A subset of the tumours was examined with PCR for microsatellite instability (MSI). Most tumours were intestinal (40 %) and gastric (40 %) IPMNs, followed by pancreatobiliary (17 %) IPMNs and IOPN (3 %). All cases were MMR proficient. We found a higher expression of MUC4, CK20 and villin in intestinal compared to gastric IPMNs (p < 0.01, p < 0.001 and p < 0.001). MUC4 was more strongly expressed in intestinal compared to pancreatobiliary IPMNs, while the opposite was found for CK17 (p < 0.05 and p < 0.05). IOPN showed strong CD117 expression (score 4), while all gastric IPMNs were negative and 50 % and 29 % of intestinal and pancreatobiliary IPMNs only showed weak expression (score 1). Our data suggest that CK20, MUC4 and villin may aid in the identification of intestinal IPMNs, while CK17 and CD117 may aid in the identification of pancreatobiliary IPMNs and IOPN, in some cases. However, additional studies evaluating these markers in pancreatic intraductal papillary neoplasms are needed.
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Affiliation(s)
- Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark.
| | - Mark Jakobsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark
| | - Michael Friberg Bruun Nielsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | - Günter Klöppel
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Michael Bau Mortensen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark; Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark; Department of Surgery, HPB Section, Odense University Hospital, J.B. Winsløws Vej 4, 5000, Odense C, Denmark
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Carmicheal J, Patel A, Dalal V, Atri P, Dhaliwal AS, Wittel UA, Malafa MP, Talmon G, Swanson BJ, Singh S, Jain M, Kaur S, Batra SK. Elevating pancreatic cystic lesion stratification: Current and future pancreatic cancer biomarker(s). Biochim Biophys Acta Rev Cancer 2019; 1873:188318. [PMID: 31676330 DOI: 10.1016/j.bbcan.2019.188318] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/25/2019] [Accepted: 10/25/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incredibly deadly disease with a 5-year survival rate of 9%. The presence of pancreatic cystic lesions (PCLs) confers an increased likelihood of future pancreatic cancer in patients placing them in a high-risk category. Discerning concurrent malignancy and risk of future PCL progression to cancer must be carefully and accurately determined to improve survival outcomes and avoid unnecessary morbidity of pancreatic resection. Unfortunately, current image-based guidelines are inadequate to distinguish benign from malignant lesions. There continues to be a need for accurate molecular and imaging biomarker(s) capable of identifying malignant PCLs and predicting the malignant potential of PCLs to enable risk stratification and effective intervention management. This review provides an update on the current status of biomarkers from pancreatic cystic fluid, pancreatic juice, and seromic molecular analyses and discusses the potential of radiomics for differentiating PCLs harboring cancer from those that do not.
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Affiliation(s)
- Joseph Carmicheal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Asish Patel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vipin Dalal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Amaninder S Dhaliwal
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Uwe A Wittel
- Department of General- and Visceral Surgery, University of Freiburg Medical Center, Faculty of Medicine, Freiburg, Germany
| | - Mokenge P Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Geoffrey Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Benjamin J Swanson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shailender Singh
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Etekpo A, Alghawalby A, Alghawalby M, Soliman AS, Hablas A, Chen B, Batra S, Soliman GA. Differences in MUC4 Expression in Pancreatic Cancers and Pancreatic Cysts in Egypt. ACTA ACUST UNITED AC 2018; 9. [PMID: 34164227 PMCID: PMC8218782 DOI: 10.4172/2157-2518.1000312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is the fourth cause of cancer deaths in the U.S. with most patients diagnosed at advanced stages followed by short survival. Therefore, biomarkers for early detection are urgently needed. Mucin 4 (MUC4) is a mucin protein encoded by the MUC4 gene and identified in the majority of pancreatic cancers. With increasing clinical identification and diagnosis of pancreatic cysts globally and transformation of some cysts into pancreatic cancer, it is important to evaluate if MUC4 is expressed in pancreatic cysts. Immunohistochemistry assays utilizing heat-induced epitope retrieval (HIER) were performed to examine MUC4 protein expression in 44 paraffin-embedded tissues of pancreatic cancers and 20 pancreatic cysts. All patients were diagnosed and operated upon at the Mansoura University Gastrointestinal Surgery Center in Egypt. Clinical, demographic, and survival information were abstracted from the patients’ medical records. Logistic regression was performed to predict expression of MUC4 protein in cancer and cysts, by type of cysts. Pancreatic cyst patients were significantly younger than pancreatic cancer patients (Mean age of 28.7 ± 5.25 vs. 54.84 ± 10.60 years) (p=0.0001). Expression of MUC4 was not different between cancers and pancreatic cysts (p=0.16). However, type of pancreatic cysts was predictive of MUC4 expression. Mucinous cystic neoplasms and serous cystadenoma cysts showed significantly higher MUC4 expression than non-specified and pseudocysts (80%, 75%, 25%, and 0% expression for the 4 types of cysts, respectively) (p=0.022). MUC4 expression may be associated with certain types of cysts. Follow-up of pancreatic cyst patients who show MUC4 expression might reveal clues to early detection of pancreatic cancer.
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Affiliation(s)
- Asserewou Etekpo
- Department of Epidemiology, University of Nebraska Medical Center, College of Public Health, Omaha Nebraska, USA
| | - Ahmad Alghawalby
- Department of Radiotherapy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Marwa Alghawalby
- Department of Radiotherapy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Amr S Soliman
- Department of Community Health and Social Medicine, School of Medicine, City University of New York, New York, USA
| | | | - Baojiang Chen
- Department of Biostatistics, University of Nebraska Medical Center, College of Public Health, Omaha, Nebraska, USA
| | - Surinder Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha Nebraska, USA
| | - Ghada A Soliman
- Department of Environmental, Occupational, and Geospatial Health Sciences, Graduate School of Public Health and Health Policy, City University of New York, New York, USA.,Advanced Science Research Center, City University of New York, New York, USA
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Chang YR, Park T, Park SH, Kim YK, Lee KB, Kim SW, Jang JY. Prognostic significance of E-cadherin and ZEB1 expression in intraductal papillary mucinous neoplasm. Oncotarget 2017; 9:306-320. [PMID: 29416615 PMCID: PMC5787467 DOI: 10.18632/oncotarget.23012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023] Open
Abstract
There is an urgent need to investigate the genetic changes that occur in intraductal papillary mucinous neoplasm (IPMN), which is a well-known precursor of pancreatic cancer. In this study, gene expression profiling was performed by removing unwanted variation to determine the differentially expressed genes (DEGs) associated with malignant progression of IPMN. Among the identified DEGs, zinc finger E-box binding homeobox 1 (ZEB1) and E-cadherin, a crucial regulator of epithelial-to-mesenchymal transition (EMT), was validated among identified DEGs. A total of 76 fresh-frozen tissues were used for gene expression profiling and formalin-fixed, paraffin-embedded blocks from 87 patients were obtained for immunohistochemical analysis. Loss of E-cadherin expression (p = 0.023, odd ratio [OR] = 4.923) and expression of ZEB1 in stromal cells (stromal ZEB1, p < 0.001, OR = 26.800) were significantly correlated with degree of dysplasia. The hazard of death was significantly increased in patients with loss of E-cadherin expression (hazard ratio [HR] = 13.718, p = 0.004), expression of epithelial ZEB1 (HR = 19.117, p = 0.001), and stromal ZEB1 (HR = 6.373, p = 0.043). Based on the results of this study, loss of E-cadherin and expression of stromal ZEB1 are associated with increased risk of malignant progression. Epithelial and stromal ZEB1, as well as E-cadherin may be strong predictors of survival in patients with IPMN. Our finding suggests that these EMT markers may be utilized as potential prognosticators and may be used to improve and personalize treatment of IPMN.
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Affiliation(s)
- Ye Rim Chang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Dankook University College of Medicine, Cheonan, Korea
| | - Taesung Park
- Department of Statistics, Seoul National University College of Natural Sciences, Seoul, Korea
| | - Sung Hyo Park
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Kang Kim
- Department of Statistics, Seoul National University College of Natural Sciences, Seoul, Korea
| | - Kyoung Bun Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Niv Y. Mucin expression and the pancreas: A systematic review and meta-analysis. World J Meta-Anal 2017; 5:63-70. [DOI: 10.13105/wjma.v5.i2.63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 02/17/2017] [Accepted: 03/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess mucin expression in pancreatic premalignant and malignant states, and to establish its role as a prognostic marker.
METHODS English Medical literature searches were conducted for “mucin” and “pancreas”. Observational studies were included. Meta-analysis was performed by using Comprehensive meta-analysis software. Pooled odds ratios and 95%CIs were calculated.
RESULTS Out of 949 eligible papers we found 20 according to the inclusion criteria, including 4262 patients, published till May 31, 2016. Mucin expression increased in pancreatic lesions with OR 10.206 (95%CI: 4.781-21.781, P < 0.0001). Measure of heterogeneity was high: Q = 296.973, df (Q) = 55.00, I2 = 81.48%. We found a significant increase in the expression of MUC2, MUC4 and MUC5AC, 13.39, 118.43 and 13.91 times respectively, in pancreatic lesion in comparison with normal pancreatic tissue, and decreased expression of MUC5B.
CONCLUSION Mucin expression may serve as prognostic marker for transformation of intraductal papillary mucinous neoplasms to ductal adenocarcinoma, for aggressiveness of the pancreatic tumor, and as targets for potential therapy.
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Tinsley S, Wilkinson EJ, Fowler LJ. A study to improve the identification of pancreatobiliary adenocarcinoma utilizing fine-needle aspiration cytology and immunohistochemical application for KOC and S100P. J Am Soc Cytopathol 2016; 5:116-121. [PMID: 31042491 DOI: 10.1016/j.jasc.2015.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 10/20/2015] [Accepted: 10/23/2015] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The identification of pancreatic adenocarcinoma by fine-needle aspiration (FNA) cytology is a difficult, yet critical, task. This study uses a panel of two immunohistochemical (IHC) markers, KOC and S100P, to augment the interpretation of pancreatic adenocarcinoma using cytopathology specimens and to compare these to corresponding surgical specimens. MATERIALS AND METHODS We retrospectively reviewed 33 surgical specimens with pancreatic adenocarcinoma and 33 corresponding, preceding FNA cytology specimens. IHC studies for KOC and S100P were performed on both the surgical specimens and cytology cell blocks. Three pathologists reviewed the staining intensity and amount of tumor cell staining within these blocks. The findings were then analyzed for sensitivity, specificity, and combined sensitivity and specificity for the 2 markers. RESULTS KOC performed similarly to S100P in sensitivity for surgical specimens (90.9% for both) and better for FNA specimens (92.3% versus 82.7%, respectively). The specificity of KOC was significantly better than S100P for surgical and FNA specimens (100% for KOC in both specimens versus 72.7% and 89.7% for S100P in both specimens, respectively). The combined sensitivity of the panel of KOC and S100P was 99.2% for surgical specimens and 98.7% for FNA specimens. The combined specificity was 72.7% for surgical specimens and 89.7% for FNA specimens. CONCLUSIONS We found using KOC and S100P on FNA cell block cytology specimens to be a useful adjunct for interpretation when an interpretation of atypical or suspicious for pancreatic ductal adenocarcinoma is being considered and there are atypical epithelial cell groups in the cell block.
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Affiliation(s)
- Sarah Tinsley
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida
| | - Edward J Wilkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.
| | - Larry J Fowler
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida
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Schmuck RB, de Carvalho-Fischer CV, Neumann C, Pratschke J, Bahra M. Distal bile duct carcinomas and pancreatic ductal adenocarcinomas: postulating a common tumor entity. Cancer Med 2015; 5:88-99. [PMID: 26645826 PMCID: PMC4708893 DOI: 10.1002/cam4.566] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 08/27/2015] [Accepted: 09/23/2015] [Indexed: 12/15/2022] Open
Abstract
The set definition of distal cholangiocarcinomas and adenocarcinomas of the pancreatic head is challenged by their close anatomical relation, similar growth pattern, and corresponding therapeutic outcome. They show a mutual development during embryologic organ formation and share phenotypic characteristics. This review will highlight the similarities with regard to the common origin of their primary organs, histopathological similarities, and modern clinical management. Thus, we propose to subsume those entities under a common superfamily.
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Affiliation(s)
- Rosa B Schmuck
- General, Visceral and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Christopher Neumann
- General, Visceral and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- General, Visceral and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marcus Bahra
- General, Visceral and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Brosens LAA, Hackeng WM, Offerhaus GJ, Hruban RH, Wood LD. Pancreatic adenocarcinoma pathology: changing "landscape". J Gastrointest Oncol 2015; 6:358-74. [PMID: 26261723 DOI: 10.3978/j.issn.2078-6891.2015.032] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/22/2015] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.
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Affiliation(s)
- Lodewijk A A Brosens
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Wenzel M Hackeng
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - G Johan Offerhaus
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Ralph H Hruban
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Laura D Wood
- 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma. Pancreas 2015; 44:728-34. [PMID: 25906442 PMCID: PMC4464972 DOI: 10.1097/mpa.0000000000000362] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). METHODS Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features. RESULTS The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002). CONCLUSIONS Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.
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12
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Macha MA, Rachagani S, Pai P, Gupta S, Lydiatt WM, Smith RB, Johansson SL, Lele SM, Kakar SS, Lee JH, Meza J, Ganti AK, Jain M, Batra SK. MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. Oncogene 2015; 34:1698-708. [PMID: 24747969 PMCID: PMC4205229 DOI: 10.1038/onc.2014.102] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 03/10/2014] [Accepted: 03/17/2014] [Indexed: 12/13/2022]
Abstract
The limited effectiveness of therapy for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However, its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. This study revealed a significant upregulation of MUC4 in 78% (68/87) of HNSCC tissues compared with 10% positivity (1/10) in benign samples (P=0.006, odds ratio (95% confidence interval)=10.74 (2.0-57.56). MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated β-galactosidase (SA-β-Gal)-positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2. This resulted in decreased histone acetylation (H3K9) at cyclin E promoter leading to its downregulation. Orthotopic implantation of MUC4 KD SCC1 cells into the floor of the mouth in nude mice resulted in the formation of significantly smaller tumors (170±18.30 mg) compared to those (375±17.29 mg) formed by control cells (P=0.00007). In conclusion, our findings showed that MUC4 overexpression has a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.
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Affiliation(s)
- Muzafar A. Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Priya Pai
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Suprit Gupta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Williams M. Lydiatt
- Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Russell B. Smith
- Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Sonny L. Johansson
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Subodh M. Lele
- Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Sham S. Kakar
- Department of Physiology and Biophysics, University of Louisville, KY 40208
| | - John H. Lee
- Sanford ENT-Head and Neck Surgery, Sanford Cancer Research Center, Sioux Falls SD 57104-0589
| | - Jane Meza
- College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198
| | - Apar K. Ganti
- Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198
- Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198
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Klöppel G, Basturk O, Schlitter AM, Konukiewitz B, Esposito I. Intraductal neoplasms of the pancreas. Semin Diagn Pathol 2014; 31:452-466. [DOI: 10.1053/j.semdp.2014.08.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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14
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Paini M, Crippa S, Partelli S, Scopelliti F, Tamburrino D, Baldoni A, Falconi M. Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas. World J Gastroenterol 2014; 20:10008-10023. [PMID: 25110429 PMCID: PMC4123331 DOI: 10.3748/wjg.v20.i29.10008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Since the first description of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in the eighties, their identification has dramatically increased in the last decades, hand to hand with the improvements in diagnostic imaging and sampling techniques for the study of pancreatic diseases. However, the heterogeneity of IPMNs and their malignant potential make difficult the management of these lesions. The objective of this review is to identify the molecular characteristics of IPMNs in order to recognize potential markers for the discrimination of more aggressive IPMNs requiring surgical resection from benign IPMNs that could be observed. We briefly summarize recent research findings on the genetics and epigenetics of intraductal papillary mucinous neoplasms, identifying some genes, molecular mechanisms and cellular signaling pathways correlated to the pathogenesis of IPMNs and their progression to malignancy. The knowledge of molecular biology of IPMNs has impressively developed over the last few years. A great amount of genes functioning as oncogenes or tumor suppressor genes have been identified, in pancreatic juice or in blood or in the samples from the pancreatic resections, but further researches are required to use these informations for clinical intent, in order to better define the natural history of these diseases and to improve their management.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/classification
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Papillary/classification
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Carcinoma, Papillary/pathology
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genetic Testing
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/classification
- Neoplasms, Cystic, Mucinous, and Serous/genetics
- Neoplasms, Cystic, Mucinous, and Serous/metabolism
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreatic Neoplasms/classification
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Phenotype
- Predictive Value of Tests
- Signal Transduction
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15
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Kamikawa Y, Kanmura Y, Hamada T, Yamada N, Macha MA, Batra SK, Higashi M, Yonezawa S, Sugihara K. Combination of MUC1 and MUC4 expression predicts clinical outcome in patients with oral squamous cell carcinoma. Int J Clin Oncol 2014; 20:298-307. [PMID: 24909613 DOI: 10.1007/s10147-014-0710-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/12/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Both MUC1 and MUC4 are high molecular weight glycoproteins and are independent indicators of worse prognosis in many human epithelial cancers including oral squamous cell carcinoma (OSCC). However, there has been no investigation of the clinical importance of the co-expression of MUC1 and MUC4 in OSCC. The aim of this study was to evaluate the co-expression profile of MUC1/MUC4 and analyze the prognostic significance in OSCC. METHODS We examined the expression profile of MUC1 and MUC4 in OSCC tissues from 206 patients using immunohistochemistry. The co-expression profile of MUC1/MUC4 and its prognostic significance in OSCC was statistically analyzed. RESULTS MUC1 and MUC4 overexpression were strongly correlated with each other (p < 0.0001) and a combination of both MUC1 and MUC4 expression was a powerful indicator for tumor aggressiveness such as tumor size (p = 0.014), lymph node metastasis (0.0001), tumor stage (p = 0.006), diffuse invasion (p = 0.028), and vascular invasion (p = 0.014). The MUC1/MUC4 double-positive patients showed the poorest overall and disease-free survival. Multivariate analysis revealed that MUC1/MUC4 double-positivity was the strong independent prognostic factor for overall and disease-free survival (p = 0.007 and (p = 0.0019), in addition to regional recurrence (p = 0.0025). CONCLUSIONS Taken together, these observations indicate that the use of a combination of MUC1/MUC4 can predict outcomes for patients with OSCC. This combination is also a useful marker for predicting regional recurrence. MUC1 and MUC4 may be attractive targets for the selection of treatment methods in OSCC.
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Affiliation(s)
- Yoshiaki Kamikawa
- Department of Oral Surgery, Kagoshima University Hospital, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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16
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Yokoyama S, Kitamoto S, Higashi M, Goto Y, Hara T, Ikebe D, Yamaguchi T, Arisaka Y, Niihara T, Nishimata H, Tanaka S, Takaori K, Batra SK, Yonezawa S. Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice. PLoS One 2014; 9:e93760. [PMID: 24714692 PMCID: PMC3979708 DOI: 10.1371/journal.pone.0093760] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/06/2014] [Indexed: 12/19/2022] Open
Abstract
Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.
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Affiliation(s)
- Seiya Yokoyama
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Sho Kitamoto
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Michiyo Higashi
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Yuko Goto
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
| | - Taro Hara
- Division of Endoscopy, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Dai Ikebe
- Division of Surgical Pathology, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Taketo Yamaguchi
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Chiba, Japan
| | - Yoshifumi Arisaka
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Toru Niihara
- Division of Gastroenterology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Hiroto Nishimata
- Division of Gastroenterology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Sadao Tanaka
- Division of Surgical Pathology, Nanpuh Hospital, Kagoshima, Kagoshima, Japan
| | - Kyoichi Takaori
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Kyoto, Japan
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Suguru Yonezawa
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima, Japan
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Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BIOMED RESEARCH INTERNATIONAL 2014; 2014:474905. [PMID: 24783207 PMCID: PMC3982269 DOI: 10.1155/2014/474905] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 02/08/2014] [Accepted: 02/10/2014] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
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MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression. Neurosci Lett 2014; 566:82-7. [PMID: 24582898 DOI: 10.1016/j.neulet.2014.02.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 02/09/2014] [Accepted: 02/18/2014] [Indexed: 01/03/2023]
Abstract
Glioblastoma (GBM), the most common primary brain tumor, is the leading cause of deaths related to tumors in the central nervous system. The prognosis of GBM patients is currently poor, and the mechanisms underlying GBM genesis remain unclear. The expression of MUC4, a high-molecular-weight and highly glycosylated protein, has been studied in many cancers. However, information on MUC4 expression in GBM is limited. In this study, we found that MUC4 was overexpressed in GBM cell lines and tissues. The proliferation and invasive potential of GBM cells were significantly increased by the ectopic expression of MUC4. By contrast, RNA interference targeting MUC4 in GBM cells significantly decreased the proliferation and invasive potential of GBM cells. We also found that the expression of epidermal growth factor receptor (EGFR) was modulated by MUC4. EGFR inhibition by siRNA reversed the MUC4-induced proliferation and invasion. These results indicated that MUC4 expression in GBM was important in GBM cell proliferation and invasion, which may be partly associated with EGFR overexpression.
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