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1
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Erickson A, Jackson LR, Camphausen K, Krauze AV. Mucins as Precision Biomarkers in Glioma: Emerging Evidence for Their Potential in Biospecimen Analysis and Outcome Prediction. Biomedicines 2024; 12:2806. [PMID: 39767713 PMCID: PMC11673638 DOI: 10.3390/biomedicines12122806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/06/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Despite attempts at improving survival by employing novel therapies, progression in glioma is nearly universal. Precision biomarkers are critical to advancing outcomes; however, biomarkers for glioma are currently unknown. Most data on which the field can draw for biomarker identification comprise tissue-based analysis requiring the biospecimen to be removed from the tumor. Non-invasive specimen-based precision biomarkers are needed. Mucins are captured in tissue and blood and are increasingly studied in cancer, with several studies exploring their role as biomarkers to detect disease and monitor disease progression. CA125, also known as MUC16, is implemented as a biomarker in the clinic for ovarian cancer. Similarly, several mucins are membrane-bound, facilitating downstream signaling associated with tumor resistance and hallmarks of cancer. Evidence supports mucin expression in glioma cells with relationships to tumor detection, progression, resistance, and patient outcomes. The differential expression of mucins across tissues and organs could also provide a means of attributing signals measured in serum or plasma. In this review, we compiled existing research on mucins as candidate precision biomarkers in glioma, focusing on promising mucins in relationship to glioma and leading to a framework for mucin analysis in biospecimens as well as avenues for validation as data evolve.
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2
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Benson KK, Sheel A, Rahman S, Esnakula A, Manne A. Understanding the Clinical Significance of MUC5AC in Biliary Tract Cancers. Cancers (Basel) 2023; 15:cancers15020433. [PMID: 36672382 PMCID: PMC9856870 DOI: 10.3390/cancers15020433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Biliary tract cancers (BTC) arise from biliary epithelium and include cholangiocarcinomas or CCA (including intrahepatic (ICC) and extrahepatic (ECC)) and gallbladder cancers (GBC). They often have poor outcomes owing to limited treatment options, advanced presentations, frequent recurrence, and poor response to available systemic therapy. Mucin 5AC (MUC5AC) is rarely expressed in normal biliary epithelium, but can be upregulated in tissues of benign biliary disease, premalignant conditions (e.g., biliary intraepithelial neoplasia), and BTCs. This mucin's numerous glycoforms can be divided into less-glycosylated immature and heavily-glycosylated mature forms. Reported MUC5AC tissue expression in BTC varies widely, with some associations based on cancer location (e.g., perihilar vs. peripheral ICC). Study methods were variable regarding cancer subtypes, expression positivity thresholds, and MUC5AC glycoforms. MUC5AC can be detected in serum of BTC patients at high concentrations. The hesitancy in developing MUC5AC into a clinically useful biomarker in BTC management is due to variable evidence on the diagnostic and prognostic value. Concrete conclusions on tissue MUC5AC are difficult, but serum detection might be relevant for diagnosis and is associated with poor prognosis. Future studies are needed to further the understanding of the potential clinical value of MUC5AC in BTC, especially regarding predictive and therapeutic value.
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Affiliation(s)
- Katherine K. Benson
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Ankur Sheel
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Shafia Rahman
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Ashwini Esnakula
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +1-614-366-2982
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3
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Kinzler MN, Schulze F, Gretser S, Abedin N, Trojan J, Zeuzem S, Schnitzbauer AA, Walter D, Wild PJ, Bankov K. Expression of MUC16/CA125 Is Associated with Impaired Survival in Patients with Surgically Resected Cholangiocarcinoma. Cancers (Basel) 2022; 14:cancers14194703. [PMID: 36230626 PMCID: PMC9563928 DOI: 10.3390/cancers14194703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/23/2022] [Indexed: 11/24/2022] Open
Abstract
MUC16/CA125 is associated with cancer proliferation in several tumor entities. The data on MUC16 expression in cholangiocarcinoma (CCA) tissue are very limited. The aim of this study was to assess the MUC16 status and its impact on survival in CCA patients. All the patients with surgically resected CCA that were diagnosed between August 2005 and December 2021 at the University Hospital Frankfurt were retrospectively analyzed. A 7-Mucin biomarker panel was assessed by immunohistochemistry. For overall survival (OS), Kaplan−Meier curves and Cox-regression analyses were performed. Randomly selected intrahepatic cholangiocarcinoma (iCCA) were further processed for differential expression profiling. A total of 168 patients with CCA were classified as MUC16 (−) (66%, n = 111) and MUC16 (+) (34%, n = 57). Subgroup analyses revealed a median OS of 56.1 months (95% CI = 42.4−69.9 months) and 27.4 months (95% CI = 15.8−39.1 months) for MUC16 (−) and MUC16 (+), respectively (p < 0.001). In multivariate analysis, MUC16 (+) (HR = 1.6, 95% CI = 1−2.6, p = 0.032) was an independent risk factor for poor prognosis. Prominently deregulated pathways have been identified following MUC16 expression, overrepresented in cell cycle and immune system exhaustion processes. These findings suggest including MUC16 in clinical routine diagnostics as well as studying its molecular pathways to identify further mechanistic key players.
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Affiliation(s)
- Maximilian N. Kinzler
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
- Correspondence: ; Tel.: +49-69-6301-5297
| | - Falko Schulze
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Steffen Gretser
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Nada Abedin
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Jörg Trojan
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Andreas A. Schnitzbauer
- Department of General, Visceral, Transplant and Thoracic Surgery, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Dirk Walter
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Peter J. Wild
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
- Frankfurt Institute for Advanced Studies (FIAS), 60438 Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
| | - Katrin Bankov
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany
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4
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Brown ZJ, Patwardhan S, Bean J, Pawlik TM. Molecular diagnostics and biomarkers in cholangiocarcinoma. Surg Oncol 2022; 44:101851. [PMID: 36126350 DOI: 10.1016/j.suronc.2022.101851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/26/2022] [Accepted: 09/09/2022] [Indexed: 10/14/2022]
Abstract
Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.
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Affiliation(s)
- Zachary J Brown
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
| | - Satyajit Patwardhan
- Dept of HPB Surgery and Liver Transplantation, Global Hospital, Mumbai, India
| | - Joal Bean
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The State Wexner Medical Center, Columbus, OH, USA.
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5
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Boonnate P, Vaeteewoottacharn K, Kariya R, Fujikawa S, Boonmars T, Pinlaor S, Pairojkul C, Okada S. Mucin-producing hamster cholangiocarcinoma cell line, Ham-2, possesses the aggressive cancer phenotypes with liver and lung metastases. In Vitro Cell Dev Biol Anim 2021; 57:825-834. [PMID: 34549357 DOI: 10.1007/s11626-021-00608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/20/2021] [Indexed: 11/29/2022]
Abstract
Cholangiocarcinoma (CCA) is an aggressive bile duct cancer. Opisthorchis viverrini (O. viverrini) infection is a significant cause of CCA in the Greater Mekong subregion. Currently, there is no standard chemotherapeutic regimen for CCA. A unique hamster carcinogenesis model of O. viverrini-associated CCA was established. Molecular targets identified from the hamster CCA-comparative model are valuable for target identification and validation. Hamster CCA was induced by the administration of O. viverrini metacercariae and N-nitrosodimethylamine. Hamster-derived cancer cells were isolated and continuously cultured for more than 6 months. Ham-2 cell line was established and characterized in vitro and in vivo. Ham-2 exhibited chromosome hyperploidy. A comparative study with previously established cell line, Ham-1, demonstrated that Ham-2 acquired slower growth, higher adhesion, higher migration, and resistance to doxorubicin and 5-fluorouracil (5-FU). In BALB/c Rag-2/Jak3 double-deficient (BRJ) mice, Ham-2 subcutaneous transplantation formed mucin-producing cancers, which morphologically resemble human tubular cholangiocarcinoma. Intravenous-injected Ham-2 established the metastatic nodules in the lungs and livers of BRJ mice. Altogether, a new hamster cholangiocarcinoma cell line, Ham-2, which acquired more aggressive phenotypes in vitro and in vivo, was established. This cell line might be a valuable tool for comparative drug target identification and validation.
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Affiliation(s)
- Piyanard Boonnate
- Division of Hematopoiesis, Graduate School of Medicine and Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Kulthida Vaeteewoottacharn
- Division of Hematopoiesis, Graduate School of Medicine and Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - Ryusho Kariya
- Division of Hematopoiesis, Graduate School of Medicine and Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan
| | - Sawako Fujikawa
- Division of Hematopoiesis, Graduate School of Medicine and Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan
| | - Thidarut Boonmars
- Department of Parasitology, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Khon Kaen University, Khon Kaen, 40002, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Seiji Okada
- Division of Hematopoiesis, Graduate School of Medicine and Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
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Understanding the Clinical Impact of MUC5AC Expression on Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2021; 13:cancers13123059. [PMID: 34205412 PMCID: PMC8235261 DOI: 10.3390/cancers13123059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Management of pancreatic cancer is challenging as there are limited treatment options, and most cases are diagnosed at advanced stages. In addition, there are no dependable tests available to predict bad outcomes or treatment responses in current clinical practice. Here, we shed light on the available evidence on mucin, MUC5AC in predicting the outcome of pancreatic cancers. We also discuss variants of MUC5AC believed to have a role in the malignant transformation of pancreatic tissues. Abstract Mucin-5AC (MUC5AC) is a heavily glycosylated gel-forming secreted mucin with a reliable prognostic value when detected in multiple malignancies. It is highly prevalent (70%) in PDA and is nonexistent in normal pancreatic tissues. Retrospective studies on PDA tumor tissue (detected by immunohistochemistry or IHC)) have investigated the prognostic value of MUC5AC expression but were equivocal. Some studies associated it with poor outcomes (survival or pathological features such as lymph node disease, vascular/neural invasion in resected tumors), while others have concluded that it is a good prognostic marker. The examination of expression level threshold (5%, 10%, or 25%) and the detected region (apical vs. cytoplasmic) were variable among the studies. The maturation stage and glycoform of MUC5AC detected also differed with the Monoclonal antibody (Mab) employed for IHC. CLH2 detects less mature/less glycosylated versions while 45M1 or 21-1 detect mature/more glycosylated forms. Interestingly, aberrantly glycosylated variants of MUC5AC were detected using lectin assays (Wheat Germ Agglutinin-MUC5AC), and Mabs such as NPC-1C and PAM4 have are more specific to malignant pancreatic tissues. NPC-1C and PAM4 antibody reactive epitopes on MUC5AC are immunogenic and could represent specific changes on the native MUC5AC glycoprotein linked to carcinogenesis. It was never studied to predict treatment response.
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7
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Expression of Mucoproteins in Gallbladder Cancer. Indian J Surg 2021. [DOI: 10.1007/s12262-021-02989-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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8
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Establishment of a Potential Serum Biomarker Panel for the Diagnosis and Prognosis of Cholangiocarcinoma Using Decision Tree Algorithms. Diagnostics (Basel) 2021; 11:diagnostics11040589. [PMID: 33806004 PMCID: PMC8064492 DOI: 10.3390/diagnostics11040589] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
Potential biomarkers which include S100 calcium binding protein A9 (S100A9), mucin 5AC (MUC5AC), transforming growth factor β1 (TGF-β1), and angiopoietin-2 have previously been shown to be effective for cholangiocarcinoma (CCA) diagnosis. This study attempted to measure the sera levels of these biomarkers compared with carbohydrate antigen 19-9 (CA19-9). A total of 40 serum cases of CCA, gastrointestinal cancers (non-CCA), and healthy subjects were examined by using an enzyme-linked immunosorbent assay. The panel of biomarkers was evaluated for their accuracy in diagnosing CCA and subsequently used as inputs to construct the decision tree (DT) model as a basis for binary classification. The findings showed that serum levels of S100A9, MUC5AC, and TGF-β1 were dramatically enhanced in CCA patients. In addition, 95% sensitivity and 90% specificity for CCA differentiation from healthy cases, and 70% sensitivity and 83% specificity for CCA versus non-CCA cases was obtained by a panel incorporating all five candidate biomarkers. In CCA patients with low CA19-9 levels, S100A9 might well be a complementary marker for improved diagnostic accuracy. The high levels of TGF-β1 and angiopoietin-2 were both associated with severe tumor stages and metastasis, indicating that they could be used as a reliable prognostic biomarkers panel for CCA patients. Furthermore, the outcome of the CCA burden from the Classification and Regression Tree (CART) algorithm using serial CA19-9 and S100A9 showed high diagnostic efficiency. In conclusion, results have shown the efficacy of CCA diagnosis and prognosis of the novel CCA-biomarkers panel examined herein, which may prove be useful in clinical settings.
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9
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Detarya M, Sawanyawisuth K, Aphivatanasiri C, Chuangchaiya S, Saranaruk P, Sukprasert L, Silsirivanit A, Araki N, Wongkham S, Wongkham C. The O-GalNAcylating enzyme GALNT5 mediates carcinogenesis and progression of cholangiocarcinoma via activation of AKT/ERK signaling. Glycobiology 2020; 30:312-324. [PMID: 31868214 DOI: 10.1093/glycob/cwz098] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 11/07/2019] [Accepted: 11/13/2019] [Indexed: 12/25/2022] Open
Abstract
Mucin type O-glycosylation is a posttranslational modification of membrane and secretory proteins. Transferring of N-acetylgalactosamine, the first sugar of O-glycosylation, is catalyzed by one of the 20 isoforms of polypeptide N-acetylgalactosaminyltransferases (GALNTs). In this study, Vicia villosa lectin (VVL), a lectin that recognizes O-GalNAcylated glycans, was used to detect VVL-binding glycans (VBGs) in cholangiocarcinoma (CCA). The elevation of VBGs in tumor tissues of the liver fluke associated with CCA from hamsters and patients was noted. VBGs were detected in hyperplastic/dysplastic bile ducts and CCA but not in normal biliary epithelia and hepatocytes, indicating the association of VBGs with CCA development and progression. GALNT5 was shown to be the major isoform found in human CCA cell lines with high VBG expression. Suppression of GALNT5 expression using siRNA significantly reduced VBG expression, signifying the connection of GALNT5 and VBGs observed. Knocked-down GALNT5 expression considerably inhibited proliferation, migration and invasion of CCA cells. Increased expression of GALNT5 using pcDNA3.1-GALNT5 expression vector induced invasive phenotypes in CCA cells with low GALNT5 expression. Increasing of claudin-1 and decreasing of slug and vimentin expression together with inactivation of Akt/Erk signaling were noted in GALNT5 knocked-down cells. These observations were reversed in GALNT5 over-expressing cells. GALNT5-modulated progression of CCA cells was shown to be, in part, via GALNT5-mediated autocrine/paracrine factors that stimulated activations of Akt/Erk signaling and the epithelial to mesenchymal transition process. GALNT5 and its O-GalNAcylated products may have important roles in promoting progression of CCA and could possibly be novel targets for treatment of metastatic CCA.
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Affiliation(s)
- Marutpong Detarya
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Chaiwat Aphivatanasiri
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Sriwipa Chuangchaiya
- Department of Community Health, Faculty of Public Health, Kasetsart University, Chalermphrakiat Sakon Nakhon Province Campus, Sakon Nakhon 47000, Thailand
| | - Paksiree Saranaruk
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Lukkana Sukprasert
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Norie Araki
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
| | - Sopit Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
| | - Chaisiri Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparb Rd., Muang, Khon Kaen 40002, Thailand
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10
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Wang S, You L, Dai M, Zhao Y. Mucins in pancreatic cancer: A well-established but promising family for diagnosis, prognosis and therapy. J Cell Mol Med 2020; 24:10279-10289. [PMID: 32745356 PMCID: PMC7521221 DOI: 10.1111/jcmm.15684] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/12/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Mucins are a family of multifunctional glycoproteins that mostly line the surface of epithelial cells in the gastrointestinal tract and exert pivotal roles in gut lubrication and protection. Pancreatic cancer is a lethal disease with poor early diagnosis, limited therapeutic effects, and high numbers of cancer‐related deaths. In this review, we introduce the expression profiles of mucins in the normal pancreas, pancreatic precursor neoplasia and pancreatic cancer. Mucins in the pancreas contribute to biological processes such as the protection, lubrication and moisturization of epithelial tissues. They also participate in the carcinogenesis of pancreatic cancer and are used as diagnostic biomarkers and therapeutic targets. Herein, we discuss the important roles of mucins that lead to the lethality of pancreatic adenocarcinoma, particularly MUC1, MUC4, MUC5AC and MUC16 in disease progression, and present a comprehensive analysis of the clinical application of mucins and their promising roles in cancer treatment to gain a better understanding of the role of mucins in pancreatic cancer.
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Affiliation(s)
- Shunda Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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11
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Expression and Serum Levels of Mucin 5AC (MUC5AC) as a Biomarker for Cholangiocarcinoma: a Meta-analysis. J Gastrointest Cancer 2019; 50:54-61. [PMID: 29139058 DOI: 10.1007/s12029-017-0032-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
AIM The potential of biomarkers in detecting early cholangiocarcinoma (CCA) is facilitated by examining CCA-associated proteins from primary studies. One such protein is mucin 5AC (MUC5AC) but inconsistency of reported associations between its expression/serum levels and CCA prompts a meta-analysis to obtain more precise estimates. METHODS A literature search yielded 17 included articles where multiple data in some raised the number of studies to 22. We calculated pooled odds ratios (OR) and 95% confidence intervals from negative and positive readings of MUC5AC levels. Data were subgrouped by ethnicity, detection method, sample source, and cancer type. RESULTS Outcome in the overall analysis was non-significant but those in the subgroups were. Thus, significant associations (P < 0.001) indicating high MUC5AC levels were found in three subgroups: (i) Thai (OR 8.32) and (ii) serum (OR 4.52). Heterogeneity of these two outcomes (I2 = 90-93%) was erased with outlier treatment (I2 = 0%) which also modulated the pooled effects (OR 2.48-2.59). (iii) Immunoblot (OR 2.61) had low initial heterogeneity (I2 = 2%). Robustness and significant tests for interaction (Pinteraction = 0.01-0.02) improved MUC5AC associations with CCA in the Thai population. CONCLUSIONS Our pooled effect findings target the biomarker potential of MUC5AC to the Thai population.
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12
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Harada F, Matsuyama R, Mori R, Kumamoto T, Morioka D, Taguri M, Yamanaka S, Endo I. Outcomes of surgery for 2010 WHO classification-based intraductal papillary neoplasm of the bile duct: Case–control study of a single Japanese institution's experience with special attention to mucin expression patterns. Eur J Surg Oncol 2019; 45:761-768. [DOI: 10.1016/j.ejso.2018.10.532] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 10/20/2018] [Accepted: 10/22/2018] [Indexed: 01/18/2023] Open
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13
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Kasprzak A, Adamek A. Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis. Int J Mol Sci 2019; 20:ijms20061288. [PMID: 30875782 PMCID: PMC6471604 DOI: 10.3390/ijms20061288] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 03/08/2019] [Accepted: 03/10/2019] [Indexed: 12/13/2022] Open
Abstract
Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis. Analysis of mucin expression in PLC has both basic research and clinical value. Mucins may act as oncogenes and tumour-promoting (e.g., MUC1, MUC13), and/or tumour-suppressing factors (e.g., MUC15). Given their role in promoting PLC progression, both classic (MUC1, MUC2, MUC4, MUC5AC, MUC6) and currently tested mucins (e.g., MUC13, MUC15, MUC16) have been proposed to be important diagnostic and prognostic markers. The purpose of this review was to summarize and update the role of classic and currently tested mucins in pathogenesis of PLC, with explaining the mechanisms of their action in HCC carcinogenesis. It also focuses on determination of the diagnostic and prognostic role of these glycoproteins in PLC, especially focusing on HCC, CC and other hepatic tumours with- and without biliary differentiation.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland.
| | - Agnieszka Adamek
- Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Szwajcarska Street 3, 61-285 Poznań, Poland.
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Krishn SR, Ganguly K, Kaur S, Batra SK. Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view. Carcinogenesis 2019; 39:633-651. [PMID: 29415129 DOI: 10.1093/carcin/bgy019] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022] Open
Abstract
Heavily glycosylated secreted mucin MUC5AC, by the virtue of its cysteine-rich repeats, can form inter- and intramolecular disulfide linkages resulting in complex polymers, which in turn craft the framework of the polymeric mucus gel on epithelial cell surfaces. MUC5AC is a molecule with versatile functional implications including barrier functions to epithelial cells, host-pathogen interaction, immune cell attraction to sites of premalignant or malignant lesions and tumor progression in a context-dependent manner. Differential expression, glycosylation and localization of MUC5AC have been associated with a plethora of benign and malignant pathologies. In this era of robust technologies, overexpression strategies and genetically engineered mouse models, MUC5AC is emerging as a potential diagnostic, prognostic and therapeutic target for various malignancies. Considering the clinical relevance of MUC5AC, this review holistically encompasses its genomic organization, domain structure, glycosylation patterns, regulation, functional and molecular connotation from benign to malignant pathologies. Furthermore, we have here explored the incipient and significant experimental tools that are being developed to study this structurally complex and evolutionary conserved gel-forming mucin.
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Affiliation(s)
- Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, 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.,Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
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Danese E, Ruzzenente A, Montagnana M, Lievens PMJ. Current and future roles of mucins in cholangiocarcinoma-recent evidences for a possible interplay with bile acids. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:333. [PMID: 30306072 DOI: 10.21037/atm.2018.07.16] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is rare but highly malignant tumour. The diagnosis is difficult due to its silent clinical character and the inefficiency of currently available diagnostic markers. An enhanced understanding of the molecular pathways involved in CCA carcinogenesis would herald targeted, individualized therapies, as well as new early diagnostic tool with improvement of patient survival. Recently, two mucin proteins, MUC4 and MUC5 have gained interest for their involvement in tumour growth and progression and possible use as diagnostic and prognostic cancer biomarkers. Moreover, a number of studies have demonstrated an association between biliary or serum bile acids (BAs) and some forms of cancers including CCA. More importantly, BAs have been shown to participate in tumour progression by inducing alterations in the expression of oncogenic mucins. This review summarizes the most important findings regarding the possible use of mucin glycoproteins and BAs in the diagnosis and prognostication of CCA and discuss evidences suggesting a role of BAs in regulating the expression of transmembrane and secreted mucins.
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Affiliation(s)
- Elisa Danese
- Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Section of General and Hepatobiliary Surgery, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy
| | - Martina Montagnana
- Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Patricia Marie-Jeanne Lievens
- Section of Biology and Genetics, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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Saengboonmee C, Sawanyawisuth K, Chamgramol Y, Wongkham S. Prognostic biomarkers for cholangiocarcinoma and their clinical implications. Expert Rev Anticancer Ther 2018; 18:579-592. [PMID: 29676221 DOI: 10.1080/14737140.2018.1467760] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 04/18/2018] [Indexed: 12/16/2022]
Abstract
Cholangiocarcinoma (CCA) is a poorly prognostic cancer with limited treatment options. Most patients have unresectable tumors when they are diagnosed and the chemotherapies provided are of limited benefit. Prognostic markers are therefore necessary to predict the disease outcome, risk of relapse, or to suggest the best treatment option. Areas covered: This article provides an up-to-date review of biomarkers with promising characteristics to be prognostic markers for CCA reported in the past 5 years. The biomarkers are sub-classified into tissue and serum markers. Proteins, RNAs, peripheral blood cells etc., that are associated with aggressive phenotypes, signal pathways, chemo-drug resistance, and those that reflect the survival time of CCA patients are evaluated for their prognostic prediction values. Expert commentary: CCAs are heterogeneous tumors of different histo-pathological subtypes and genetic influences and, therefore, potential markers should be validated in larger collectives with varied epidemiological backgrounds. A systematic review and meta-analysis should be done to clarify the impact of the reported biomolecules for their potential prognostic values. Non- or low-invasive sample collections, as well as the simple and affordable determination methods, should be constructed to make the prognostic biomarkers available in clinical practice.
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Affiliation(s)
- Charupong Saengboonmee
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand
- b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
| | - Kanlayanee Sawanyawisuth
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand
- b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
| | - Yaovalux Chamgramol
- b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
- c Department of Pathology, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand
| | - Sopit Wongkham
- a Department of Biochemistry, Faculty of Medicine , Khon Kaen University , Khon Kaen , Thailand
- b Cholangiocarcinoma Research Institute , Khon Kaen University , Khon Kaen , Thailand
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Cuenco J, Wehnert N, Blyuss O, Kazarian A, Whitwell HJ, Menon U, Dawnay A, Manns MP, Pereira SP, Timms JF. Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis. Oncotarget 2018; 9:17430-17442. [PMID: 29707118 PMCID: PMC5915126 DOI: 10.18632/oncotarget.24732] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 03/06/2018] [Indexed: 01/02/2023] Open
Abstract
The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich α2-glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre-diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73–0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma-glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial.
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Affiliation(s)
- Joy Cuenco
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
| | - Natascha Wehnert
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, 30625, Germany
| | - Oleg Blyuss
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
| | - Anna Kazarian
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
| | - Harry J Whitwell
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
| | - Usha Menon
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
| | - Anne Dawnay
- Clinical Biochemistry, University College London Hospitals NHS Foundation Trust, London, W1T 4EU, UK
| | - Michael P Manns
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, 30625, Germany
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, NW3 2PG, UK
| | - John F Timms
- Institute for Women's Health, University College London, London, WC1E 6BT, UK
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Saentaweesuk W, Silsirivanit A, Vaeteewoottacharn K, Sawanyawisuth K, Pairojkul C, Cha'on U, Indramanee S, Pinlaor S, Boonmars T, Araki N, Wongkham C. Clinical significance of GalNAcylated glycans in cholangiocarcinoma: Values for diagnosis and prognosis. Clin Chim Acta 2018; 477:66-71. [PMID: 29217428 DOI: 10.1016/j.cca.2017.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 12/01/2017] [Accepted: 12/03/2017] [Indexed: 12/23/2022]
Abstract
Cancer cells exhibited the aberrant cancer-associated glycans that are potential biomarkers for diagnosis and monitoring of the cancer. In this study, Sophora japonica agglutinin (SJA) was used to detect SJA-specific N-acetylgalactosamine-associated glycans (SNAG) in liver tissues and sera from cholangiocarcinoma (CCA) patients. Whether SNAG could be the diagnostic and prognostic markers for CCA was evaluated. SJA-histochemistry revealed that SNAG was undetec2 in normal bile ducts but was highly expressed in hyperplastic/dysplastic bile ducts and CCA. SNAG was negative in hepatocytes and hepatoma tissues indicating SNAG as a differential marker of CCA and hepatoma. SJA-histochemistry of CCA hamster tissues revealed the involvement of SNAG in the early pathogenesis of bile duct epithelia and CCA development. A SJA-based ELISA was successfully developed to determine SNAG in serum. Serum-SNAG from CCA patients was significantly higher than those of non-CCA control groups with the diagnostic values of 59.5% sensitivity and 73.6% specificity, comparable to those of serum CA19-9. High levels of serum SNAG (≥69AU/ml) indicated poor survival of CCA patients. Taken together, SNAG was first demonstrated here to be a glycobiomarker for diagnosis and prognosis of CCA. Association of SNAG with pathogenesis of bile ducts and CCA development were suggested. (198).
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Affiliation(s)
- Waraporn Saentaweesuk
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Atit Silsirivanit
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
| | - Kulthida Vaeteewoottacharn
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanlayanee Sawanyawisuth
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Chawalit Pairojkul
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Ubon Cha'on
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somsiri Indramanee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Thidarut Boonmars
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Norie Araki
- Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Chaisiri Wongkham
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
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Toba T, Inoshita N, Kaise M, Nomura K, Kuribayashi Y, Tanaka M, Yamashita S, Furuhata T, Kikuchi D, Matsui A, Mitani T, Iizuka T, Hoteya S. Clinicopathological features of superficial non-ampurally duodenal epithelial tumor; gastric phenotype of histology correlates to higher malignant potency. J Gastroenterol 2018; 53:64-70. [PMID: 28321513 DOI: 10.1007/s00535-017-1327-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/01/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Superficial non-ampullary duodenal epithelial tumors (SNADETs) are relatively rare, but they are now being detected more frequently due to advances in endoscopic technology. Nevertheless, the pathological nature of SNADETs remains unclear and a management strategy for these tumors has not been established. METHODS To elucidate the clinicopathological features, we conducted a retrospective analysis of 138 endoscopically resected SNADETs. Lesions were classified into two groups by histological grade according to the Vienna classification: category 3 (71 lesions, 51.4%) and category 4/5 (67 lesions, 48.6%). RESULTS Compared with category 3 lesions, category 4/5 lesions were significantly more common in elderly patients (p < 0.001) and had a significantly larger tumor diameter (p = 0.001). Immunohistochemical analysis showed that category 4/5 lesions expressed MUC5AC (p = 0.002), MUC6 (p < 0.001), and p53 (p = 0.003) significantly more frequently and expressed CD10 (p = 0.002) and CDX2 (p = 0.029) significantly less frequently. Multivariate regression analysis showed that advanced age (p < 0.001), MUC6 expression (p = 0.001), and p53 expression (p = 0.004) were independent risk factors for a classification of category 4/5. In addition, advanced age (p = 0.010) and MUC5AC expression (p = 0.011) were identified as risk factors for lesions classified as category 4.2 (noninvasive carcinoma) or higher. All category 5 lesions expressed MUC5AC. CONCLUSIONS The gastric phenotype of MUC5AC and MUC6 may be linked to the malignant potential of SNADETs.
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Affiliation(s)
- Takahito Toba
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan. .,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Omori Medical Center, Tokyo, 143-8541, Japan.
| | - Naoko Inoshita
- Department of Pathology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Mitsuru Kaise
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Kosuke Nomura
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | | | - Masami Tanaka
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Satoshi Yamashita
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Tsukasa Furuhata
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Daisuke Kikuchi
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Akira Matsui
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Toshifumi Mitani
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Toshiro Iizuka
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
| | - Shu Hoteya
- Department of Gastroenterology, Toranomon Hospital, Tokyo, 105-8470, Japan
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Immunohistochemical Classification of Ampullary Carcinomas: Critical Reappraisal Fails to Confirm Prognostic Relevance for Recently Proposed Panels, and Highlights MUC5AC as a Strong Prognosticator. Am J Surg Pathol 2017; 41:865-876. [PMID: 28505002 DOI: 10.1097/pas.0000000000000863] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recently, immunohistochemistry-based classifications of ampullary carcinomas have been proposed (Ang and colleagues [PMID: 24832159]; Chang and colleagues [PMID: 23439753]). In this study, the prognostic value of Ang/Chang panel markers (CK20, MUC1, MUC2, CDX2) as well as other markers (CK7, MUC5AC, and MUC6) were tested on full-faced sections of 136 ampullary carcinoma resections with substantial (>5 mm) invasion. Immunohistochemistry was correlated with both histologic classification (intestinal [INT], pancreatobiliary [PB], or nontubular based on ≥3/5 observer agreement) and clinical outcome. No prognostic correlation was found with MUC1, CDX2, MUC2 or CK20 despite testing with different quantitative cutoffs. CK7 and CK20 were nonspecific. Ang classification had reasonable correlation with histologic subclassification of tubular cases as INT versus PB with high specificity but low sensitivity and ambiguous category was large (29%) and included also some classical cases. Prognostically, Ang classification approached but did not reach statistical significance, even when their large "ambiguous" group was eliminated and only tubular cases were analyzed (Ang-INT vs. Ang-PB; P=0.08). The Chang panel, in which the definition of the INT subcategory is not clearly defined, only marginally reached prognostic significance when tested as MUC1+/CDX2- versus MUC1-/CDX2+ and only by Wilcoxon test (P=0.0485) but 31% of the cases were "unclassifiable." The only individual marker that was found to have direct and strong correlation with the clinical outcome was MUC5AC (not used in the Ang or Chang panels), with statistically significant survival differences found with various cutoffs tested (for 20% cutoff, 5-y survival, 68% vs. 31%; P=0.0002). In addition, MUC5AC significantly stratified the histologically PB and INT cases (P=0.01 and 0.03, respectively), as well as Ang's ambiguous and Chang's unclassified cases (P=0.006 and 0.007, respectively). In conclusion, the widely used putative lineage markers, MUC1/MUC2/CK7/CK20/CDX2, do not seem to have direct/significant prognostic correlation either individually or in combination of Ang and Chang panels. Ang panel is helpful as an adjunct in determining the cell lineage with a few caveats. MUC5AC proves to be a significant independent prognosticator and should be incorporated into evaluation of ampullary carcinomas.
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Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol 2016; 8:725-734. [PMID: 27795812 PMCID: PMC5064050 DOI: 10.4251/wjgo.v8.i10.725] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/19/2016] [Accepted: 08/15/2016] [Indexed: 02/05/2023] Open
Abstract
Tumors of the pancreas, the ampulla of Vater, and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system. This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors. Mucins, especially MUC-1, -2, -4 and -5AC, are important candidates for developing into such reliable biomarkers. Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia (PanIN). Positive expression of MUC2 in intraductal papillary mucinus neoplasms (IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1, while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution. De novo MUC4 expression correlates to the severity of dysplasia in PanIN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas. In biliary intraepithelial neoplasia (BilIN), increased expression of MUC1 is associated with higher degrees of dysplasia. Intrahepatic cholangiocarcinomas (ICC) are characterized by increased expression of all glycoforms of MUC1. Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts (IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element. Absent MUC2 expression in any degree of BilIN may prove useful in differentiating them from IPNB. De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts (EHBDC). High de novo expression of MUC5AC is found in all degrees of BilIN and all types of IPNB and ICC. The MUC5AC is useful in the detection of neoplastic lesions of the bile duct at an early stage. Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor, such as lymph node metastasis, infiltration of the pancreas and duodenum, advanced TNM classification and worse prognosis. Patients with intra-ampullary papillary-tubular neoplasm (IAPN) of the pancreatobiliary immunophenotype did not show MUC2, while those of the intestinal immunophenotype are MUC2 positive. The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis. Moreover, it appears that MUC4 positivity correlates with recurrence of the tumor. Expression of MUC5AC is associated with the invasive potential of the tumor.
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Wang X, Yan F, Shi R, Huang X, Lu S, Xu L, Ren B. Hyper Expression of Mucin 5ac Indicates Poor Cancer Prognoses: A Meta-Analysis. Medicine (Baltimore) 2016; 95:e2396. [PMID: 26735541 PMCID: PMC4706261 DOI: 10.1097/md.0000000000002396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The aim of the study was to explore the association between mucin 5ac expression and cancer prognosis. A systematically comprehensive search was performed through PubMed, the Web of Science, and the China National Knowledge Infrastructure (CNKI). The prognostic value of mucin 5ac expression in cancer patients was evaluated. The overexpression of mucin 5ac was found to be significantly associated with a poor prognosis in cancer patients (pooled HR: 1.53, 95%CI: 1.158-2.028, P = 0.003). This association was also detected in a biliary subgroup (pooled HR: 1.83, 95%CI: 1.269-2.639, P = 0.001) and a gastrointestinal subgroup (pooled HR: 1.44, 95%CI: 1.069-1.949 P = 0.017). In the geography subgroup analysis, a statistical association was found in the Asian subgroup (pooled HR: 1.69, 95%CI: 1.200-2.384, P = 0.003). In the clinical characteristics analysis, a statistical association was found between the hyper expression of mucin 5ac and lymphatic metastasis. We indicated that mucin 5ac is a promising prognostic predictor for cancer, especially for biliary and gastrointestinal cancer, and is more suitable for predicting cancer prognoses in Asians.
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Affiliation(s)
- Xin Wang
- From the Fourth Clinical College of Nanjing Medical University, Nanjing, China (XW, FY, RS, XH, SL); Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital (XW, RS, LX, BR); and Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, PR China (XW, FY, RS, XH, LX, BR)
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Maeda S, Morikawa T, Takadate T, Suzuki T, Minowa T, Hanagata N, Onogawa T, Motoi F, Nishimura T, Unno M. Mass spectrometry-based proteomic analysis of formalin-fixed paraffin-embedded extrahepatic cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:683-91. [PMID: 25917007 DOI: 10.1002/jhbp.262] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 04/21/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Extrahepatic cholangiocarcinoma is very difficult to diagnose at an early stage, and has a poor prognosis. Novel markers for diagnosis and optimal treatment selection are needed. However, there has been very limited data on the proteome profile of extrahepatic cholangiocarcinoma. This study was designed to unravel the proteome profile of this disease and to identify overexpressed proteins using mass spectrometry-based proteomic approaches. METHODS We analyzed a discovery set of formalin-fixed paraffin-embedded tissues of 14 extrahepatic cholangiocarcinomas using shotgun mass spectrometry, and compared proteome profiles with those of seven controls. Then, selected candidates were verified by quantitative analysis using scheduled selected reaction monitoring-based mass spectrometry. Furthermore, immunohistochemical staining used a validation set of 165 cases. RESULTS In total, 1,992 proteins were identified and 136 proteins were overexpressed. Verification of 58 selected proteins by quantitative analysis revealed 11 overexpressed proteins. Immunohistochemical validation for 10 proteins showed positive rates of S100P (84%), CEAM5 (75%), MUC5A (62%), OLFM4 (60%), OAT (42%), CAD17 (41%), FABPL (38%), AOFA (30%), K1C20 (25%) and CPSM (22%) in extrahepatic cholangiocarcinomas, which were rarely positive in controls. CONCLUSIONS We identified 10 proteins associated with extrahepatic cholangiocarcinoma using proteomic approaches. These proteins are potential targets for future diagnostic biomarkers and therapy.
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Affiliation(s)
- Shimpei Maeda
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Surgery, South Miyagi Medical Center, Miyagi, Japan
| | - Takanori Morikawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tatsuyuki Takadate
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Suzuki
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Minowa
- Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Japan
| | - Nobutaka Hanagata
- Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Japan
| | - Tohru Onogawa
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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Macha MA, Krishn SR, Jahan R, Banerjee K, Batra SK, Jain M. Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer. Cancer Treat Rev 2015; 41:277-88. [PMID: 25624117 DOI: 10.1016/j.ctrv.2015.01.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 12/31/2014] [Accepted: 01/07/2015] [Indexed: 02/07/2023]
Abstract
Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to the pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy.
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Affiliation(s)
- Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Shiv Ram Krishn
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Rahat Jahan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kasturi Banerjee
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Danese E, Ruzzenente O, Ruzzenente A, Iacono C, Bertuzzo F, Gelati M, Conci S, Bendinelli S, Bonizzato G, Guglielmi A, Salvagno GL, Lippi G, Guidi GC. Assessment of bile and serum mucin5AC in cholangiocarcinoma: diagnostic performance and biologic significance. Surgery 2014; 156:1218-1224. [PMID: 25151557 DOI: 10.1016/j.surg.2014.05.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 05/12/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Recent studies have showed the efficacy of mucin5AC (MUC5AC) as a diagnostic and prognostic serum biomarker in biliary tract tumors. The aim of the present investigation was to improve the current knowledge on the biologic relevance of MUC5AC in malignant and benign biliary disorders by comparing its diagnostic performance in both bile and serum samples of patients with cholangiocarcinoma (CCA) or benign biliary disorders. METHODS A quantitative determination of MUC5AC by enzyme-linked immunosorbent assay was performed in bile and serum specimens from 26 patients with extrahepatic CCA and 20 subjects with benign biliary disorders (10 with biliary stones and 10 with cholangitis). Verification analysis was made by immunoblot. RESULTS MUC5AC of serum and biliary origin contributed to different extent to total levels of MUC5AC in the different groups of patients. In particular, the transition toward a greater degree of injury of bile duct epithelium was accompanied by a greater amount of MUC5AC in serum than in bile. The diagnostic performance of MUC5AC expressed as serum/bile ratio showed excellent diagnostic performance for differentiating CCA from cholangitis (area under the curve [AUC], 0.94; 95% CI, 0.86-1.00; P < .0001), CCA from biliary stones (AUC, 0.99; 95% CI, 0.98-1.00; P < .0001), as well as cholangitis from biliary stones (AUC, 0.93; 95% CI, 0.82-1.00; P = .001). CONCLUSION These findings provide new insight into the biologic importance of MUC5AC in biliary disorders and suggest that combined assessment of MUC5AC in bile and serum with expression of data in terms of serum to bile ratio may improve the diagnostic performance of MUC5AC quantification in serum alone.
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Affiliation(s)
- Elisa Danese
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy.
| | - Orazio Ruzzenente
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Unit of Hepato Pancreato Biliary Surgery, Division of General Surgery "A", Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Calogero Iacono
- Unit of Hepato Pancreato Biliary Surgery, Division of General Surgery "A", Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Francesca Bertuzzo
- Unit of Hepato Pancreato Biliary Surgery, Division of General Surgery "A", Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Matteo Gelati
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
| | - Simone Conci
- Unit of Hepato Pancreato Biliary Surgery, Division of General Surgery "A", Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Sharon Bendinelli
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
| | - Giada Bonizzato
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
| | - Alfredo Guglielmi
- Unit of Hepato Pancreato Biliary Surgery, Division of General Surgery "A", Department of Surgery, University Hospital of Verona, Verona, Italy
| | - Gian Luca Salvagno
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
| | - Giuseppe Lippi
- Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy
| | - Gian Cesare Guidi
- Section of Clinical Biochemistry, Department of Life and Reproduction Sciences, University Hospital of Verona, Verona, Italy
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Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol 2014; 25:1086-1097. [PMID: 24705974 PMCID: PMC4037856 DOI: 10.1093/annonc/mdu006] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 11/05/2013] [Accepted: 11/08/2013] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.
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Affiliation(s)
- S G Barreto
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
| | - A Dutt
- The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India
| | - A Chaudhary
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon
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Abstract
CONTEXT Bile duct cancer (BDC) is a disease with a very grave prognosis, often diagnosed too late. OBJECTIVE The aim of this review is to evaluate available literature on tumor markers in serum from patients with BDC. METHODS Using the search words "serum markers", "bile duct cancer", "cholangiocarcinoma", "biomarker" and "tumor marker", a search was carried out. RESULTS Seventy-five studies were included in the review. CONCLUSION CA19-9 is by far the most studied and most promising diagnostic and/or prognostic marker in BDC. But also the different mucins are interesting as new markers of BDC in serum.
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Affiliation(s)
- M Grunnet
- Department of Oncology, Rigshospitalet, Danish National Hospital , Copenhagen , Denmark
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Shibahara H, Higashi M, Koriyama C, Yokoyama S, Kitazono I, Kurumiya Y, Narita M, Kuze S, Kyokane T, Mita S, Arai T, Kato T, Yuasa N, Yamaguchi R, Kubota H, Suzuki H, Baba S, Rousseau K, Batra SK, Yonezawa S. Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer. PLoS One 2014; 9:e86111. [PMID: 24722639 PMCID: PMC3982950 DOI: 10.1371/journal.pone.0086111] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Accepted: 12/04/2013] [Indexed: 12/20/2022] Open
Abstract
Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p = 0.026), venous invasion (p<0.001) and curative resection (p<0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8-17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.
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Affiliation(s)
| | - Michiyo Higashi
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
- * E-mail:
| | - Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Seiya Yokoyama
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Iwao Kitazono
- Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | | | | | - Shingo Kuze
- Department of Surgery, Chutoen General Medical Center, Kakegawa, Japan
| | - Takanori Kyokane
- Department of Surgery, Chutoen General Medical Center, Kakegawa, Japan
| | - Saburo Mita
- Department of Surgery, Chita City Hospital, Chita, Japan
| | | | - Takehito Kato
- Department of Surgery, Toyohashi Municipal Hospital, Toyohashi, Japan
| | - Norihiro Yuasa
- Department of Surgery, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan
| | - Ryuzo Yamaguchi
- Department of Surgery, Kasugai Municipal Hospital, Kasugai, Japan
| | - Hitoshi Kubota
- Department of Surgery, Handa City Hospital, Handa, Japan
| | - Hideaki Suzuki
- Department of Surgery, Handa City Hospital, Handa, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, University Hospital Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Karine Rousseau
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, United Kingdom
| | - Surinder K. Batra
- Departments 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, Japan
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Ruzzenente A, Iacono C, Conci S, Bertuzzo F, Salvagno G, Ruzzenente O, Campagnaro T, Valdegamberi A, Pachera S, Bagante F, Guglielmi A. A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC). Surgery 2014; 155:633-639. [PMID: 24468034 DOI: 10.1016/j.surg.2013.12.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 12/06/2013] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Mucin 5AC (MUC5AC) is a glycoprotein found in different epithelial cancers, including biliary tract cancer (BTC). The aims of this study were to investigate the role of MUC5AC as serum marker for BTC and its prognostic value after operation with curative intent. PATIENTS AND METHOD From January 2007 to July 2012, a quantitative assessment of serum MUC5AC was performed with enzyme-linked immunoassay in a total of 88 subjects. Clinical and biochemical data (including CEA and Ca 19-9) of 49 patients with BTC were compared with a control population that included 23 patients with benign biliary disease (BBD) and 16 healthy control subjects (HCS). RESULTS Serum MUC5AC was greater in BTC patients (mean 17.93 ± 10.39 ng/mL) compared with BBD (mean 5.95 ± 5.39 ng/mL; P < .01) and HCS (mean 2.74 ± 1.35 ng/mL) (P < .01). Multivariate analysis showed that MUC5AC was related with the presence of BTC compared with Ca 19-9 and CEA: P < .01, P = .080, and P = .463, respectively. In the BTC group, serum MUC5AC ≥ 14 ng/mL was associated with lymph-node metastasis (P = .050) and American Joint Committee on Cancer and International Union for Cancer Control stage IVb disease (P = .047). Moreover, in patients who underwent operation with curative intent, serum MUC5AC ≥ 14 ng/mL was related to a worse prognosis compared with patients with lesser levels, with 3-year survival rates of 21.5% and 59.3%, respectively (P = .039). CONCLUSION MUC5AC could be proposed as new serum marker for BTC. Moreover, the quantitative assessment of serum MUC5AC could be related to tumor stage and long-term survival in patients with BTC undergoing operation with curative intent.
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Affiliation(s)
- Andrea Ruzzenente
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Calogero Iacono
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy.
| | - Simone Conci
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Francesca Bertuzzo
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Gianluca Salvagno
- Department of Life and Reproduction Sciences, Division of Clinical Biochemistry, GB Rossi University Hospital, University of Verona, Verona, Italy
| | - Orazio Ruzzenente
- Department of Life and Reproduction Sciences, Division of Clinical Biochemistry, GB Rossi University Hospital, University of Verona, Verona, Italy
| | - Tommaso Campagnaro
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Alessandro Valdegamberi
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Silvia Pachera
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Fabio Bagante
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
| | - Alfredo Guglielmi
- Department of Surgery, Division of General Surgery "A," Unit of Hepato Pancreato Biliary Surgery, Verona, Italy
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Skipworth JRA, Timms JF, Pereira SP. Novel diagnostic and prognostic biomarkers in biliary tract cancer. ACTA ACUST UNITED AC 2014; 7:487-99. [PMID: 23971898 DOI: 10.1517/17530059.2013.826646] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The worldwide incidence of biliary tract carcinoma (BTC, tumours of the bile ducts and gall-bladder) continues to rise, with the only potentially curative treatment remaining surgical resection or transplantation, possible in only a minority of patients. Late presentation and a paucity of effective treatments mandate the development of techniques for early lesion detection. AREAS COVERED This article reviews currently available biomarkers for the diagnosis and prognosis of BTC, as well as recently published studies describing novel serum, bile and urinary biomarkers. EXPERT OPINION The incorporation of novel analysis techniques, such as digital image analysis and fluorescence in situ hybridization, into existing management algorithms enhances the accuracy of brush cytology taken at the time of therapeutic endoscopy. However, a key goal is the discovery of reliable non-invasive biomarkers with high sensitivity and specificity. Recent advances in gene sequencing and expression, clonal evolution and tumour heterogeneity in other cancers should advance understanding of BTC tumour biology and facilitate biomarker discovery.
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Affiliation(s)
- James R A Skipworth
- University College London, Division of Surgery and Interventional Science, 4th Floor, 74 Huntley Street, London, WC1E6AU, UK
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Silsirivanit A, Araki N, Wongkham C, Vaeteewoottacharn K, Pairojkul C, Kuwahara K, Narimatsu Y, Sawaki H, Narimatsu H, Okada S, Sakaguchi N, Wongkham S. CA-S27: a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma. Cancer Sci 2013; 104:1278-1284. [PMID: 23809433 PMCID: PMC7656540 DOI: 10.1111/cas.12222] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 06/17/2013] [Accepted: 06/18/2013] [Indexed: 02/06/2023] Open
Abstract
Early and specific diagnosis is critical for treatment of cholangiocarcinoma (CCA). In this study, a carbohydrate antigen-S27 (CA-S27) monoclonal antibody (mAb) was established using pooled CCA tissue-extract as immunogen. The epitope recognized by CA-S27-mAb was a new Lewis-a (Le(a)) associated modification of MUC5AC mucin. A Soybean agglutinin/CA-S27-mAb sandwich ELISA to determine CA-S27 in serum was successfully developed. High level of CA-S27 was detected in serum of CCA patients and could differentiate CCA patients from those of gastro-intestinal cancers, hepatomas, benign hepatobiliary diseases and healthy subjects with high sensitivity (87.5%) and high negative predictive value (90.4%). The level of serum CA-S27 was dramatically reduced after tumor removal, indicating tumor origin of CA-S27. Patients with high serum CA-S27 had significantly shorter survivals than those with low serum CA-S27 regardless of serum MUC5AC levels. Fucosyltransferase-III (FUT3) was shown to be a regulator of CA-S27 expression. Suppression of CA-S27 expression with siRNA-FUT3 or neutralization with CA-S27 mAb significantly reduced growth, adhesion, invasion and migration potentials of CCA cells in vitro. In summary, we demonstrate that serum CA-S27, a novel carbohydrate antigen, has potential as diagnostic and prognostic markers for CCA patients. CA-S27 involves in promoting cell growth, adhesion, migration and invasion of CCA cells.
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Affiliation(s)
- Atit Silsirivanit
- Department of Biochemistry, Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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Sawanyawisuth K, Silsirivanit A, Kunlabut K, Tantapotinan N, Vaeteewoottacharn K, Wongkham S. A novel carbohydrate antigen expression during development of Opisthorchis viverrini- associated cholangiocarcinoma in golden hamster: A potential marker for early diagnosis. Parasitol Int 2012; 61:151-4. [PMID: 21784171 DOI: 10.1016/j.parint.2011.07.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2011] [Revised: 07/07/2011] [Accepted: 07/10/2011] [Indexed: 10/17/2022]
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Long-term survival after resection of mass-forming type intrahepatic cholangiocarcinoma directly infiltrating the transverse colon and sequential brain metastasis: Report of a case. Surg Today 2011; 41:1410-3. [DOI: 10.1007/s00595-010-4500-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Accepted: 06/21/2010] [Indexed: 11/27/2022]
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Xiong L, Yang Z, Yang L, Liu J, Miao X. Expressive levels of MUC1 and MUC5AC and their clinicopathologic significances in the benign and malignant lesions of gallbladder. J Surg Oncol 2011; 105:97-103. [PMID: 21815153 DOI: 10.1002/jso.22055] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2010] [Accepted: 07/13/2011] [Indexed: 12/26/2022]
Abstract
OBJECTIVE This article is intended to make a study on the expressive levels of mucin core proteins (MUC1 and MUC5AC) and detect their clinicopathologic significances in the benign and malignant lesions of gallbladder. METHODS EnVision immunohistochemical method for determining the expressions of MUC1 and MUC5AC was used in routinely paraffin-embedded sections of surgically resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenoma (n = 15), and chronic cholecystitis (n = 35). RESULTS The positive rate of MUC1 expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (χ(2) = 16.49, P < 0.01), adenoma (χ(2) = 7.40, P < 0.01), and chronic cholecystitis (χ(2) = 28.57, P < 0.01), while the positive rate of MUC5AC expression was significantly lower in gallbladder adenocarcinoma than that in peritumoral tissues (χ(2) = 12.83, P < 0.01), adenoma (χ(2) = 4.22, P < 0.05), and chronic cholecystitis (χ(2) = 20.25, P < 0.01). The positive cases of MUC1 and the negative ones of MUC5AC in the benign lesions showed moderate- or severe-dysplasia of gallbladder epithelium. The positive rates of MUC1 were significantly lower in gallbladder adenocarcinomas with maximal diameter of mass <2 cm, no metastasis of lymph node, and no invasiveness of regional tissues (P < 0.05 or P < 0.01) than those in gallbladder adenocarcinomas with maximal diameter of mass >2 cm, metastasis of lymph node, and invasiveness of regional tissues (P < 0.05 or P < 0.01). However, the positive rates of MUC5AC were significantly higher in the highly differentiated adenocarcinoma with maximal diameter of mass <2 cm than those in the low-differentiated adenocarcinoma with maximal diameter of mass ≥2 cm. Univariate Kaplan-Meier analysis showed that increased expression of MUC1 (P = 0.064) or decreased expression of MUC5AC (P = 0.017) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MUC5AC (P = 0.008) was an independent prognostic predictor to gallbladder adenocarcinoma. CONCLUSIONS The expression of MUC1 and MUC5AC might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.
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Affiliation(s)
- Li Xiong
- Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, China.
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Silsirivanit A, Araki N, Wongkham C, Pairojkul C, Narimatsu Y, Kuwahara K, Narimatsu H, Wongkham S, Sakaguchi N. A novel serum carbohydrate marker on mucin 5AC. Cancer 2011; 117:3393-403. [PMID: 21287531 DOI: 10.1002/cncr.25912] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2010] [Revised: 12/07/2010] [Accepted: 12/07/2010] [Indexed: 01/05/2023]
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GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin. Oncogene 2010; 30:714-23. [PMID: 20972463 DOI: 10.1038/onc.2010.459] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Krüppel-like zinc-finger protein GLI1 functions as a downstream transcription factor of Hedgehog signaling and plays a pivotal role in the cellular proliferation of many types of tumors, including pancreatic ductal adenocarcinoma (PDA). PDA develops from dysplastic lesions called pancreatic intraepithelial neoplasia (PanIN) through a multistep carcinogenesis process that changes its cellular characteristics, including a mucin expression profile. Increased expression of a gel-forming mucin, MUC5AC, was previously revealed as a major biomarker for the poor prognosis of PDA patients, but the molecular mechanisms responsible for its expression and correlation with poor prognosis are not fully understood. Here we show that MUC5AC is a direct transcriptional target of GLI1 in PDA cells. Overexpression of GLI1 enhanced MUC5AC expression, and a double knockdown of GLI1 and GLI2 suppressed endogenous MUC5AC expression in PDA cells. Luciferase reporter assays revealed that GLI1 and GLI2 can activate the MUC5AC promoter through its conserved CACCC-box-like cis-regulatory elements. We also found that GLI1-upregulated MUC5AC was expressed in the intercellular junction between cultured PDA cells and interfered with the membrane localization of E-cadherin, leading to decreased E-cadherin-dependent cell-cell adhesion and promoting the migration and invasion of PDA cells. Consistently, GLI1 induced the nuclear accumulation and target gene expression of β-catenin in a MUC5AC-dependent manner. Finally, immunohistochemical analysis revealed that GLI1 expression statistically correlated with MUC5AC expression and also with altered subcellular localization of E-cadherin and β-catenin in PanIN lesions and PDA. This evidence revealed a new aspect of GLI1 function in modulating E-cadherin/β-catenin-regulated cancer cell properties through the expression of a gel-forming mucin.
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Vilkin A, Geller A, Levi Z, Niv Y. Mucin gene expression in bile of patients with and without gallstone disease, collected by endoscopic retrograde cholangiography. World J Gastroenterol 2009; 15:2367-71. [PMID: 19452580 PMCID: PMC2684604 DOI: 10.3748/wjg.15.2367] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the pattern of mucin expression and concentration in bile obtained during endoscopic retrograde cholangiography (ERC) in relation to gallstone disease.
METHODS: Bile samples obtained at ERC from 29 consecutive patients, 17 with and 12 without gallstone disease were evaluated for mucin content by gel filtration on a Sepharose CL-4B column. Dot blot analysis for bile mucin apoproteins was performed with antibodies to Mucin 1 (MUC1), MUC2, MUC3, MUC5AC, MUC5B and MUC6. Staining intensity score (0-3) was used as a measure of antigen expression.
RESULTS: MUC1, MUC2, MUC3, MUC5AC, MUC5B and MUC6 were demonstrated in 34.4%, 34.4%, 51.7%, 51.7%, 55.1% and 27.5% of bile samples, respectively. The staining intensity scores were 0.62 ± 0.94, 0.58 ± 0.90, 0.79 ± 0.97, 1.06 ± 1.22, 1.20 ± 1.26 and 0.41 ± 0.73, respectively. Mean mucin concentration measured in bile by the Sepharose CL-4B method was 22.8 ± 24.0 mg/mL (range 3.4-89.0 mg/mL). Mean protein concentration was 8.1 ± 4.8 mg/mL (range 1.7-23.2 mg/mL).
CONCLUSION: High levels of MUC3, MUC5AC and MUC5B are expressed in bile aspirated during ERC examination. A specific pattern of mucin gene expression or change in mucin concentration was not found in gallstone disease.
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Huang Q, Ren XF, Liu CH, Qi W. Construction of the specific MUC5AC-siRNA expression plasmid and effect of siRNA on proliferation and apoptosis in human bile duct cancer line HCCC-9810. Shijie Huaren Xiaohua Zazhi 2009; 17:566-572. [DOI: 10.11569/wcjd.v17.i6.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe specific siRNA silencing effect on Mucin-5 subtype AC gene in human intrahepatic cholangiocarcinoma cell line HCCC-9810 as well as to investigate the influence on proliferation and apoptosis after silencing the Mucin-5 subtype AC gene.
METHODS: Three pairs of specific MUC5AC-siRNA were designed and synthesized through transcription in vitro. Three different siRNA expression plasmids (pRNAT-U6.1/Neo-MUC5AC-siRNA1/2/3) were constructed by gene recombination. Then three stable expression plasmids and the comparison plasmid (empty plasmid-transfected control) were transfected into HCCC-9810 by liposome-mediated transfection. Transfection efficiency was evaluated by nonspecific small molecular siRNA (fluorescent conjugate). MUC5AC-mRNA level was detected by RT-PCR. Expression of Mucin-5 subtype AC was investigated by immunohistochemical SABC method. Cell apoptosis and proliferation were analyzed by flow cytometry and MTT, respectively.
RESULTS: The results of gene sequencing indicated that the pRNAT-U6.1/Neo-MUC5AC-siRNA1/2/3 was successfully constructed. After the transfection, the efficiency of fluorescent protein expression reached 28.57%; the results of RT-PCR and immunocytochemistry showed that constructed plasmids down-regulated mRNA and protein of Mucin-5 subtype AC at 48 h after transfection. The results of MTT indicated that the growth of HCCC-9810 was obviously inhibited after silencing the Mucin-5 subtype AC gene. Apoptosis was induced in the tumor cells after suppressing the expression of Mucin-5 subtype AC gene by flow cytometry.
CONCLUSION: Three different stable expression plasmids of siRNA specific for Mucin-5 subtype AC gene obviously inhibit the expression at MUC5AC-mRNA and protein level. The blockage of Mucin-5 subtype AC gene expression in HCCC-9810 cells shows significant effect on cell apoptosis and proliferation.
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Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer 2008; 45:33-47. [PMID: 18938071 DOI: 10.1016/j.ejca.2008.08.024] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2008] [Revised: 08/06/2008] [Accepted: 08/26/2008] [Indexed: 12/24/2022]
Abstract
The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.
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Affiliation(s)
- Christopher D Briggs
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, Leicester, United Kingdom.
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40
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Xu Y, Zhang L, Hu G. Potential application of alternatively glycosylated serum MUC1 and MUC5AC in gastric cancer diagnosis. Biologicals 2008; 37:18-25. [PMID: 18848467 DOI: 10.1016/j.biologicals.2008.08.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Revised: 08/14/2008] [Accepted: 08/18/2008] [Indexed: 12/12/2022] Open
Abstract
Post-transcription modification of proteins can be altered during carcinogenesis. In this study, quantitative sandwich enzyme immunoassays were utilized to explore the clinical diagnostic value of the alternatively glycosylated MUC1 and MUC5AC. Four pairs of antibodies were selected to construct quantitative sandwich enzyme immunoassay. Serum mucin levels of 104 primary gastric cancer patients and 120 healthy individuals were measured using the four antibody pairs. The detection sensitivities of each antibody pair against gastric cancers were 42.31%, 25.00%, 38.46% and 30.77% respectively, with a specificity of 90.00%, significantly higher than widely used tumor markers CEA (21.15%) and CA19-9 (18.27%). When monitoring in parallel with all of the four antibody pairs, the detection sensitivity increased to 75.00%, with the same 90.00% specificity. Immunoblotting of the serum samples using the anti-mucin antibodies revealed highly variable glycosylation patterns among gastric cancer patients. In addition, real-time PCR indicated the elevated mRNA levels of MUC1 and/or MUC5AC in gastric cancers. The cancer-specific epitopes were also detected in other alimentary canal epithelium cancers such as colonic, nasopharyngeal and esophageal cancers, but with much lower sensitivities. Our results suggested that alternatively glycosylated MUC1 and MUC5AC could be of significant potential as effective tumor markers in gastric cancer diagnosis.
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Affiliation(s)
- Ye Xu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, No. 320 Yueyang Road, Shanghai 20031, China
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41
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Abstract
Alterations in epithelial mucin expression are associated with carcinogenesis, but there are few data in biliary tract cancer (BTC). In pancreatic malignancy, MUC4 is a diagnostic and prognostic tumour marker, whereas MUC5AC has been proposed as a sensitive serological marker for BTC. We assessed MUC4 and MUC5AC expression in (i) prospectively collected bile and serum specimens from 72 patients with biliary obstruction (39 BTC) by real-time reverse transcriptase–PCR (qPCR) and western blot analysis, and (ii) 79 archived biliary tissues (69 BTC) by immunohistochemistry. In bile, MUC4 protein was detected in 27% of BTC and 29% of primary sclerosing cholangitis (PSC) cases, but not in other benign and malignant biliary diseases (P<0.01 and P=0.06). qPCR revealed a 1.9-fold increased MUC4 mRNA expression in BTC patients’ bile compared with benign disease. In archived tissues, MUC4 protein was detected in 37% of BTC but in none of the benign samples (P=0.03). In serum, MUC5AC was found exclusively in BTC and PSC sera (44% and 13%, respectively; P<0.001 for BTC vs non-BTC) and correlated negatively with BTC survival. Biliary MUC4 and serum MUC5AC are highly specific tumour-associated mucins that may be useful in the diagnosis and formulation of therapeutic strategies in BTC.
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Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Iguchi T, Taketomi A, Maehara Y, Tsuneyoshi M. Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression. Hum Pathol 2007; 38:1819-25. [PMID: 17854859 DOI: 10.1016/j.humpath.2007.04.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2007] [Revised: 04/23/2007] [Accepted: 04/24/2007] [Indexed: 11/21/2022]
Abstract
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 (<or=50%), and negative AQP-1 expression was observed in 46 (41%), 20 (19%), and 46 (41%) cases of intrahepatic cholangiocarcinoma, respectively. Large tumor size (>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.
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Affiliation(s)
- Shinichi Aishima
- Department of Pathology, Hamanomachi Hospital, Fukuoka 810-8539, Japan.
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43
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Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Taketomi A, Maehara Y, Tsuneyoshi M. Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behaviour. Histopathology 2006; 49:35-44. [PMID: 16842244 DOI: 10.1111/j.1365-2559.2006.02414.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
AIMS To identify the role of mucus core protein (MUC) in intrahepatic cholangiocarcinoma (ICC). METHODS AND RESULTS We examined the expression profile of MUC2, MUC5AC and MUC6 by immunohistochemical staining in 100 ICCs and compared the clinicopathological factors and the immunohistochemical results. The expression frequency was: MUC2, 9%; MUC5AC, 40%; and MUC6, 21%. According to the gastric mucin expression profile, ICCs were classified into the following groups: null type (n = 43), gastric foveolar type (n = 36), pyloric gland type (n = 11) and gastric combined type (n = 10). Half of the gastric foveolar type and the gastric combined type were located in the hilar region, but the other types were predominant at the periphery (P = 0.0004). Well-differentiated components were more often detected in the gastric combined type and the pyloric gland type (P = 0.0281). The gastric foveolar type was associated with a higher incidence of lymph node metastasis (P < 0.0001). The pyloric gland type was associated with better survival and the gastric foveolar type was associated with worse survival. The gastric mucin phenotype was an independent prognostic factor by multivariate survival analysis. CONCLUSION The gastric foveolar type of ICC was more often associated with aggressive tumour development, whereas the pyloric gland type exhibited less aggressive behaviour.
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Affiliation(s)
- S Aishima
- Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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44
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Bamrungphon W, Prempracha N, Bunchu N, Rangdaeng S, Sandhu T, Srisukho S, Boonla C, Wongkham S. A new mucin antibody/enzyme-linked lectin-sandwich assay of serum MUC5AC mucin for the diagnosis of cholangiocarcinoma. Cancer Lett 2006; 247:301-8. [PMID: 16793202 DOI: 10.1016/j.canlet.2006.05.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2006] [Revised: 05/09/2006] [Accepted: 05/11/2006] [Indexed: 12/31/2022]
Abstract
We have previously used agarose gel electrophoresis and immunoblotting to qualitatively measure serum MUC5AC mucin for diagnosing cholangiocarcinoma. In this study, we developed a quantitative determination of serum MUC5AC by sandwich ELISA using MUC5AC mucin monoclonal antibody and soybean agglutinin. A cut-off value of the absorbance 0.074 was obtained from a complete statistical Receiver Operating Characteristic curves with an area under the curve=0.8141. The assay could discriminate cholangiocarcinoma patients from the controls with 71% sensitivity and 90% specificity. The test is simple to perform, reproducible, and probably used for detecting cholangiocarcinoma in a high-risk group or suspected patients.
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Affiliation(s)
- Wichuda Bamrungphon
- Department of Microbiology, Faculty of Medicine, Chiang Mai Universtiy, Chiang Mai 50002, Thailand
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Boonla C, Sripa B, Thuwajit P, Cha-On U, Puapairoj A, Miwa M, Wongkham S. MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma. World J Gastroenterol 2005; 11:4939-46. [PMID: 16124042 PMCID: PMC4321906 DOI: 10.3748/wjg.v11.i32.4939] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expressions of MUC1 and MUC5AC in intrahepatic cholangiocarcinoma (ICC). Association of expressions of mucins MUC1 and MUC5AC with clinical findings, metastasis, and survival of the liver fluke-associated ICC patients was determined.
METHODS: The expressions of MUC1 and MUC5AC mucins were examined by immunohistochemical staining in 87 cases of histologically-proven ICC. The expressions of mucins in relationship between clinicopathological significance and prognosis of the patients were evaluated.
RESULTS: Fifty-two patients (60%) exhibited both MUC1 and MUC5AC expressions, whereas 31% expressed either MUC1 or MUC5AC, and 9% expressed neither. High MUC1 immunoreactivity displayed a significant correlation with tumor progression as reflected by vascular invasion (P<0.001), whereas high expression of MUC5AC significantly correlated with neural invasion (P = 0.022) and advanced ICC stage (P = 0.008). Patients with high expression of MUC1 had a significantly shorter survival (P = 0.0002). According to multivariate analyses, MUC1 reactivity (P = 0.026), histological grading and stage of tumor represented the least probability of survival.
CONCLUSION: MUC1 is overexpressed in liver fluke-associated cholangiocarcinoma and relates to vascular invasion and poor prognosis, whereas MUC5AC mucin is neoexpressed and relates to neural invasion and advanced ICC stage. High MUC1 expression in tumor may be useful for predicting the poor outcome of ICC patients.
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Affiliation(s)
- Chanchai Boonla
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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Abstract
Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-beta, MUC1 and MUC4, beta-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma.
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Affiliation(s)
- Alphonse E Sirica
- Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus, Richmond, VA 23298-0297, USA.
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47
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Abstract
PURPOSE OF REVIEW Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Most cancers of the biliary tract will have grown beyond the limits of curative resection by the time they become clinically evident. This reality has fostered therapeutic nihilism, and most physicians and surgeons, in their pessimism, have to run ambitious trials evaluating new diagnostic tools and therapeutic techniques in this disease. RECENT FINDINGS Advances in imaging over the period of the last 5 years now allow for earlier diagnosis and better surgical planning. Recent improvements in operative technique have substantially improved the outlook of patients with this cancer. Palliative management of obstructive disease recently has been improved with the advent of photodynamic therapy. Among the different drugs tested in this disease, gemcitabine seems to have the best efficacy:toxicity ratio. However, efficacy results remain disappointing, and combination schedules need to be developed to improve the results. Among them, the gemcitabine-oxaliplatin combination seems to be one of the most promising schedules. Biological studies, especially those evaluating mutation-independent activation of the Hedgehog pathway, have provided interesting information on the carcinogenesis of this rare tumor. Furthermore, these results bring us the opportunity of development of future targeted therapies in biliary tract cancer. SUMMARY Biliary tract neoplasm remains one of the most aggressive malignancies. However, as for other gastrointestinal malignancies, biological studies and diagnostic and therapeutic improvements have provided interesting results that could lead to a major improvement in the prognosis of this disease.
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Affiliation(s)
- David Malka
- Unité de Gastroentérologie, Institut Gustave Roussy, Villejuif, France
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Rullier A, Le Bail B, Fawaz R, Blanc JF, Saric J, Bioulac-Sage P. Cytokeratin 7 and 20 expression in cholangiocarcinomas varies along the biliary tract but still differs from that in colorectal carcinoma metastasis. Am J Surg Pathol 2000; 4:534-540. [PMID: 10843291 DOI: 10.3892/ol.2012.756] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 06/06/2012] [Indexed: 01/01/2023]
Abstract
In the liver, the immunostaining of cytokeratins (CK) 7 and 20 has been used to distinguish usual peripheral cholangiocarcinomas (CC) and colorectal carcinoma metastasis (CRM). However, other subtypes of CC are not infrequent and may be particularly difficult to distinguish from CRM by histology and even immunohistochemistry. Therefore, 48 CC from different locations, either peripheral (n = 19), or nonperipheral, that is, from the large intrahepatic bile ducts, the hilum, and the extrahepatic bile ducts (n = 29), and with different cytoarchitectural patterns were tested for CK7 and CK20 and compared with 31 CRM. CC were positive for CK7 and CK20 in 96% and 70%, respectively, whatever the architecture and differentiation of the tumor. The labeling index (LI) of CK7 in CC was always high, whereas it was low or moderate for CK20. CK20-positive phenotype was significantly more frequent in nonperipheral than in peripheral CC (82% vs 47%; p = 0.007). CRM were all positive for CK20 with a high LI, and mostly negative (81%) for CK7. In conclusion, (1) the CK immunoprofile of CC varies according to the location of the tumor in the biliary tract, peripheral CC being more often CK7+/CK20-, and nonperipheral ones CK7+/CK20+; and (2) a decision tree based on CK20 LI and CK7 positivity allows the distinction of CRM and CC, even for the nonperipheral type.
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Affiliation(s)
- A Rullier
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Pellegrin, Université Victor Ségalen, Bordeaux, France
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