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Chen X, Tu J, Yang M, Wang Y, Liu B, Qiu H, Yuan X. RUNX1-MUC13 Interaction Activates Wnt/β-Catenin Signaling Implications for Colorectal Cancer Metastasis. Int J Biol Sci 2024; 20:4999-5026. [PMID: 39309442 PMCID: PMC11414392 DOI: 10.7150/ijbs.98396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/07/2024] [Indexed: 09/25/2024] Open
Abstract
Background: Colorectal cancer (CRC) remains a significant global health challenge, often characterized by late-stage metastasis and poor prognosis. The Runt-related transcription factor 1 (RUNX1) plays a dual role as both an oncogene and a tumor suppressor in various cancers, including CRC. However, the specific regulatory mechanisms of RUNX1 in CRC, particularly its direct roles, are not fully understood. Objective: This study aimed to investigate the role of RUNX1 in CRC progression and its interaction with Mucin 13 (MUC13) as a potential regulatory target. Methods: RUNX1 expression was analyzed in CRC tissues and cell lines compared to controls. In vitro and in vivo assays were conducted to assess the effects of RUNX1 overexpression and knockdown on cell behavior. ChIP-seq and RNA-seq analyses were performed to identify RUNX1 targets, with a focus on MUC13. Results: RUNX1 expression was significantly upregulated in CRC tissues and cells, correlating with advanced pathological characteristics and poor patient outcomes. RUNX1 overexpression enhanced CRC cell proliferation, migration, invasion, and G2/M phase arrest, while its knockdown had the opposite effects. MUC13 was identified as a direct transcriptional target of RUNX1, with its expression contributing to the activation of the Wnt/β-catenin signaling pathway. Disruption of MUC13 partially reversed the malignant phenotypes induced by RUNX1. Conclusion: RUNX1 promotes CRC progression by upregulating MUC13 and activating the Wnt/β-catenin pathway. This RUNX1-MUC13 axis represents a potential therapeutic target for managing CRC.
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Affiliation(s)
| | | | | | | | - Bo Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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2
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Malik S, Sikander M, Wahid M, Dhasmana A, Sarwat M, Khan S, Cobos E, Yallapu MM, Jaggi M, Chauhan SC. Deciphering cellular and molecular mechanism of MUC13 mucin involved in cancer cell plasticity and drug resistance. Cancer Metastasis Rev 2024; 43:981-999. [PMID: 38498072 DOI: 10.1007/s10555-024-10177-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 02/26/2024] [Indexed: 03/19/2024]
Abstract
There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.
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Affiliation(s)
- Shabnam Malik
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohammed Sikander
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Mohd Wahid
- Unit of Research and Scientific Studies, College of Nursing and Allied Health Sciences, University of Jazan, Jizan, Saudi Arabia
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Maryam Sarwat
- Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Noida, India
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Everardo Cobos
- Department of Medicine, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, Biomedical Research Building, University of Texas Rio Grande Valley, 5300 North L Street, McAllen, TX, 78504, USA.
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA.
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3
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Chen Y, Zhang W, Zeng Y, Yang P, Li Y, Liang X, Liu K, Lin H, Dai Y, Zhou J, Hou B, Ma Z, Lin Y, Pang W, Zeng L. GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase. Oncogene 2024; 43:2564-2577. [PMID: 39020072 DOI: 10.1038/s41388-024-03102-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 07/05/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.
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Affiliation(s)
- Yutong Chen
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Weiyu Zhang
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
- Center for Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Yan Zeng
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Pengfei Yang
- Department of Pathology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Yaning Li
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Xinyue Liang
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Kecheng Liu
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Hai Lin
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Yalan Dai
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Jiancong Zhou
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Bingqi Hou
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Zhenting Ma
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China
| | - Yujing Lin
- Department of Pathology, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Wenzheng Pang
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China.
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
| | - Linjuan Zeng
- Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, 519000, Guangdong Province, China.
- Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
- Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
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4
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Sun F, Ding Z, Shao F, Gao X, Tian H, Zhang X, Chen H, Wang C. Albumin-Based MUC13 Peptide Nanomedicine Suppresses Liver Cancer Stem Cells via JNK-ERK Signaling Pathway-Mediated Autophagy Inhibition. ACS APPLIED MATERIALS & INTERFACES 2024; 16:38968-38978. [PMID: 39024013 DOI: 10.1021/acsami.4c06034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Targeting liver cancer stem cells (LCSCs) is a promising strategy for hepatocellular carcinoma (HCC) therapy. Target selection and corresponding inhibitor screening are of vital importance for eliminating the stemness of LCSCs. Peptide-based agents are hopeful but have long been hindered for in vivo application. Herein, we selected a clinically significant target MUC13 and screened out a suitable peptide for preparation of an albumin-based MUC13 peptide nanomedicine, P3@HSA, which suppressed liver cancer stem cells via JNK-ERK signaling pathway-mediated autophagy inhibition. The selected target MUC13 was highly expressed in LCSCs and associated with the prognosis of liver cancer patients. Encouraged by this observation, we screened the corresponding peptide-based inhibitor P3 for further evaluation. P3 could interact with albumin through the intrinsic hydrophobic force and formed the nanomedicine P3@HSA. The prepared nanomedicine could inhibit LCSCs through JNK-ERK signaling pathway-mediated autophagy inhibition and exert potent antitumor effect both in vitro and in vivo. Together, this study provides a promising peptide-based nanomedicine for high-performance HCC treatment.
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Affiliation(s)
- Fen Sun
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zongyao Ding
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Fengying Shao
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiaoyang Gao
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Haina Tian
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Xiao Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
- Key Laboratory of Biopharmaceutical Preparation and Delivery, Chinese Academy of Sciences, Beijing 100190, China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huaqing Chen
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Changlong Wang
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271016, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
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林 琳, 常 静, 田 耀, 陈 姣. [Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1]. SHENG WU YI XUE GONG CHENG XUE ZA ZHI = JOURNAL OF BIOMEDICAL ENGINEERING = SHENGWU YIXUE GONGCHENGXUE ZAZHI 2024; 41:313-320. [PMID: 38686412 PMCID: PMC11058487 DOI: 10.7507/1001-5515.202306011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 01/10/2024] [Indexed: 05/02/2024]
Abstract
Targeting p21-activated kinase 1 (PAK1) is a novel strategy for pancreatic cancer treatment. Compound Kushen injection contains many anti-pancreatic cancer components, but the specific targets are unknown. In this study, 14α-hydroxymatrine, an active component of Kushen injection, was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening. Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket. Meanwhile, 14α-hydroxymatrine induced the β-folding region at the adenosine triphosphate (ATP)-binding pocket of PAK1 to close inward, resulting in the ATP-binding pocket in a "semi-closed" state which caused the inactivation of PAK1. After removal of 14α-hydroxymatrine, PAK1 showed a tendency to change from the inactive conformation to the active conformation. We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1. This study used modern technologies and methods to study the active components of traditional Chinese medicine, which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.
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Affiliation(s)
- 琳 林
- 南京中医药大学 附属中西医结合医院（南京 210028）Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, P. R. China
- 江苏省中医药研究院（南京 210028）Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P. R. China
- 广州中医药大学 深圳医院（福田）（广东深圳 518000）Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518000, P. R. China
| | - 静杰 常
- 南京中医药大学 附属中西医结合医院（南京 210028）Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, P. R. China
| | - 耀洲 田
- 南京中医药大学 附属中西医结合医院（南京 210028）Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, P. R. China
- 江苏省中医药研究院（南京 210028）Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P. R. China
| | - 姣 陈
- 南京中医药大学 附属中西医结合医院（南京 210028）Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, P. R. China
- 江苏省中医药研究院（南京 210028）Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P. R. China
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6
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Doxtater K, Tripathi MK, Sekhri R, Hafeez BB, Khan S, Zafar N, Behrman SW, Yallapu MM, Jaggi M, Chauhan SC. MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway. Life Sci Alliance 2023; 6:e202301975. [PMID: 37793774 PMCID: PMC10551643 DOI: 10.26508/lsa.202301975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
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Affiliation(s)
- Kyle Doxtater
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Manish K Tripathi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Radhika Sekhri
- Department of Pathology, Montefiore Medical Center College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Bilal B Hafeez
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Sheema Khan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Nadeem Zafar
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Murali M Yallapu
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, USA
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Wu X, Wabitsch M, Yang J, Sakharkar MK. Effects of adipocyte-conditioned cell culture media on S1P treatment of human triple-negative breast cancer cells. PLoS One 2023; 18:e0286111. [PMID: 37220155 DOI: 10.1371/journal.pone.0286111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a wide range of biological functions such as cell proliferation, cell apoptosis and angiogenesis. Its cellular level is elevated in breast cancer, which, in turn, would promote cancer cell proliferation, survival, growth and metastasis. However, the cellular concentration of S1P is normally in the low nanomolar range, and our previous studies showed that S1P selectively induced apoptosis of breast cancer cells at high concentrations (high nanomolar to low micromolar). Thus, local administration of high-concentration S1P alone or in combination of chemotherapy agents could be used to treat breast cancer. The breast mainly consists of mammary gland and connective tissue stroma (adipose), which are dynamically interacting each other. Thus, in the current study, we evaluated how normal adipocyte-conditioned cell culture media (AD-CM) and cancer-associated adipocyte-conditioned cell culture media (CAA-CM) would affect high-concentration S1P treatment of triple-negative breast cancer (TNBC) cells. Both AD-CM and CAA-CM may suppress the anti-proliferative effect and reduce nuclear alteration/apoptosis caused by high-concentration S1P. This implicates that adipose tissue is likely to be detrimental to local high-concentration S1P treatment of TNBC. Because the interstitial concentration of S1P is about 10 times higher than its cellular level, we undertook a secretome analysis to understand how S1P would affect the secreted protein profile of differentiated SGBS adipocytes. At 100 nM S1P treatment, we identified 36 upregulated and 21 downregulated secretome genes. Most of these genes are involved in multiple biological processes. Further studies are warranted to identify the most important secretome targets of S1P in adipocytes and illustrate the mechanism on how these target proteins affect S1P treatment of TNBC.
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Affiliation(s)
- Xiyuan Wu
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Martin Wabitsch
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Jian Yang
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
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8
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Muilenburg KM, Isder CC, Radhakrishnan P, Batra SK, Ly QP, Carlson MA, Bouvet M, Hollingsworth MA, Mohs AM. Mucins as contrast agent targets for fluorescence-guided surgery of pancreatic cancer. Cancer Lett 2023; 561:216150. [PMID: 36997106 PMCID: PMC10150776 DOI: 10.1016/j.canlet.2023.216150] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/16/2023] [Accepted: 03/26/2023] [Indexed: 03/31/2023]
Abstract
Pancreatic cancer is difficult to resect due to its unique challenges, often leading to incomplete tumor resections. Fluorescence-guided surgery (FGS), also known as intraoperative molecular imaging and optical surgical navigation, is an intraoperative tool that can aid surgeons in complete tumor resection through an increased ability to detect the tumor. To target the tumor, FGS contrast agents rely on biomarkers aberrantly expressed in malignant tissue compared to normal tissue. These biomarkers allow clinicians to identify the tumor and its stage before surgical resection and provide a contrast agent target for intraoperative imaging. Mucins, a family of glycoproteins, are upregulated in malignant tissue compared to normal tissue. Therefore, these proteins may serve as biomarkers for surgical resection. Intraoperative imaging of mucin expression in pancreatic cancer can potentially increase the number of complete resections. While some mucins have been studied for FGS, the potential ability to function as a biomarker target extends to the entire mucin family. Therefore, mucins are attractive proteins to investigate more broadly as FGS biomarkers. This review summarizes the biomarker traits of mucins and their potential use in FGS for pancreatic cancer.
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Affiliation(s)
- Kathryn M Muilenburg
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA.
| | - Carly C Isder
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA.
| | - Prakash Radhakrishnan
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, S 45th St, Omaha, NE, 68198, USA.
| | - Quan P Ly
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Department of Surgery, University of Nebraska Medical Center, 983280 Nebraska Medical Center, Omaha, NE, 68198-3280, USA.
| | - Mark A Carlson
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Department of Surgery, University of Nebraska Medical Center, 983280 Nebraska Medical Center, Omaha, NE, 68198-3280, USA.
| | - Michael Bouvet
- Department of Surgery, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA; VA San Diego Healthcare System, 3350 La Jolla Village Dr, San Diego, CA, 92161, USA.
| | - Michael A Hollingsworth
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA.
| | - Aaron M Mohs
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 505 S 45th St, Omaha, NE, 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, S 45th St, Omaha, NE, 68198, USA.
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9
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Sojka L, Opattova A, Bartu L, Horak J, Korenkova V, Novosadova V, Krizkova V, Bruha J, Liska V, Schneiderova M, Kubecek O, Vodickova L, Urbanova M, Simsa J, Vodicka P, Vymetalkova V. MUC13-miRNA-4647 axis in colorectal cancer: Prospects to identifications of risk factors and clinical outcomes. Oncol Lett 2022; 25:72. [PMID: 36688110 PMCID: PMC9843305 DOI: 10.3892/ol.2022.13658] [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: 08/04/2022] [Accepted: 12/09/2022] [Indexed: 01/01/2023] Open
Abstract
MUC13, a transmembrane mucin glycoprotein, is overexpressed in colorectal cancer (CRC), however, its regulation and functions are not fully understood. It has been shown that MUC13 protects colonic epithelial cells from apoptosis. Therefore, studying MUC13 and MUC13-regulated pathways may reveal promising therapeutic approaches for CRC treatment. Growing evidence suggests that microRNAs (miRs) are involved in the development and progression of CRC. In the present study, the MUC13-miR-4647 axis was addressed in association with survival of patients. miR-4647 is predicted in silico to bind to the MUC13 gene and was analyzed by RT-qPCR in 187 tumors and their adjacent non-malignant mucosa of patients with CRC. The impact of previously mentioned genes on survival and migration abilities of cancer cells was validated in vitro. Significantly upregulated MUC13 (P=0.02) in was observed tumor tissues compared with non-malignant adjacent mucosa, while miR-4647 (P=0.05) showed an opposite trend. Higher expression levels of MUC13 (log-rank P=0.05) were associated with worse patient's survival. The ectopic overexpression of studied miR resulted in decreased migratory abilities and worse survival of cells. Attenuated MUC13 expression levels confirmed the suppression of colony forming of CRC cells. In summary, the present data suggested the essential role of MUC13-miR-4647 in patients' survival, and this axis may serve as a novel therapeutic target. It is anticipated MUC13 may hold significant potential in the screening, diagnosis and treatment of CRC.
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Affiliation(s)
- Ladislav Sojka
- Department of Surgery, Thomayer Hospital, 14200 Prague, Czech Republic,Institute of Experimental Medicine, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic
| | - Alena Opattova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Linda Bartu
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic
| | - Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Department of Medical Genetics, 3rd Medical Faculty, Charles University, 10000 Prague, Czech Republic
| | - Vlasta Korenkova
- Institute of Immunology and Microbiology, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
| | - Vendula Novosadova
- Centre for Phenogenomics, Institute of Molecular Genetics, BIOCEV, 25250 Vestec, Czech Republic
| | - Vera Krizkova
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Jan Bruha
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Vaclav Liska
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, 30166 Pilsen, Czech Republic
| | - Michaela Schneiderova
- Department of Surgery, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, 10034 Prague, Czech Republic
| | - Ondrej Kubecek
- Department of Oncology and Radiotherapy, University Hospital and Faculty of Medicine in Hradec Kralove, Charles University, 50005 Hradec Kralove, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Marketa Urbanova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic
| | - Jaromir Simsa
- Department of Surgery, Thomayer Hospital, 14200 Prague, Czech Republic
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, 14200 Prague, Czech Republic,Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12108 Prague, Czech Republic,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic,Correspondence to: Dr Veronika Vymetalkova, Department of Molecular Biology of Cancer, Institute of Experimental Medicine of The Czech Academy of Sciences, Videnska 1083, 14200 Prague, Czech Republic, E-mail:
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10
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Long-Term Characteristics of Human-Derived Biliary Organoids under a Single Continuous Culture Condition. Cells 2022; 11:cells11233797. [PMID: 36497057 PMCID: PMC9741396 DOI: 10.3390/cells11233797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Organoids have been used to investigate the three-dimensional (3D) organization and function of their respective organs. These self-organizing 3D structures offer a distinct advantage over traditional two-dimensional (2D) culture techniques by creating a more physiologically relevant milieu to study complex biological systems. The goal of this study was to determine the feasibility of establishing organoids from various pediatric liver diseases and characterize the long-term evolution of cholangiocyte organoids (chol-orgs) under a single continuous culture condition. We established chol-orgs from 10 different liver conditions and characterized their multicellular organization into complex epithelial structures through budding, merging, and lumen formation. Immunofluorescent staining, electron microscopy, and single-nucleus RNA (snRNA-seq) sequencing confirmed the cholangiocytic nature of the chol-orgs. There were significant cell population differences in the transcript profiles of two-dimensional and organoid cultures based on snRNA-seq. Our study provides an approach for the generation and long-term maintenance of chol-orgs from various pediatric liver diseases under a single continuous culture condition.
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11
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Riley NM, Wen RM, Bertozzi CR, Brooks JD, Pitteri SJ. Measuring the multifaceted roles of mucin-domain glycoproteins in cancer. Adv Cancer Res 2022; 157:83-121. [PMID: 36725114 PMCID: PMC10582998 DOI: 10.1016/bs.acr.2022.09.001] [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] [Indexed: 11/05/2022]
Abstract
Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression and glycosylation of mucins are known hallmarks in numerous malignancies, yet mucin-domain glycoproteins remain enigmatic in the broad landscape of cancer glycobiology. Here we review the multifaceted roles of mucins in cancer through the lens of the analytical and biochemical methods used to study them. We also describe a collection of emerging tools that are specifically equipped to characterize mucin-domain glycoproteins in complex biological backgrounds. These approaches are poised to further elucidate how mucin biology can be understood and subsequently targeted for the next generation of cancer therapeutics.
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Affiliation(s)
- Nicholas M Riley
- Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, United States.
| | - Ru M Wen
- Department of Urology, Stanford University School of Medicine, Stanford, CA, United States
| | - Carolyn R Bertozzi
- Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, United States; Howard Hughes Medical Institute, Stanford, CA, United States
| | - James D Brooks
- Department of Urology, Stanford University School of Medicine, Stanford, CA, United States; Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Sharon J Pitteri
- Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA, United States.
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12
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Li X, Li F. p21-Activated Kinase: Role in Gastrointestinal Cancer and Beyond. Cancers (Basel) 2022; 14:cancers14194736. [PMID: 36230657 PMCID: PMC9563254 DOI: 10.3390/cancers14194736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/23/2022] [Accepted: 09/23/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Gastrointestinal tumors are the most common tumors with a high mortality rate worldwide. Numerous protein kinases have been studied in anticipation of finding viable tumor therapeutic targets, including PAK. PAK is a serine/threonine kinase that plays an important role in the malignant phenotype of tumors. The function of PAK in tumors is highlighted in cell proliferation, survival, motility, tumor cell plasticity and the tumor microenvironment, therefore providing a new possible target for clinical tumor therapy. Based on the current research works of PAK, we summarize and analyze the PAK features and signaling pathways in cells, especially the role of PAK in gastrointestinal tumors, thereby hoping to provide a theoretical basis for both the future studies of PAK and potential tumor therapeutic targets. Abstract Gastrointestinal tumors are the most common tumors, and they are leading cause of cancer deaths worldwide, but their mechanisms are still unclear, which need to be clarified to discover therapeutic targets. p21-activating kinase (PAK), a serine/threonine kinase that is downstream of Rho GTPase, plays an important role in cellular signaling networks. According to the structural characteristics and activation mechanisms of them, PAKs are divided into two groups, both of which are involved in the biological processes that are critical to cells, including proliferation, migration, survival, transformation and metabolism. The biological functions of PAKs depend on a large number of interacting proteins and the signaling pathways they participate in. The role of PAKs in tumors is manifested in their abnormality and the consequential changes in the signaling pathways. Once they are overexpressed or overactivated, PAKs lead to tumorigenesis or a malignant phenotype, especially in tumor invasion and metastasis. Recently, the involvement of PAKs in cellular plasticity, stemness and the tumor microenvironment have attracted attention. Here, we summarize the biological characteristics and key signaling pathways of PAKs, and further analyze their mechanisms in gastrointestinal tumors and others, which will reveal new therapeutic targets and a theoretical basis for the clinical treatment of gastrointestinal cancer.
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13
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Glycosylation in Renal Cell Carcinoma: Mechanisms and Clinical Implications. Cells 2022; 11:cells11162598. [PMID: 36010674 PMCID: PMC9406705 DOI: 10.3390/cells11162598] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Renal cell carcinoma (RCC) is one of the most prevalent malignant tumors of the urinary system, accounting for around 2% of all cancer diagnoses and deaths worldwide. Clear cell RCC (ccRCC) is the most prevalent and aggressive histology with an unfavorable prognosis and inadequate treatment. Patients' progression-free survival is considerably improved by surgery; however, 30% of patients develop metastases following surgery. Identifying novel targets and molecular markers for RCC prognostic detection is crucial for more accurate clinical diagnosis and therapy. Glycosylation is a critical post-translational modification (PMT) for cancer cell growth, migration, and invasion, involving the transfer of glycosyl moieties to specific amino acid residues in proteins to form glycosidic bonds through the activity of glycosyltransferases. Most cancers, including RCC, undergo glycosylation changes such as branching, sialylation, and fucosylation. In this review, we discuss the latest findings on the significance of aberrant glycans in the initiation, development, and progression of RCC. The potential biomarkers of altered glycans for the diagnosis and their implications in RCC have been further highlighted.
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14
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Cai T, Peng B, Hu J, He Y. Long noncoding RNA BBOX1-AS1 promotes the progression of gastric cancer by regulating the miR-361-3p/Mucin 13 signaling axis. Bioengineered 2022; 13:13407-13421. [PMID: 36700475 PMCID: PMC9275992 DOI: 10.1080/21655979.2022.2072629] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Gastric cancer (GC) places a heavy burden on global health, and the information on the molecular mechanism of the progression of GC is still inadequate. Long noncoding RNA (LncRNA) has been confirmed to be widely involved in regulating the progression of GC. Our aim in this study was to explore the role and potential regulatory mechanism of lncRNA BBOX1-AS1 in GC. The expression levels of BBOX1-AS1, miR-361-3p, and MUC13 in GC tissues and cells were evaluated using quantitative real-time polymerase chain reaction and western blotting. The silencer of BBOX1 antisense RNA 1 (BBOX1-AS1) and mucin 13 (MUC13), the mimics and inhibitor of miR-361-3p, and their negative controls were used to alter the expression of these genes. Luciferase reporter, pull-down, and RNA immunoprecipitation assays were performed to verify the correlation between miR-361-3p, BBOX1-AS1, and MUC13. GC cell proliferation, invasion, and apoptosis were detected by cell counting kit-8, transwell, and flow cytometry assays, respectively. An in vivo functional experiment was performed to assess the effect of BBOX1-AS1 on GC. The results showed that BBOX1-AS1 was significantly upregulated in GC tissues. Silencing of BBOX1-AS1 inhibited GC cell proliferation and invasion and inhibited tumor growth in vivo, whereas it promoted apoptosis. MiR-361-3p was significantly downregulated in GC and counteracted the inhibitory effects of BBOX1-AS1 on GC progression. MUC13, which is targeted by miR-361-3p, is significantly upregulated in GC. MUC13 silencing inhibited GC progression was aborgated by miR-361-3p inhibitor. Collectively, BBOX1-AS1 silencing inhibits GC progression by regulating the miR-361-3p/MUC13 axis, providing a potential therapeutic biomarker for GC.
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Affiliation(s)
- Tao Cai
- Department of Gastrointestinal Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Binyu Peng
- Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Jun Hu
- Department of Gastrointestinal Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China
| | - Yan He
- Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan, Hubei, China,CONTACT Yan He Department of Thyroid and Breast Surgery, Hubei No. 3 People’s Hospital of Jianghan University, No. 26 Zhongshan Avenue, Qiaokou District, Wuhan 430033, Hubei, China
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15
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Ji W, Sun X, Gao Y, Lu M, Zhu L, Wang D, Hu C, Chen J, Cao P. Natural Compound Shikonin Is a Novel PAK1 Inhibitor and Enhances Efficacy of Chemotherapy against Pancreatic Cancer Cells. Molecules 2022; 27:2747. [PMID: 35566098 PMCID: PMC9102431 DOI: 10.3390/molecules27092747] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/18/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Shikonin is the main component of root extracts from the Chinese herbal medicine Lithospermum erythrorhizon, which is commonly used for the treatment of various diseases including cancer. Previous research showed that shikonin suppressed pancreatic cancer growth; nevertheless, its molecular targets and mechanisms have not been elucidated. This study aimed to investigate the interaction and regulatory mechanisms of shikonin on its potential target p21-activated kinase 1 (PAK1). Through a labchip-based screening method, shikonin was identified as a potential bioactive PAK1 inhibitor. Molecular docking technology was used to detect the interaction sites of shikonin and PAK1 kinase. Western blot was performed to validate the mechanism. MTT and flow cytometry were practiced to investigate the effect of shikonin against pancreatic cancer cells. The results show that shikonin significantly inhibited the activity of PAK1 kinase with IC50 value of 7.252 ± 0.054 μM. Molecular docking studies showed that shikonin binds to the ATP-binding pocket of the PAK1 kinase domain. Moreover, shikonin inhibited PAK1 activation and its downstream signaling pathway proteins, while reducing proliferation and inducing apoptosis of pancreatic cancer cells. Further studies showed that the treatment of shikonin sensitized pancreatic cancer cells to chemotherapeutic drugs. These results suggest that shikonin, a potential natural inhibitor targeting PAK1 kinase, has promising potent applications in the treatment of pancreatic cancer and chemotherapy sensitization.
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Affiliation(s)
- Wenjing Ji
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China;
| | - Xiaoyan Sun
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Yang Gao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Man Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Lingxia Zhu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Dawei Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Chunping Hu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Jiao Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; (X.S.); (Y.G.); (M.L.); (L.Z.); (D.W.); (C.H.)
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16
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Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway. Nat Cell Biol 2022; 24:364-372. [PMID: 35292781 PMCID: PMC8924000 DOI: 10.1038/s41556-022-00857-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/27/2022] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape autodigestion by digestive enzymes. Here we show that human PDAC tumour cells use gasdermin E (GSDME), a pore-forming protein, to mediate digestive resistance. GSDME facilitates the tumour cells to express mucin 1 and mucin 13, which form a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME−/− PDAC cells results in subcutaneous but not orthotopic tumour formation in mice. Inhibition or knockout of mucin 1 or mucin 13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME–YBX1–mucin axis is also confirmed in patients with PDAC. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments. Lv et al. reveal a non-canonical role for gasdermin E in protecting pancreatic cancer cells from chymotrypsin-mediated digestion in the microenvironment by promoting the transcription factor YBX1 to induce mucin expression.
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17
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Pang Y, Zhang Y, Zhang HY, Wang WH, Jin G, Liu JW, Zhu ZJ. MUC13 promotes lung cancer development and progression by activating ERK signaling. Oncol Lett 2021; 23:37. [PMID: 34966453 PMCID: PMC8669675 DOI: 10.3892/ol.2021.13155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 05/14/2021] [Indexed: 01/14/2023] Open
Abstract
Mucin 13 (MUC13) is a glycoprotein that is expressed on the cell surface and participates in the tumorigenesis of multiple malignancies, including pancreatic cancer, colorectal cancer and renal cancer. However, to the best of our knowledge, the expression levels and function of MUC13 in lung cancer progression have not yet been demonstrated. Therefore, the present study examined the expression pattern and regulatory role of MUC13 in lung cancer tumorigenesis. The results demonstrated that MUC13 was highly expressed in lung cancer tissues and cell lines compared with that in normal tissues and cell lines. Functionally, knockdown of MUC13 inhibited cell proliferation and enhanced the apoptosis of A549 and NCI-H1650 lung cancer cells. Furthermore, silencing of MUC13 suppressed the migration and invasion of lung cancer cells. Additionally, a xenograft tumor model demonstrated that knockdown of MUC13 delayed the development of the lung cancer xenograft and suppressed the expression of proliferation marker Ki-67 in tumor tissues. Mechanistically, MUC13 activated the ERK signaling pathway by enhancing the phosphorylation of ERK, JNK and p38 in lung cancer tissues compared with that in normal tissues. Knockdown of MUC13 inhibited the phosphorylation of ERK/JNK/p38 in A549 and NCI-H1650 cells. Overall, these findings suggested that MUC13 could act as an oncogenic glycoprotein to accelerate the progression of lung cancer via abnormal activation of the ERK/JNK/p38 signaling pathway and might serve as a therapeutic target for lung cancer treatment.
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Affiliation(s)
- Yao Pang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yu Zhang
- Department of Clinical Medicine, Gansu Health Vocational College, Lanzhou, Gansu 730000, P.R. China
| | - Hong-Yi Zhang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Wen-Hao Wang
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Gang Jin
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Jia-Wei Liu
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zi-Jiang Zhu
- Department of Thoracic Surgery No. 2, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
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18
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Lee DH, Choi S, Park Y, Jin HS. Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy. Pharmaceuticals (Basel) 2021; 14:ph14101053. [PMID: 34681277 PMCID: PMC8537522 DOI: 10.3390/ph14101053] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 01/18/2023] Open
Abstract
The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.
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Affiliation(s)
- Dong-Hee Lee
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Seunghyun Choi
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
| | - Yoon Park
- Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
| | - Hyung-seung Jin
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (Y.P.); (H.-s.J.)
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19
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Mashayekhi V, Mocellin O, Fens MH, Krijger GC, Brosens LA, Oliveira S. Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma. Theranostics 2021; 11:9022-9037. [PMID: 34522225 PMCID: PMC8419040 DOI: 10.7150/thno.60350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.
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Affiliation(s)
- Vida Mashayekhi
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Orsola Mocellin
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Marcel H.A.M. Fens
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Gerard C. Krijger
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A.A. Brosens
- Department of Pathology, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Sabrina Oliveira
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
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Moghbeli M, Zangouei AS, Nasrpour Navaii Z, Taghehchian N. Molecular mechanisms of the microRNA-132 during tumor progressions. Cancer Cell Int 2021; 21:439. [PMID: 34419060 PMCID: PMC8379808 DOI: 10.1186/s12935-021-02149-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/13/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer as one of the leading causes of human deaths has always been one of the main health challenges in the world. Despite recent advances in therapeutic and diagnostic methods, there is still a high mortality rate among cancer patients. Late diagnosis is one of the main reasons for the high ratio of cancer related deaths. Therefore, it is required to introduce novel early detection methods. Various molecular mechanisms are associated with the tumor progression and metastasis. MicroRNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) family that has important functions in regulation of the cellular processes such as cell proliferation, apoptosis, and tumor progression. Moreover, they have higher stability in body fluids compared with mRNAs which can be introduced as non-invasive diagnostic markers in cancer patients. MiR-132 has important functions as tumor suppressor or oncogene in different cancers. In the present review, we have summarized all of the studies which have been reported the role of miR-132 during tumor progressions. We categorized the miR-132 target genes based on their cell and molecular functions. Although, it has been reported that the miR-132 mainly functions as a tumor suppressor, it has also oncogenic functions especially in pancreatic tumors. MiR-132 mainly exerts its roles during tumor progressions by regulation of the transcription factors and signaling pathways. Present review clarifies the tumor specific molecular mechanisms of miR-132 to introduce that as an efficient non-invasive diagnostic marker in various cancers.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Nasrpour Navaii
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
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21
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Yan L, Tu B, Yao J, Gong J, Carugo A, Bristow CA, Wang Q, Zhu C, Dai B, Kang Y, Han L, Feng N, Jin Y, Fleming J, Heffernan TP, Yao W, Ying H. Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition. Cancer Res 2021; 81:4054-4065. [PMID: 34117030 DOI: 10.1158/0008-5472.can-20-3792] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 04/22/2021] [Accepted: 06/09/2021] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D -driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D -driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. SIGNIFICANCE: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.
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Affiliation(s)
- Liang Yan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bo Tu
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jun Yao
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Gong
- Department of Biochemistry and Molecular Biology, UTHealth Medical School, Houston, Texas
| | - Alessandro Carugo
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christopher A Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Qiuyun Wang
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cihui Zhu
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bingbing Dai
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ya'an Kang
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Leng Han
- Department of Biochemistry and Molecular Biology, UTHealth Medical School, Houston, Texas
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yanqing Jin
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jason Fleming
- Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Division of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Timothy P Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), The University of Texas MD Anderson Cancer Center, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wantong Yao
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Haoqiang Ying
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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22
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Ganguly K, Rauth S, Marimuthu S, Kumar S, Batra SK. Unraveling mucin domains in cancer and metastasis: when protectors become predators. Cancer Metastasis Rev 2020; 39:647-659. [PMID: 32488403 PMCID: PMC7487023 DOI: 10.1007/s10555-020-09896-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type D domain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.
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Affiliation(s)
- Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Saravanakumar Marimuthu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffet Cancer Center, 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 and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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23
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ErBb Family Proteins in Cholangiocarcinoma and Clinical Implications. J Clin Med 2020; 9:jcm9072255. [PMID: 32708604 PMCID: PMC7408920 DOI: 10.3390/jcm9072255] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022] Open
Abstract
The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the receptor tyrosine kinases (RTK) epidermal growth factor receptor (EGFR; also called ERBB1), ERBB2, ERBB3, and ERBB4. This family is closely associated with the progression of cholangiocarcinoma (CC) through the regulation of cellular networks, which are enhanced during tumorigenesis, metastasis, and chemoresistance. Additionally, the constitutive activation of cellular signaling by the overexpression and somatic mutation-mediated alterations conferred by the ErBb family on cholangiocarcinoma and other cancers enhances tumor aggressiveness and chemoresistance by contributing to the tumor microenvironment. This review summarizes the recent findings on the molecular functions of the ErBb family and their mutations during the progression of cholangiocarcinoma. It also discusses the developments and applications of various devising strategies for targeting the ErBb family through different inhibitors in various stages of clinical trials, which are essential for improving targeted clinical therapies.
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24
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MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways. J Hepatol 2020; 72:761-773. [PMID: 31837357 DOI: 10.1016/j.jhep.2019.11.021] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 10/31/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.
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25
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Liberelle M, Jonckheere N, Melnyk P, Van Seuningen I, Lebègue N. EGF-Containing Membrane-Bound Mucins: A Hidden ErbB2 Targeting Pathway? J Med Chem 2020; 63:5074-5088. [PMID: 32027502 DOI: 10.1021/acs.jmedchem.9b02001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein-protein interactions, with receptor tyrosine kinase ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome, thus raising interest in therapeutic targeting. This paper aims to demonstrate that MUC3, MUC4, MUC12, MUC13, and MUC17 have a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure-function relationship analysis of the conserved domains indicated that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes is discussed, revealing ErbB2-related pathways of cell signaling to be targeted.
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Affiliation(s)
- Maxime Liberelle
- Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Nicolas Jonckheere
- Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.,Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Patricia Melnyk
- Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Isabelle Van Seuningen
- Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.,Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-UMR-S 1277-Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Nicolas Lebègue
- Univ. Lille, Inserm CHU Lille, UMR-S1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, F-59000 Lille, France.,Univ. Lille, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille Neuroscience & Cognition, F-59000 Lille, France
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26
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Reynolds IS, Fichtner M, McNamara DA, Kay EW, Prehn JHM, Burke JP. Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers. Cancer Metastasis Rev 2020; 38:237-257. [PMID: 30680581 DOI: 10.1007/s10555-019-09781-w] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers.
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Affiliation(s)
- Ian S Reynolds
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Michael Fichtner
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Deborah A McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin 9, Ireland
- Department of Pathology, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland.
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27
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Massey AE, Doxtater KA, Yallapu MM, Chauhan SC. Biophysical changes caused by altered MUC13 expression in pancreatic cancer cells. Micron 2020; 130:102822. [PMID: 31927412 DOI: 10.1016/j.micron.2019.102822] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 12/31/2019] [Accepted: 12/31/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal cancers in the United States. This is partly due to the difficulty in early detection of this disease as well as poor therapeutic responses to currently available regimens. Our previous reports suggest that mucin 13 (MUC13, a transmembrane mucin common to gastrointestinal cells) is aberrantly expressed in this disease state, and has been implicated with a worsened prognosis and an enhanced metastatic potential in PanCa. However, virtually no information currently exists to describe the biophysical ramifications of this protein. METHODS To demonstrate the biophysical effect of MUC13 in PanCa, we generated overexpressing and knockdown model cell lines for PanCa and subsequently subjected them to various biophysical experiments using atomic force microscopy (AFM) and cellular aggregation studies. RESULTS AFM-based nanoindentation data showed significant biophysical effects with MUC13 modulation in PanCa cells. The overexpression of MUC13 in Panc-1 cells led to an expected decrease in modulus, and a corresponding decrease in adhesion. With MUC13 knockdown, HPAF-II cells exhibited an increased modulus and adhesion. These results were confirmed with altered cell-cell adhesion as seen with aggregation assays. CONCLUSIONS MUC13 led to significant biophysical changes in PanCa cells and which exhibited characteristic phenotypic changes in cells demonstrated in previous work from our lab. This work gives insight into the use of biophysical measurements that could be used to help diagnose or monitor cancers as well as determine the effects of genetic alterations at a mechanical level.
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Affiliation(s)
- Andrew E Massey
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States
| | - Kyle A Doxtater
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States.
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28
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Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer). Cells 2019; 9:cells9010103. [PMID: 31906106 PMCID: PMC7017063 DOI: 10.3390/cells9010103] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/23/2019] [Accepted: 12/25/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PanCa) is one of the leading causes of death from cancer in the United States. The current standard treatment for pancreatic cancer is gemcitabine, but its success is poor due to the emergence of drug resistance. Natural products have been widely investigated as potential candidates in cancer therapies, and cucurbitacin D (Cuc D) has shown excellent anticancer properties in various models. However, there is no report on the therapeutic effect of Cuc D in PanCa. In the present study, we investigated the effects of the Cuc D on PanCa cells in vitro and in vivo. Cuc D inhibited the viability of PanCa cells in a dose and time dependent manner, as evident by MTS assays. Furthermore, Cuc D treatment suppressed the colony formation, arrest cell cycle, and decreased the invasion and migration of PanCa cells. Notably, our findings suggest that mucin 13 (MUC13) is down-regulated upon Cuc D treatment, as demonstrated by Western blot and qPCR analyses. Furthermore, we report that the treatment with Cuc D restores miR-145 expression in PanCa cells/tissues. Cuc D treatment suppresses the proliferation of gemcitabine resistant PanCa cells and inhibits RRM1/2 expression. Treatment with Cuc D effectively inhibited the growth of xenograft tumors. Taken together, Cuc D could be utilized as a novel therapeutic agents for the treatment/sensitization of PanCa.
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29
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Prognostic and Clinicopathological Significance of MUC Family Members in Colorectal Cancer: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract 2019; 2019:2391670. [PMID: 31933627 PMCID: PMC6942850 DOI: 10.1155/2019/2391670] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 10/24/2019] [Accepted: 11/11/2019] [Indexed: 12/11/2022] Open
Abstract
Objective To assess the association between MUC expression levels in colorectal cancer (CRC) tissues and prognosis and investigate the associations between MUC expression levels and CRC clinicopathological characteristics. Methods The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception through September 13, 2019, to identify studies investigating the association between MUC expression levels in CRC tissues and prognosis. Pooled hazard ratios (HRs) or odds ratio (ORs) with 95% confidence intervals (CIs) were used to evaluate associations between MUC expression levels and prognosis or clinicopathological characteristics, respectively. The heterogeneity between studies was assessed by the I2 values, whereas the likelihood of publication bias was assessed by Egger's linear regression and Begg's rank correlation test. Results Among 33 included studies (n = 6032 patients), there were no associations between combined MUC phenotype expression levels and overall survival (OS) or disease-free survival (DFS)/relapse-free survival (RFS) in patients with CRC. In subgroup analyses, the upregulated MUC1 expression (HR = 1.50; 95% CI, 1.29–1.74; P < 0.00001) was associated with poor OS. However, the upregulated MUC2 expression (HR = 0.64; 95% CI, 0.52–0.79; P < 0.00001) was associated with better OS. Furthermore, a high level of MUC1 expression (HR = 1.99; 95% CI, 0.99–3.99; P = 0.05) was associated with shorter DFS/RFS. However, patients with a low level of MUC2 tumors showed better DFS/RFS than patients with a high level of MUC2 tumors (HR = 0.71; 95% CI, 0.49–1.04; P = 0.08; P = 0.0.009, I2 = 67%) and MUC5AC expression (HR = 0.56; 95% CI, 0.38–0.82; P = 0.003) was associated with longer DFS/RFS. In addition, a high level of MUC1 expression was associated with CRC in the rectum, deeper invasion, lymph node metastasis, distant metastasis, advanced tumor stage, and lymphatic invasion. A high level of MUC2 expression had a protective effect. High secretion of MUC5AC is associated with colon cancer compared with rectal cancer. Conclusion The protein expression of MUC1 might be a poor biomarker in colorectal cancer and might play a role in tumor transformation and metastasis. However, the protein expression of MUC2 expression might have a protective effect. Furthermore, randomized controlled trials (RCTs) of large patients are needed to confirm the results.
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30
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Samanta K, Setua S, Kumari S, Jaggi M, Yallapu MM, Chauhan SC. Gemcitabine Combination Nano Therapies for Pancreatic Cancer. Pharmaceutics 2019; 11:E574. [PMID: 31689930 PMCID: PMC6920852 DOI: 10.3390/pharmaceutics11110574] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/28/2019] [Accepted: 10/28/2019] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy.
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Affiliation(s)
- Kamalika Samanta
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Saini Setua
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Sonam Kumari
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| | - Meena Jaggi
- Department of Immunology and Microbiology, Institute for Cancer Immunotherapy, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA.
| | - Murali M Yallapu
- Department of Immunology and Microbiology, Institute for Cancer Immunotherapy, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA.
| | - Subhash C Chauhan
- Department of Immunology and Microbiology, Institute for Cancer Immunotherapy, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78503, USA.
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Yan L, Raj P, Yao W, Ying H. Glucose Metabolism in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11101460. [PMID: 31569510 PMCID: PMC6826406 DOI: 10.3390/cancers11101460] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC.
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Affiliation(s)
- Liang Yan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Priyank Raj
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Wantong Yao
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Haoqiang Ying
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity. Oncogene 2019; 38:7294-7310. [PMID: 31427737 DOI: 10.1038/s41388-019-0951-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 02/26/2019] [Accepted: 05/12/2019] [Indexed: 12/13/2022]
Abstract
Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103+ dendritic cells and CD8+ T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.
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Symeonidis N, Lambropoulou M, Pavlidis E, Anagnostopoulos C, Tsaroucha A, Kotini A, Nikolaidou C, Kiziridou A, Simopoulos C. PAK1 Expression in Pancreatic Cancer: Clinicopathological Characteristics and Prognostic Significance. Clin Med Insights Oncol 2019; 13:1179554919831990. [PMID: 30799970 PMCID: PMC6379789 DOI: 10.1177/1179554919831990] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 01/17/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Improvement of the management of pancreatic cancer requires a better understanding of the genetic and molecular changes responsible for the development of the disease. The family of p21-activated kinases (PAKs) and especially PAK1 appears to mediate many cellular processes that contribute to the development and progression of pancreatic cancer, but the clinical relevance of PAK1 expression with the disease still remains unclear. Aim of the study was to assess the clinical value and the potential prognostic significance of PAK1 in pancreatic adenocarcinoma. METHODS We investigated the relationship between the PAK1 expression and the clinical and histopathologic characteristics of pancreatic cancer patients and the potential significance of PAK1 on survival. We examined tissue samples from 51 patients operated for pancreatic cancer. PAK1 expression was investigated with immunohistochemistry and correlated to clinicopathological parameters. RESULTS PAK1 was detected in all tumor samples and high expression was found in most patients. High PAK1 expression was also associated with younger age and well-differentiated tumors, but no association was found between PAK1 expression and Tumor-Node-Metastasis stage as well as deceased or alive status on follow-up. Moderate to high PAK1 expression favored higher 6-month and 1-year survival and low PAK1 expression 2-year survival but without statistical significance. CONCLUSIONS Our results indicate that PAK1 could potentially be used as a prognostic marker in pancreatic cancer. Further studies could clarify whether utilization of PAK1 in therapeutic protocols for the treatment of pancreatic cancer will render them more effective.
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Affiliation(s)
- Nikolaos Symeonidis
- Postgraduate Program in
Hepatobiliary/Pancreatic Surgery, School of Medicine, Democritus University of
Thrace, Alexandroupolis, Greece
- 2nd Surgical Propedeutic Department,
Hippokratio General Hospital, Thessaloniki, Greece
| | - Maria Lambropoulou
- Laboratory of Histology-Embryology,
School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Efstathios Pavlidis
- Postgraduate Program in
Hepatobiliary/Pancreatic Surgery, School of Medicine, Democritus University of
Thrace, Alexandroupolis, Greece
| | | | - Alexandra Tsaroucha
- 2nd Department of Surgery and Laboratory
of Experimental Surgery—Postgraduate Program in Hepatobiliary/Pancreatic Surgery,
School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Athanasia Kotini
- Laboratory of Medical Physics, School of
Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Christina Nikolaidou
- Laboratory of Histology-Embryology,
School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Anastasia Kiziridou
- Department of Pathology, Theagenio
Anticancer Hospital, Thessaloniki, Greece
| | - Constantinos Simopoulos
- 2nd Department of Surgery and Laboratory
of Experimental Surgery—Postgraduate Program in Hepatobiliary/Pancreatic Surgery,
School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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LaMonte GM, Orjuela-Sanchez P, Calla J, Wang LT, Li S, Swann J, Cowell AN, Zou BY, Abdel-Haleem Mohamed AM, Villa Galarce ZH, Moreno M, Tong Rios C, Vinetz JM, Lewis N, Winzeler EA. Dual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection. Nat Commun 2019; 10:488. [PMID: 30700707 PMCID: PMC6353872 DOI: 10.1038/s41467-019-08349-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 12/24/2018] [Indexed: 12/28/2022] Open
Abstract
The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human mucosal immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host mucosal immunity is reprogrammed during the progression of infection.
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Affiliation(s)
- Gregory M LaMonte
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Pamela Orjuela-Sanchez
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Jaeson Calla
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Lawrence T Wang
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Shangzhong Li
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
- Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, La Jolla, CA, 92093, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Justine Swann
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Annie N Cowell
- Division of Infectious Diseases, Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Bing Yu Zou
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Alyaa M Abdel-Haleem Mohamed
- Computational Bioscience Research Centre (CBRC) and Biological and Environmental Sciences and Engineering (BESE) division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Zaira Hellen Villa Galarce
- Laboratorio ICEMR-Amazonia, Laboratorio de Investigación y Desarrollo, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Marta Moreno
- Laboratorio ICEMR-Amazonia, Laboratorio de Investigación y Desarrollo, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, Peru
- London School of Hygiene and Tropical Medicine, Department of Immunology and Infection, London, UK
| | - Carlos Tong Rios
- Laboratorio ICEMR-Amazonia, Laboratorio de Investigación y Desarrollo, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Joseph M Vinetz
- Division of Infectious Diseases, Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
- Laboratorio ICEMR-Amazonia, Laboratorio de Investigación y Desarrollo, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Lima, Peru
- Yale School of Medicine, Section of Infectious Diseases, Department of Internal Medicine, New Haven, CT, USA
| | - Nathan Lewis
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA
- Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, La Jolla, CA, 92093, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Elizabeth A Winzeler
- Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA.
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Kashyap VK, Wang Q, Setua S, Nagesh PKB, Chauhan N, Kumari S, Chowdhury P, Miller DD, Yallapu MM, Li W, Jaggi M, Hafeez BB, Chauhan SC. Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:29. [PMID: 30674344 PMCID: PMC6343279 DOI: 10.1186/s13046-018-1009-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/17/2018] [Indexed: 12/15/2022]
Abstract
Background The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. Methods We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. Results We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model. Conclusions This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment. Electronic supplementary material The online version of this article (10.1186/s13046-018-1009-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vivek K Kashyap
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Qinghui Wang
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Saini Setua
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Prashanth K B Nagesh
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Neeraj Chauhan
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Sonam Kumari
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Pallabita Chowdhury
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Duane D Miller
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Wei Li
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA.
| | - Bilal Bin Hafeez
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA.
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences, Institute of Biomarker and Molecular Therapeutics (IBMT), College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA.
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Stiles ZE, Khan S, Patton KT, Jaggi M, Behrman SW, Chauhan SC. Transmembrane mucin MUC13 distinguishes intraductal papillary mucinous neoplasms from non-mucinous cysts and is associated with high-risk lesions. HPB (Oxford) 2019; 21:87-95. [PMID: 30115565 PMCID: PMC6349495 DOI: 10.1016/j.hpb.2018.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 04/25/2018] [Accepted: 07/09/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intraductal papillary mucinous neoplasms (IPMN) are currently managed based on imaging characteristics and cyst fluid sampling. This study was designed to determine if MUC13, a glycoprotein aberrantly overexpressed in pancreatic adenocarcinoma, might aid in distinguishing high-risk lesions (high grade dysplasia/invasive disease) from low-grade lesions. METHODS MUC13 immunohistochemical staining was performed on surgically resected formalin-fixed tissue specimens from 49 IPMNs and 23 non-mucinous cysts. Membranous MUC13 expression was measured by H-score, which quantifies staining intensity and the percentage of cells involved (range 0-300). RESULTS MUC13 expression was detected in all IPMNs and was significantly greater than in non-mucinous cysts (median 210 vs 40, p < 0.001). MUC13 expression was similar among main (n = 26), branch (n = 15), and mixed (n = 8) duct lesions (median 210, 200, 225, respectively). The highest expression was observed in tumors with intestinal and pancreatobiliary histologic features (both median 225) and the lowest in gastric type lesions (median 200). MUC13 expression was significantly greater in high-risk lesions (n = 21) compared to those with low-grade dysplasia (n = 28) (median 250 vs 195, p < 0.001). CONCLUSION MUC13 expression was significantly greater in high-risk IPMNs in this analysis. The preoperative assessment of MUC13 in cyst fluid samples warrants further investigation.
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Affiliation(s)
- Zachary E Stiles
- Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Sheema Khan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Kurt T Patton
- Pathology Group of the Midsouth, Germantown, TN, 38138, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Stephen W Behrman
- Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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Chen ST, Kuo TC, Liao YY, Lin MC, Tien YW, Huang MC. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene 2018; 37:6041-6053. [PMID: 29993037 PMCID: PMC6237765 DOI: 10.1038/s41388-018-0403-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/28/2018] [Accepted: 06/14/2018] [Indexed: 12/18/2022]
Abstract
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.
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Affiliation(s)
- Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Yu Liao
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital, Hsinchu, Hsinchu, Taiwan
- National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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Filippou PS, Ren AH, Korbakis D, Dimitrakopoulos L, Soosaipillai A, Barak V, Frenkel S, Pe'er J, Lotem M, Merims S, Molina R, Blasutig I, Bogdanos DP, Diamandis EP. Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. Clin Chem Lab Med 2018; 56:1945-1953. [PMID: 29768245 DOI: 10.1515/cclm-2018-0139] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/10/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions. METHODS We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals. RESULTS MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease. CONCLUSIONS Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential.
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Affiliation(s)
- Panagiota S Filippou
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Annie H Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Dimitrios Korbakis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lampros Dimitrakopoulos
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Antoninus Soosaipillai
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Vivian Barak
- Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Shahar Frenkel
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Jacob Pe'er
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michal Lotem
- Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Sharon Merims
- Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel
| | - Rafael Molina
- Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Ivan Blasutig
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, University of Thessaly, Larissa, Greece
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Mount Sinai Hospital, Joseph and Wolf Lebovic Ctr., 60 Murray St [Box 32], Flr 6 - Rm L6-201, Toronto, ON, M5T 3L9, Canada
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Wang K, Baldwin GS, Nikfarjam M, He H. p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation. World J Gastroenterol 2018; 24:3709-3723. [PMID: 30197477 PMCID: PMC6127653 DOI: 10.3748/wjg.v24.i33.3709] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
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Affiliation(s)
- Kai Wang
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Graham S Baldwin
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
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40
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Mito K, Saito M, Morita K, Maetani I, Sata N, Mieno M, Fukushima N. Clinicopathological and prognostic significance of MUC13 and AGR2 expression in intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 2018; 18:407-412. [PMID: 29650332 DOI: 10.1016/j.pan.2018.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 03/14/2018] [Accepted: 04/02/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a primary pancreatic ductal epithelial neoplasm with the potential to develop into an invasive adenocarcinoma. This study aimed to investigate the clinicopathologic and prognostic significance of four potential biomarkers for the preoperative evaluation of patients with IPMN. MATERIALS AND METHODS Clinicopathologic materials from 104 patients with IPMN who underwent surgical resection at Jichi Medical University Hospital were analyzed. IPMNs (110 lesions in total) were histologically classified into low-grade IPMN (Group 1; n = 68), high-grade IPMN (Group 2; n = 16), or IPMN with an associated invasive carcinoma (Group 3; n = 26). We evaluated the immunohistochemical expression of MUC13, AGR2, FUT8, and FXYD3, which were previously reported to be overexpressed in pancreatic ductal adenocarcinoma. RESULTS The expression of MUC13 was more common in Group 3 compared with groups 1 and 2 (p < 0.001) and was associated with poor prognosis (p = 0.004). The expression of MUC13 was not associated with age, sex, tumor location, histological subtype, lymphatic or vascular invasion, or neural invasion. In most cases of IPMN, the loss of expression of AGR2 appeared to show an association with tumor recurrence and poorly differentiated histology of invasive carcinoma; however, this association was not statistically significant. The expressions of FUT8 and FXYD3were not associated with the clinicopathological features of IPMNs. CONCLUSIONS The results suggest that MUC13 overexpression and loss of expression of AGR2 may predict the progression of IPMN and an unfavorable prognosis in patients with IPMN.
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Affiliation(s)
- Kumiko Mito
- Department of Pathology, Jichi Medical University, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Ohashi Medical Center, Japan
| | - Michihiro Saito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Ohashi Medical Center, Japan
| | - Kohei Morita
- Department of Pathology, Jichi Medical University, Japan
| | - Iruru Maetani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Ohashi Medical Center, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Japan
| | - Makiko Mieno
- Department of Medical Informatics, Center for Information Jichi Medical University, Japan
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Khan S, Zafar N, Khan SS, Setua S, Behrman SW, Stiles ZE, Yallapu MM, Sahay P, Ghimire H, Ise T, Nagata S, Wang L, Wan JY, Pradhan P, Jaggi M, Chauhan SC. Clinical significance of MUC13 in pancreatic ductal adenocarcinoma. HPB (Oxford) 2018; 20:563-572. [PMID: 29352660 PMCID: PMC5995635 DOI: 10.1016/j.hpb.2017.12.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/22/2017] [Accepted: 12/19/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.
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Affiliation(s)
- Sheema Khan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Nadeem Zafar
- Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Shabia S. Khan
- Department of Computer Science, University of Kashmir, Srinagar, India
| | - Saini Setua
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Stephen W. Behrman
- Department of Surgery, Baptist Memorial Hospital and the University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Zachary E Stiles
- Department of Surgery, Baptist Memorial Hospital and the University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Murali M. Yallapu
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Peeyush Sahay
- Department of Physics, University of Memphis, Memphis, Tennessee, USA
| | - Hemendra Ghimire
- Department of Physics, University of Memphis, Memphis, Tennessee, USA
| | - Tomoko Ise
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-City, Osaka, Japan
| | - Satoshi Nagata
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-City, Osaka, Japan
| | - Lei Wang
- Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jim Y. Wan
- Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Prabhakar Pradhan
- Department of Physics, University of Memphis, Memphis, Tennessee, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Subhash C. Chauhan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA,Corresponding Authors: Subhash C. Chauhan, Ph.D., Professor, Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 South Manassas, Cancer Research Building, Memphis, TN, 38163. Phone: (901) 448-2175. Fax: (901) 448-1051.
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Etekpo A, Alghawalby A, Alghawalby M, Soliman AS, Hablas A, Chen B, Batra S, Soliman GA. Differences in MUC4 Expression in Pancreatic Cancers and Pancreatic Cysts in Egypt. ACTA ACUST UNITED AC 2018; 9. [PMID: 34164227 PMCID: PMC8218782 DOI: 10.4172/2157-2518.1000312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is the fourth cause of cancer deaths in the U.S. with most patients diagnosed at advanced stages followed by short survival. Therefore, biomarkers for early detection are urgently needed. Mucin 4 (MUC4) is a mucin protein encoded by the MUC4 gene and identified in the majority of pancreatic cancers. With increasing clinical identification and diagnosis of pancreatic cysts globally and transformation of some cysts into pancreatic cancer, it is important to evaluate if MUC4 is expressed in pancreatic cysts. Immunohistochemistry assays utilizing heat-induced epitope retrieval (HIER) were performed to examine MUC4 protein expression in 44 paraffin-embedded tissues of pancreatic cancers and 20 pancreatic cysts. All patients were diagnosed and operated upon at the Mansoura University Gastrointestinal Surgery Center in Egypt. Clinical, demographic, and survival information were abstracted from the patients’ medical records. Logistic regression was performed to predict expression of MUC4 protein in cancer and cysts, by type of cysts. Pancreatic cyst patients were significantly younger than pancreatic cancer patients (Mean age of 28.7 ± 5.25 vs. 54.84 ± 10.60 years) (p=0.0001). Expression of MUC4 was not different between cancers and pancreatic cysts (p=0.16). However, type of pancreatic cysts was predictive of MUC4 expression. Mucinous cystic neoplasms and serous cystadenoma cysts showed significantly higher MUC4 expression than non-specified and pseudocysts (80%, 75%, 25%, and 0% expression for the 4 types of cysts, respectively) (p=0.022). MUC4 expression may be associated with certain types of cysts. Follow-up of pancreatic cyst patients who show MUC4 expression might reveal clues to early detection of pancreatic cancer.
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Affiliation(s)
- Asserewou Etekpo
- Department of Epidemiology, University of Nebraska Medical Center, College of Public Health, Omaha Nebraska, USA
| | - Ahmad Alghawalby
- Department of Radiotherapy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Marwa Alghawalby
- Department of Radiotherapy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Amr S Soliman
- Department of Community Health and Social Medicine, School of Medicine, City University of New York, New York, USA
| | | | - Baojiang Chen
- Department of Biostatistics, University of Nebraska Medical Center, College of Public Health, Omaha, Nebraska, USA
| | - Surinder Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha Nebraska, USA
| | - Ghada A Soliman
- Department of Environmental, Occupational, and Geospatial Health Sciences, Graduate School of Public Health and Health Policy, City University of New York, New York, USA.,Advanced Science Research Center, City University of New York, New York, USA
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43
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Xu Z, Liu Y, Yang Y, Wang J, Zhang G, Liu Z, Fu H, Wang Z, Liu H, Xu J. High expression of Mucin13 associates with grimmer postoperative prognosis of patients with non-metastatic clear-cell renal cell carcinoma. Oncotarget 2018; 8:7548-7558. [PMID: 27911274 PMCID: PMC5352342 DOI: 10.18632/oncotarget.13692] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 11/22/2016] [Indexed: 01/11/2023] Open
Abstract
Background Mucin13 (MUC13) is a transmembrane glycoprotein that is aberrantly expressed in ovarian and gastro-intestinal tumors, but its role in renal cell carcinoma remains elusive. The purpose of this study is to evaluate the prognostic value of MUC13 expression in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) after surgical resection. Results MUC13 high expression was associated with high Fuhrman grade (p < 0.001), high SSIGN score (p = 0.011), early recurrence (p < 0.001) and poor survival (p < 0.001). Multivariate Cox regression analysis identified MUC13 expression as an independent prognostic factor for RFS and OS of ccRCC patients. A nomogram integrating MUC13 expression and other independent prognosticators was established to predict RFS and OS of ccRCC patients. Optimal agreement was shown between the predictions and observations in calibration curves. Matrials and methods This study enrolled 410 postoperative non-metastatic ccRCC patients at a single institution. Clinicopathologic variables, recurrence-free survival (RFS), and overall survival (OS) were recorded. MUC13 expression was detected by immunohistochemical staining in tumor specimens. Association of MUC13 expression with clinicopathological factors was explored. Kaplan-Meier analysis was performed to compare survival curves. Univariate and multivariate Cox regression models were used to analyze the impact of prognostic factors on RFS and OS. A prognostic nomogram was constructed based on the independent prognostic factors identified by multivariate analysis. Conclusions MUC13 high expression is a novel independent adverse prognostic factor of clinical outcome in non-metastatic ccRCC patients after surgery.
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Affiliation(s)
- Zhiying Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yidong Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yuanfeng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jieti Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Guodong Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zheng Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Hangcheng Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zewei Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Haiou Liu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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MUC13 contributes to rewiring of glucose metabolism in pancreatic cancer. Oncogenesis 2018; 7:19. [PMID: 29467405 PMCID: PMC5833644 DOI: 10.1038/s41389-018-0031-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 12/04/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic tumors are rewired for high-glucose metabolism and typically present with exceptionally poor prognosis. Recently, we have shown that MUC13, which is highly expressed in pancreatic tumors, promotes tumor progression via modulation of HER2 receptor tyrosine kinase activity. Herein, we investigate a novel, MUC13-mediated molecular mechanism responsible for higher glucose metabolism in pancreatic tumors. Our results demonstrate that MUC13 expression leads to the activation/nuclear translocation of NF-κB p65 and phosphorylation of IκB, which in turn upregulates the expression of important proteins (Glut-1, c-Myc, and Bcl-2) that are involved in glucose metabolism. MUC13 functionally interacts and stabilizes Glut-1 to instigate downstream events responsible for higher glucose uptake in pancreatic cancer cells. Altered MUC13 expression by overexpression and knockdown techniques effectively modulated glucose uptake, lactate secretion, and metastatic phenotypes in pancreatic cancer cells. NF-κB inhibitor, Sulfasalazine, abrogates the MUC13 and Glut-1 interaction, and attenuates events associated with MUC13-induced glucose metabolism. Pancreatic ductal adenocarcinoma (PDAC) patient tissue samples also show a positive correlation between the expression of these two proteins. These results delineate how MUC13 rewire aberrant glucose metabolism to enhance aggressiveness of pancreatic cancer and revealed a novel mechanism to develop newer therapeutic strategies for this exceptionally difficult cancer.
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Overexpression of MUC13, a Poor Prognostic Predictor, Promotes Cell Growth by Activating Wnt Signaling in Hepatocellular Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:378-391. [DOI: 10.1016/j.ajpath.2017.10.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/25/2017] [Accepted: 10/19/2017] [Indexed: 12/27/2022]
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46
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Suh H, Pillai K, Morris DL. Mucins in pancreatic cancer: biological role, implications in carcinogenesis and applications in diagnosis and therapy. Am J Cancer Res 2017; 7:1372-1383. [PMID: 28670497 PMCID: PMC5489784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/25/2017] [Indexed: 06/07/2023] Open
Abstract
Pancreatic cancer is the fourth highest cause of cancer mortality in the world. It has very low survival rates owing to late diagnosis resulting from the absence of accurate diagnostic tools and effective therapies. Hence, there is a pressing need to develop new diagnostic and therapeutic tools. In the recent years, there has been new evidence implicating the importance of mucins in pancreatic carcinogenesis. Mucins belong to a group of heavily glycosylated proteins, and are often aberrantly expressed in a number of cancers such as pancreatic cancer. Therefore, this literature review will summarise the role of mucins and mucin expression in pancreatic neoplasms. Subsequently the paper will also discuss the most recent advances in the biological properties of mucins and their role in carcinogenesis and resistance to chemotherapy. Then it will conclude on the newest developments in diagnosis and therapy based on mucins for pancreatic cancer.
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Affiliation(s)
- Hyerim Suh
- University of New South Wales, School of MedicineSydney NSW, Australia
| | - Krishna Pillai
- Department of Surgery, St George Hospital, The University of New South WalesKogarah, Sydney NSW 2217, Australia
| | - David Lawson Morris
- Department of Surgery, St George Hospital, The University of New South WalesKogarah, Sydney NSW 2217, Australia
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47
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He L, Qu L, Wei L, Chen Y, Suo J. Reduction of miR‑132‑3p contributes to gastric cancer proliferation by targeting MUC13. Mol Med Rep 2017; 15:3055-3061. [PMID: 28339011 PMCID: PMC5428394 DOI: 10.3892/mmr.2017.6347] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 01/16/2017] [Indexed: 02/07/2023] Open
Abstract
Abnormal expression of epidermal growth factor receptor (EGFR) signaling and microRNAs (miRNAs) has been widely seen in gastric cancer. The present study focused on the miRNAs that regulate human epidermal growth factor receptor (HER) activation through mucin 13 (MUC13). The protein level of MUC13 was demonstrated to be significantly increased in gastric cancer tissues compared with normal tissues by western blot analysis and immunohistochemistry. TargetScan bioinformatic predictions indicated that miRNA (miR)‑212‑3p and miR‑132‑3p may bind to the 3'‑untranslated region of MUC13. Further investigation revealed that miR‑132‑3p was significantly decreased in gastric cancer tissues compared with normal tissues, whereas miR‑212‑3p expression was unaffected. Luciferase assays and western blot confirmed MUC13 as a target gene of miR‑132‑3p. Inhibition of miR‑132‑3p enhanced gastric cancer cell migration through activation of HER2, extracellular signal‑regulated kinase (ERK) and Akt serine/threonine kinase (Akt) signaling, which was a similar effect to that of MUC13 overexpression. In summary, reduction of miR‑132‑3p may contribute to gastric cancer proliferation by targeting MUC13.
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Affiliation(s)
- Liang He
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Linlin Qu
- Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Lijing Wei
- Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yan Chen
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jian Suo
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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48
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Rao CV, Janakiram NB, Mohammed A. Molecular Pathways: Mucins and Drug Delivery in Cancer. Clin Cancer Res 2017; 23:1373-1378. [PMID: 28039261 PMCID: PMC6038927 DOI: 10.1158/1078-0432.ccr-16-0862] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 12/12/2022]
Abstract
Over the past few decades, clinical and preclinical studies have clearly demonstrated the role of mucins in tumor development. It is well established that mucins form a barrier impeding drug access to target sites, leading to cancer chemoresistance. Recently gained knowledge regarding core enzyme synthesis has opened avenues to explore the possibility of disrupting mucin synthesis to improve drug efficacy. Cancer cells exploit aberrant mucin synthesis to efficiently mask the epithelial cells and ensure survival under hostile tumor microenvironment conditions. However, O-glycan synthesis enzyme core 2 beta 1,6 N-acetylglucosaminyltransferase (GCNT3/C2GnT-2) is overexpressed in Kras-driven mouse and human cancer, and inhibition of GCNT3 has been shown to disrupt mucin synthesis. This previously unrecognized developmental pathway might be responsible for aberrant mucin biosynthesis and chemoresistance. In this Molecular Pathways article, we briefly discuss the potential role of mucin synthesis in cancers, ways to improve drug delivery and disrupt mucin mesh to overcome chemoresistance by targeting mucin synthesis, and the unique opportunity to target the GCNT3 pathway for the prevention and treatment of cancers. Clin Cancer Res; 23(6); 1373-8. ©2016 AACR.
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Affiliation(s)
- Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Hematology and Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Hematology and Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Hematology and Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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Setua S, Khan S, Doxtater K, Yallapu MM, Jaggi M, Chauhan SC. miR-145: Revival of a Dragon in Pancreatic Cancer. JOURNAL OF NATURE AND SCIENCE 2017; 3:e332. [PMID: 28616589 PMCID: PMC5467535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Emergence of the role of MicroRNA-145 (miR-145) as a tumor suppressor in pancreatic cancer, offers its potential for novel therapeutic interventions. Our recently published studies demonstrate clinical significance of miR-145 in pancreatic cancer and suggest that the dysregulation of miR-145 in human pancreatic tumors draws in parallel with the aberrant expression of an oncogenic mucin, MUC13. These studies also present a novel therapeutic strategy of restoring the downregulated levels of miR-145 in pancreatic cancer via nanoparticle mediated efficient delivery system.
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Affiliation(s)
| | | | | | | | | | - Subhash C. Chauhan
- Corresponding Author: Subhash C. Chauhan, Ph.D., Professor, Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 South Manassas, Cancer Research Building, Memphis, TN, 38163. Phone: (901) 448-2175. Fax: (901)-448-1051.
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50
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Sheng Y, Ng CP, Lourie R, Shah ET, He Y, Wong KY, Seim I, Oancea I, Morais C, Jeffery PL, Hooper J, Gobe GC, McGuckin MA. MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance. Int J Cancer 2017; 140:2351-2363. [PMID: 28205224 DOI: 10.1002/ijc.30651] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/21/2016] [Accepted: 01/25/2017] [Indexed: 01/09/2023]
Abstract
Metastatic renal cell carcinoma is a largely incurable disease, and existing treatments targeting angiogenesis and tyrosine kinase receptors are only partially effective. Here we reveal that MUC13, a cell surface mucin glycoprotein, is aberrantly expressed by most renal cell carcinomas, with increasing expression positively correlating with tumor grade. Importantly, we demonstrated that high MUC13 expression was a statistically significant independent predictor of poor survival in two independent cohorts, particularly in stage 1 cancers. In cultured renal cell carcinoma cells MUC13 promoted proliferation and induced the cell cycle regulator, cyclin D1, and inhibited apoptosis by inducing the anti-apoptotic proteins, BCL-xL and survivin. Silencing of MUC13 expression inhibited migration and invasion, and sensitized renal cancer cells to killing by the multi-kinase inhibitors used clinically, sorafenib and sunitinib, and reversed acquired resistance to these drugs. Furthermore, we demonstrated that MUC13 promotion of renal cancer cell growth and survival is mediated by activation of nuclear factor κB, a transcription factor known to regulate the expression of genes that play key roles in the development and progression of cancer. These results show that MUC13 has potential as a prognostic marker for aggressive early stage renal cell cancer and is a plausible target to sensitize these tumors to therapy.
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Affiliation(s)
- Yonghua Sheng
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Choa Ping Ng
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Rohan Lourie
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Esha T Shah
- Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Yaowu He
- Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia
| | - Kuan Yau Wong
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Inge Seim
- Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - Iulia Oancea
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Christudas Morais
- Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia
| | - Penny L Jeffery
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.,Ghrelin Research Group, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.,Comparative and Endocrine Biology Laboratory, Translational Research Institute-Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
| | - John Hooper
- Cancer Biology Group, Mater Research Institute-University of Queensland, Brisbane, QLD, Australia
| | - Glenda C Gobe
- Centre for Kidney Disease Research, The University of Queensland School of Medicine, Translational Research Institute, Brisbane, QLD, Australia
| | - Michael A McGuckin
- Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
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