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1
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Matsumoto K, Kato H, Tsutsumi K, Otsuka M. Current status of endoscopic ultrasound-guided antitumor treatment for pancreatic cancer. Dig Endosc 2025; 37:18-28. [PMID: 38752622 PMCID: PMC11718125 DOI: 10.1111/den.14815] [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: 02/13/2024] [Accepted: 04/15/2024] [Indexed: 01/11/2025]
Abstract
Endoscopic ultrasound (EUS) was developed in the 1990s and has significantly transformed pancreatic tumor diagnosis. Subsequently, EUS has rapidly shifted from being a purely diagnostic procedure to being used in a wide range of interventional procedures. Recently, new therapeutic techniques, such as EUS-guided fine needle injection (EUS-FNI) or radiofrequency ablation (RFA), have been developed to deliver various antitumor agents. Despite technological advancements, pancreatic cancer (PC) has a poor prognosis and improvements in treatment outcomes are urgently required. One of the reasons for the limited response to antitumor agents in PC is the abundant desmoplasia and hypovascular nature of the tumor, complicating drug delivery into the tumor. Thus, changing the tumor microenvironment may be important to enhance the effectiveness of chemotherapy, and direct injection of antitumor agents into the tumor under EUS guidance can help overcome treatment challenges in PC. Treatment approaches using the EUS-FNI or RFA technique are expected to further improve the prognosis of PC. Therefore, this study reviewed the existing literature on EUS-guided antitumor therapy, specifically highlighting its application in PC to address the current challenges and to identify potential advancements in the field.
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Affiliation(s)
- Kazuyuki Matsumoto
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Hironari Kato
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Koichiro Tsutsumi
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
| | - Motoyuki Otsuka
- Department of Gastroenterology and HepatologyOkayama University HospitalOkayamaJapan
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2
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Xia Y, Pei T, Zhao J, Wang Z, Shen Y, Yang Y, Liang J. Long noncoding RNA H19: functions and mechanisms in regulating programmed cell death in cancer. Cell Death Discov 2024; 10:76. [PMID: 38355574 PMCID: PMC10866971 DOI: 10.1038/s41420-024-01832-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/16/2024] [Accepted: 01/25/2024] [Indexed: 02/16/2024] Open
Abstract
Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs with transcript lengths of >200 nucleotides. Mounting evidence suggests that lncRNAs are closely associated with tumorigenesis. LncRNA H19 (H19) was the first lncRNA to function as an oncogene in many malignant tumors. Apart from the established role of H19 in promoting cell growth, proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and metastasis, it has been recently discovered that H19 also inhibits programmed cell death (PCD) of cancer cells. In this review, we summarize the mechanisms by which H19 regulates PCD in cancer cells through various signaling pathways, molecular mechanisms, and epigenetic modifications. H19 regulates PCD through the Wnt/β-catenin pathway and the PI3K-Akt-mTOR pathway. It also acts as a competitive endogenous RNA (ceRNA) in PCD regulation. The interaction between H19 and RNA-binding proteins (RBP) regulates apoptosis in cancer. Moreover, epigenetic modifications, including DNA and RNA methylation and histone modifications, are also involved in H19-associated PCD regulation. In conclusion, we summarize the role of H19 signaling via PCD in cancer chemoresistance, highlighting the promising research significance of H19 as a therapeutic target. We hope that our study will contribute to a broader understanding of H19 in cancer development and treatment.
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Affiliation(s)
- Yuyang Xia
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China
| | - Tianjiao Pei
- Department of Reproductive Medicine, West China Second University Hospital of Sichuan University, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital of Sichuan University, Chengdu, China.
| | - Junjie Zhao
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China
| | - Zilin Wang
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China
| | - Yu Shen
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China
| | - Yang Yang
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China
| | - Jiayu Liang
- Department of Urology, Institute of Urology, West China Hospital, West China School of Medicine, Sichuan University, 610041, Chengdu, China.
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3
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Zhang R, Zeng Y, Deng JL. Long non-coding RNA H19: a potential biomarker and therapeutic target in human malignant tumors. Clin Exp Med 2023; 23:1425-1440. [PMID: 36484927 DOI: 10.1007/s10238-022-00947-5] [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: 09/06/2022] [Accepted: 11/08/2022] [Indexed: 12/13/2022]
Abstract
Long non-coding RNAs play important roles in cellular functions and disease development. H19, as a long non-coding RNA, is pervasively over-expressed in almost all kinds of human malignant tumors. Although many studies have reported that H19 is closely associated with tumor cell proliferation, apoptosis, invasion, metastasis, and chemoresistance, the role and mechanism of H19 in gene regulation and tumor development are largely unclear. In this review, we summarized the recent progress in the study of the major functions and mechanisms of H19 lncRNA in cancer development and progression. H19 possesses both oncogenic and tumor-suppressing activities, presumably through regulating target gene transcription, mRNA stability and splicing, and competitive inhibition of endogenous RNA degradation. Studies indicate that H19 may involve in cell proliferation and apoptosis, tumor initiation, migration, invasion, metastasis and chemoresistance and may serve as a potential biomarker for early diagnosis, prognosis, and novel molecular target for cancer therapy.
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Affiliation(s)
- Rui Zhang
- Department of Pharmacy, Anhui No.2 Provincial People's Hospital, Hefei, 230041, People's Republic of China
| | - Ying Zeng
- Department of Pharmacy, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410008, People's Republic of China
| | - Jun-Li Deng
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People's Republic of China.
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4
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Liao J, Chen B, Zhu Z, Du C, Gao S, Zhao G, Zhao P, Wang Y, Wang A, Schwartz Z, Song L, Hong J, Wagstaff W, Haydon RC, Luu HH, Fan J, Reid RR, He TC, Shi L, Hu N, Huang W. Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases. Genes Dis 2023; 10:1351-1366. [PMID: 37397543 PMCID: PMC10311118 DOI: 10.1016/j.gendis.2023.02.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/07/2023] [Accepted: 02/08/2023] [Indexed: 07/04/2023] Open
Abstract
Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.
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Affiliation(s)
- Junyi Liao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Bowen Chen
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Zhenglin Zhu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Chengcheng Du
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Shengqiang Gao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Piao Zhao
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Zander Schwartz
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Lily Song
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jeffrey Hong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- The Medical Scientist Training Program, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lewis Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Ning Hu
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Wei Huang
- Departments of Orthopedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Orthopedic Research Center, Chongqing Medical University, Chongqing 400016, China
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Dahiya DS, Chandan S, Ali H, Pinnam BSM, Gangwani MK, Al Bunni H, Canakis A, Gopakumar H, Vohra I, Bapaye J, Al-Haddad M, Sharma NR. Role of Therapeutic Endoscopic Ultrasound in Management of Pancreatic Cancer: An Endoscopic Oncologist Perspective. Cancers (Basel) 2023; 15:3235. [PMID: 37370843 DOI: 10.3390/cancers15123235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/08/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
Pancreatic cancer is a highly lethal disease with an aggressive clinical course. Patients with pancreatic cancer are usually asymptomatic until significant progression of their disease. Additionally, there are no effective screening guidelines for pancreatic cancer in the general population. This leads to a delay in diagnosis and treatment, resulting in poor clinical outcomes and low survival rates. Endoscopic Ultrasound (EUS) is an indispensable tool for the diagnosis and staging of pancreatic cancer. In the modern era, with exponential advancements in technology and device innovation, EUS is also being increasingly used in a variety of therapeutic interventions. In the context of pancreatic cancer where therapies are limited due to the advanced stage of the disease at diagnosis, EUS-guided interventions offer new and innovative options. Moreover, due to their minimally invasive nature and ability to provide real-time images for tumor localization and therapy, they are associated with fewer complication rates compared to conventional open and laparoscopic approaches. In this article, we detail the most current and important therapeutic applications of EUS for pancreatic cancer, namely EUS-guided Fine Needle Injections, EUS-guided Radiotherapy, and EUS-guided Ablations. Furthermore, we also discuss the feasibility and safety profile of each intervention in patients with pancreatic cancer to provide gastrointestinal medical oncologists, radiation and surgical oncologists, and therapeutic endoscopists with valuable information to facilitate patient discussions and aid in the complex decision-making process.
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Affiliation(s)
- Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology & Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, USA
| | - Saurabh Chandan
- Division of Gastroenterology and Hepatology, CHI Creighton University Medical Center, Omaha, NE 68131, USA
| | - Hassam Ali
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL 60612, USA
| | | | - Hashem Al Bunni
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andrew Canakis
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Harishankar Gopakumar
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Ishaan Vohra
- Department of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Jay Bapaye
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY 14621, USA
| | - Mohammad Al-Haddad
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Neil R Sharma
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Interventional Oncology & Surgical Endoscopy Programs (IOSE), GI Oncology Tumor Site Team, Parkview Cancer Institute, Parkview Health, Fort Wayne, IN 46845, USA
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Jiang XY, Zhu QC, Zhang XJ, Duan T, Feng J, Sui XB, Sun XN, Mou YP. Roles of lncRNAs in pancreatic ductal adenocarcinoma: Diagnosis, treatment, and the development of drug resistance. Hepatobiliary Pancreat Dis Int 2023; 22:128-139. [PMID: 36543619 DOI: 10.1016/j.hbpd.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 12/07/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, primarily due to its late diagnosis, high propensity to metastasis, and the development of resistance to chemo-/radiotherapy. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are intimately involved in the treatment resistance of pancreatic cancer cells via interacting with critical signaling pathways and may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. DATA SOURCES We carried out a systematic review on lncRNAs-based research in the context of pancreatic cancer and presented an overview of the updated information regarding the molecular mechanisms underlying lncRNAs-modulated pancreatic cancer progression and drug resistance, together with their potential value in diagnosis, prognosis, and treatment of PDAC. Literature mining was performed in PubMed with the following keywords: long non-coding RNA, pancreatic ductal adenocarcinoma, pancreatic cancer up to January 2022. Publications relevant to the roles of lncRNAs in diagnosis, prognosis, drug resistance, and therapy of PDAC were collected and systematically reviewed. RESULTS LncRNAs, such as HOTAIR, HOTTIP, and PVT1, play essential roles in regulating pancreatic cancer cell proliferation, invasion, migration, and drug resistance, thus may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. They participate in tumorigenesis mainly by targeting miRNAs, interacting with signaling molecules, and involving in the epithelial-mesenchymal transition process. CONCLUSIONS The functional lncRNAs play essential roles in pancreatic cancer cell proliferation, invasion, migration, and drug resistance and have potential values in diagnosis, prognostic prediction, and treatment of PDAC.
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Affiliation(s)
- Xiao-Yin Jiang
- The National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou 310014, China; Department of Gastrointestinal and Pancreatic Surgery, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Qi-Cong Zhu
- Department of Gastrointestinal and Pancreatic Surgery, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Xiao-Jian Zhang
- The National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou 310014, China
| | - Ting Duan
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Jiao Feng
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Xin-Bing Sui
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Xue-Ni Sun
- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China
| | - Yi-Ping Mou
- Department of Gastrointestinal and Pancreatic Surgery, Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
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Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123836. [PMID: 35744957 PMCID: PMC9230553 DOI: 10.3390/molecules27123836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/01/2022] [Accepted: 04/06/2022] [Indexed: 11/17/2022]
Abstract
Cancer is one of the most serious human diseases, causing millions of deaths worldwide annually, and, therefore, it is one of the most investigated research disciplines. Developing efficient anticancer tools includes studying the effects of different natural enzymes of plant and microbial origin on tumor cells. The development of various smart delivery systems based on enzyme drugs has been conducted for more than two decades. Some of these delivery systems have been developed to the point that they have reached clinical stages, and a few have even found application in selected cancer treatments. Various biological, chemical, and physical approaches have been utilized to enhance their efficiencies by improving their delivery and targeting. In this paper, we review advanced delivery systems for enzyme drugs for use in cancer therapy. Their structure-based functions, mechanisms of action, fused forms with other peptides in terms of targeting and penetration, and other main results from in vivo and clinical studies of these advanced delivery systems are highlighted.
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Kaur J, Jaruvongvanich V, Chandrasekhara V. Endoscopic ultrasound-guided injectable therapy for pancreatic cancer: A systematic review. World J Gastroenterol 2022; 28:2383-2395. [PMID: 35800184 PMCID: PMC9185216 DOI: 10.3748/wjg.v28.i21.2383] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/18/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Given the low survival rate in pancreatic cancer, new therapeutic techniques have been explored, especially for unresectable or borderline resectable disease. Endoscopic ultrasound (EUS) provides real-time imaging and minimally invasive access for local and targeted injection of anti-tumor agents directly into the pancreatic tumor. Limited studies have been reported using this technique for the treatment of pancreatic ductal adenocarcinoma (PDAC).
AIM To evaluate the progress made with EUS-guided injectable therapies in the treatment of PDAC.
METHODS All original articles published in English until July 15, 2021, were retrieved via a library-assisted literature search from Ovid Evidence-Based Medicine Reviews and Scopus databases. Reference lists were reviewed to identify additional relevant articles. Prospective clinical studies evaluating the use of EUS-guided injectable therapies in PDAC were included. Studies primarily directed at non-EUS injectable therapies and other malignancies were excluded. Retrieved manuscripts were reviewed descriptively with on critical appraisal of published studies based on their methods and outcome measures such as safety, feasibility, and effectiveness in terms of tumor response and survival. Heterogeneity in data outcomes and therapeutic techniques limited the ability to perform comparative statistical analysis.
RESULTS A total of thirteen articles (503 patients) were found eligible for inclusion. The EUS-injectable therapies used were heterogeneous among the studies consisting of immunotherapy (n = 5) in 59 patients, chemotherapy (n = 1) in 36 patients, and viral and other biological therapies (n = 7) in 408 patients. Eleven of the studies reviewed were single armed while two were double armed with one randomized trial and one non-randomized comparative study. Overall, the included studies demonstrated EUS-guided injectable therapies to be safe and feasible with different agents as monotherapy or in conjunction with other modalities. Promising results were also observed regarding their efficacy and survival parameters in patients with PDAC.
CONCLUSION EUS-guided injectable therapies, including immunotherapy, chemotherapy, and viral or other biological therapies have shown minimal adverse events and potential efficacy in the treatment of PDAC. Comparative studies, including controlled trials, are required to confirm these results in order to offer novel EUS-based treatment options for patients with PDAC.
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Affiliation(s)
- Jyotroop Kaur
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Vinay Chandrasekhara
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
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Increased Expression of Long Non-coding RNA H19 is Associated With Colon Cancer Recurrence. J Surg Res 2021; 269:59-68. [PMID: 34520983 DOI: 10.1016/j.jss.2021.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 07/22/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Colon cancer is a leading cause of cancer-related death. Long non-coding (Lnc) RNAs are critical mediators of tumor biology. H19 is a well-characterized lncRNA involved in p53 regulation and cancer progression. A specific colon cancer data set was utilized to determine if tumor H19 expression is associated with recurrence-free and overall survival. METHODS Clinical patient data from The Cancer Genome Atlas colon adenocarcinoma data set was downloaded using FirebrowseR and normalized H19 expression from the associated RNA-seq data set downloaded using cBioportal. Univariable and multivariable Cox proportional regression analyses were used to identify an association between H19 expression in colon cancer tissue and recurrence-free, and overall survival. RESULTS Three hundred eight patients were studied. Median age was 68 years (interquartile range: 58-77 years) and 156 patients (51%) were men. Increased H19 expression was associated with KRAS mutation status (P= 0.016). There was no difference in overall survival between the low and high H19 expression groups (log rank = 0.481); however, increased H19 expression was associated with reduced recurrence-free survival (Log-Rank = 0.012). On multivariable regression analysis, increased H19 expression (Hazard ratio = 1.83, 95%CI: 1.02-3.27, P= 0.042), and stage III or IV disease (Hazard ratio = 2.39, 95%CI: 1.34-4.27, P= 0.003) were risk factors for reduced recurrence-free survival. CONCLUSIONS Colon cancer H19 expression is associated with advanced stage of tumor disease and is a significant risk factor for reduced recurrence-free survival. Tumor expression of H19 may have potential for both prognostic and therapeutic uses in the future.
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10
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Shermane Lim YW, Xiang X, Garg M, Le MT, Li-Ann Wong A, Wang L, Goh BC. The double-edged sword of H19 lncRNA: Insights into cancer therapy. Cancer Lett 2020; 500:253-262. [PMID: 33221454 DOI: 10.1016/j.canlet.2020.11.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/25/2020] [Accepted: 11/06/2020] [Indexed: 01/03/2023]
Abstract
H19 long non-coding RNA (lncRNA) has many functions in cancer. Some studies have reported that H19 acts as an oncogene and is involved in cancer progression by activating epithelial-mesenchymal transition (EMT), the cell cycle and angiogenesis via mechanisms like microRNA (miRNA) sponging - the binding to and inhibition of miRNA activity. This makes H19 lncRNA a potential target for cancer therapeutics. However, several conflicting studies have also found that H19 suppresses tumour development. In this review, we shed light on the possible reasons for these conflicting findings. We also summarise the current literature on the applications of H19 lncRNA in cancer therapy in many cancers and explore new avenues for future research. This includes the use of H19 in recombinant vectors, chemoresistance, epigenetic regulation, tumour microenvironment alteration and cancer immunotherapy. The relationship between H19 and the master tumour suppressor gene p53 is also explored. In most studies, H19 knockdown via RNA interference (RNAi) or epigenetic silencing inhibits cancer development. Thus, H19 lncRNA could be a promising target for the development of cancer therapeutics. This warrants further investigations into its translational research to improve cancer therapy outcomes.
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Affiliation(s)
- Yun Wei Shermane Lim
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Xiaoqiang Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China.
| | - Manoj Garg
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University, Sector-125, Noida, 201313, India
| | - Minh Tn Le
- Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Andrea Li-Ann Wong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Boon-Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore; Institute for Digital Medicine and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore, 119228, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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11
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Sawant SS, Patil SM, Gupta V, Kunda NK. Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment. Int J Mol Sci 2020; 21:ijms21207575. [PMID: 33066447 PMCID: PMC7589870 DOI: 10.3390/ijms21207575] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/10/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
Conventional anti-cancer therapy involves the use of chemical chemotherapeutics and radiation and are often non-specific in action. The development of drug resistance and the inability of the drug to penetrate the tumor cells has been a major pitfall in current treatment. This has led to the investigation of alternative anti-tumor therapeutics possessing greater specificity and efficacy. There is a significant interest in exploring the use of microbes as potential anti-cancer medicines. The inherent tropism of the bacteria for hypoxic tumor environment and its ability to be genetically engineered as a vector for gene and drug therapy has led to the development of bacteria as a potential weapon against cancer. In this review, we will introduce bacterial anti-cancer therapy with an emphasis on the various mechanisms involved in tumor targeting and tumor suppression. The bacteriotherapy approaches in conjunction with the conventional cancer therapy can be effective in designing novel cancer therapies. We focus on the current progress achieved in bacterial cancer therapies that show potential in advancing existing cancer treatment options and help attain positive clinical outcomes with minimal systemic side-effects.
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12
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Sarvari R, Nouri M, Agbolaghi S, Roshangar L, Sadrhaghighi A, Seifalian AM, Keyhanvar P. A summary on non-viral systems for gene delivery based on natural and synthetic polymers. INT J POLYM MATER PO 2020. [DOI: 10.1080/00914037.2020.1825081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Raana Sarvari
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell And Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samira Agbolaghi
- Chemical Engineering Department, Faculty of Engineering, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Laila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhouman Sadrhaghighi
- Department of Orthodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alexander M. Seifalian
- Nanotechnology and Regenerative Medicine Commercialization Centre (Ltd), The London Innovation Bio Science Centre, London, UK
| | - Peyman Keyhanvar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Convergence of Knowledge, Technology and Society Network (CKTSN), Universal Scientific Education and Research Network (USERN), Tabriz, Iran
- ARTAN110 Startup Accelerator, Tabriz, Iran
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13
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Saw PE, Xu X, Chen J, Song EW. Non-coding RNAs: the new central dogma of cancer biology. SCIENCE CHINA-LIFE SCIENCES 2020; 64:22-50. [PMID: 32930921 DOI: 10.1007/s11427-020-1700-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023]
Abstract
The central dogma of molecular biology states that the functions of RNA revolve around protein translation. Until the last decade, most researches were geared towards characterization of RNAs as intermediaries in protein translation, namely, messenger RNAs (mRNAs) as temporary copies of genetic information, ribosomal RNAs (rRNAs) as a main component of ribosome, or translators of codon sequence (tRNAs). The statistical reality, however, is that these processes account for less than 2% of the genome, and insufficiently explain the functionality of 98% of transcribed RNAs. Recent discoveries have unveiled thousands of unique non-coding RNAs (ncRNAs) and shifted the perception of them from being "junk" transcriptional products to "yet to be elucidated"-and potentially monumentally important-RNAs. Most ncRNAs are now known as key regulators in various networks in which they could lead to specific cellular responses and fates. In major cancers, ncRNAs have been identified as both oncogenic drivers and tumor suppressors, indicating a complex regulatory network among these ncRNAs. Herein, we provide a comprehensive review of the various ncRNAs and their functional roles in cancer, and the pre-clinical and clinical development of ncRNA-based therapeutics. A deeper understanding of ncRNAs could facilitate better design of personalized therapeutics.
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Affiliation(s)
- Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Jianing Chen
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Er-Wei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. .,Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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14
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Zhou H, Feng B, Abudoureyimu M, Lai Y, Lin X, Tian C, Huang G, Chu X, Wang R. The functional role of long non-coding RNAs and their underlying mechanisms in drug resistance of non-small cell lung cancer. Life Sci 2020; 261:118362. [PMID: 32871184 DOI: 10.1016/j.lfs.2020.118362] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid cancer and the main origin of cancer-related deaths worldwide. Current strategies to treat advanced NSCLC are based on a combined approach of targeted therapy and chemotherapy. But most patients will eventually get resistance to either chemotherapy or targeted therapy, leading to the poor prognosis. The mechanism of NSCLC drug resistance is inconclusive and is affected by multiple factors. Long non-coding RNAs (LncRNAs) are non-coding RNAs (ncRNAs) longer than 200 nucleotides. Recent studies show that lncRNAs are involved in many cellular physiological activities, including drug resistance of NSCLC. It is of great clinical significance to understand the specific mechanisms and the role of lncRNAs in it. CONCLUSIONS Herein, we focus on the functional roles and the underlying mechanisms of lncRNAs in acquired drug resistance of NSCLC. LncRNAs have potential values as novel prognostic biomarkers and even therapeutic targets in the clinical management of NSCLC.
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Affiliation(s)
- Hao Zhou
- Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Bing Feng
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Mubalake Abudoureyimu
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Yongting Lai
- Department of Medical Oncology, Nanjing School of Clinical Medicine, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Xinrong Lin
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Chuan Tian
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Guichun Huang
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China.
| | - Xiaoyuan Chu
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China; Department of Medical Oncology, Nanjing School of Clinical Medicine, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, China; Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China.
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15
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Wang J, Zhao L, Shang K, Liu F, Che J, Li H, Cao B. Long non-coding RNA H19, a novel therapeutic target for pancreatic cancer. Mol Med 2020; 26:30. [PMID: 32272875 PMCID: PMC7146949 DOI: 10.1186/s10020-020-00156-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, which threats peoples’ health. Unfortunately, the pathogenesis of PDAC remains unclear. Recent studies have indicated that long non-coding RNAs (lncRNAs) can regulate the development and progression of malignant tumors through varying mechanisms. LncRNA H19 has a unique expression profile and can act as a sponger of specific miRNAs to regulate the pathogenic process of many diseases, including PDAC and several other types of cancers. Here, we review the research approaches to understanding the regulatory role of H19 and potential mechanisms in the progression of PDAC and other types of cancers and diseases. These studies suggest that H19 may be a novel therapeutic target for PDAC and our findings may open new revenues for scientific researches and development of valuable therapies for these diseases in the future.
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Affiliation(s)
- Jing Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China.,Yale School of Medicine, New Haven, CT, USA
| | - Lei Zhao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China
| | - Kun Shang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China
| | - Fang Liu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China.,Yale School of Medicine, New Haven, CT, USA.,Department of Cardiology, Chaoyang Hospital, Capital Medical University, Beijing, Chaoyang District, China
| | - Juanjuan Che
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China
| | - Huihui Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, #95 Yong An Road, Beijing, Xicheng District, China.
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16
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Effect of Diphtheria Toxin-Based Gene Therapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12020472. [PMID: 32085552 PMCID: PMC7072394 DOI: 10.3390/cancers12020472] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global malignancy, responsible for >90% of primary liver cancers. Currently available therapeutic options have poor performances due to the highly heterogeneous nature of the tumor cells; recurrence is highly probable, and some patients develop resistances to the therapies. Accordingly, the development of a novel therapy is essential. We assessed gene therapy for HCC using a diphtheria toxin fragment A (DTA) gene-expressing plasmid, utilizing a non-viral hydrodynamics-based procedure. The antitumor effect of DTA expression in HCC cell lines (and alpha-fetoprotein (AFP) promoter selectivity) is assessed in vitro by examining HCC cell growth. Moreover, the effect and safety of the AFP promoter-selective DTA expression was examined in vivo using an HCC mice model established by the hydrodynamic gene delivery of the yes-associated protein (YAP)-expressing plasmid. The protein synthesis in DTA transfected cells is inhibited by the disappearance of tdTomato and GFP expression co-transfected upon the delivery of the DTA plasmid; the HCC cell growth is inhibited by the expression of DTA in HCC cells in an AFP promoter-selective manner. A significant inhibition of HCC occurrence and the suppression of the tumor marker of AFP and des-gamma-carboxy prothrombin can be seen in mice groups treated with hydrodynamic gene delivery of DTA, both 0 and 2 months after the YAP gene delivery. These results suggest that DTA gene therapy is effective for HCC.
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17
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Kamimura K, Yokoo T, Abe H, Terai S. Gene Therapy for Liver Cancers: Current Status from Basic to Clinics. Cancers (Basel) 2019; 11:cancers11121865. [PMID: 31769427 PMCID: PMC6966544 DOI: 10.3390/cancers11121865] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 02/06/2023] Open
Abstract
The liver is a key organ for metabolism, protein synthesis, detoxification, and endocrine function, and among liver diseases, including hepatitis, cirrhosis, malignant tumors, and congenital disease, liver cancer is one of the leading causes of cancer-related deaths worldwide. Conventional therapeutic options such as embolization and chemotherapy are not effective against advanced-stage liver cancer; therefore, continuous efforts focus on the development of novel therapeutic options, including molecular targeted agents and gene therapy. In this review, we will summarize the progress toward the development of gene therapies for liver cancer, with an emphasis on recent clinical trials and preclinical studies.
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Affiliation(s)
- Kenya Kamimura
- Correspondence: ; Tel.: +81-25-227-2207; Fax: +81-25-227-0776
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18
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Moutinho-Ribeiro P, Liberal R, Macedo G. Endoscopic ultrasound in pancreatic cancer treatment: Facts and hopes. Clin Res Hepatol Gastroenterol 2019; 43:513-521. [PMID: 30935904 DOI: 10.1016/j.clinre.2019.02.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 02/12/2019] [Accepted: 02/16/2019] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma is one of the most common causes of cancer-related deaths. Since most patients present with advanced disease, its prognosis is dismal. New and more effective therapeutic strategies are needed. Endoscopic ultrasound is currently an indispensable tool for the diagnosis and staging of pancreatic ductal adenocarcinoma. In recent years, endoscopic ultrasound has evolved to become also a therapeutic procedure. On one hand, the role of endoscopic ultrasound in the management of pancreatic cancer-related symptoms (pain, obstructive jaundice, and gastric outlet obstruction) is now well established. On the other hand, its use as a mean to the delivery of anti-tumor therapies (injecting anti-tumor agents, assisting in radiotherapy, and guiding ablative therapies) is still mostly experimental, despite growing evidence supporting its feasibility, safety and efficacy.
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Affiliation(s)
- Pedro Moutinho-Ribeiro
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao and World Gastroenterology Organisation (WGO) Porto Training Center, Porto, Portugal.
| | - Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao and World Gastroenterology Organisation (WGO) Porto Training Center, Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao and World Gastroenterology Organisation (WGO) Porto Training Center, Porto, Portugal
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19
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Han X, Kuang T, Ren Y, Lu Z, Liao Q, Chen W. Haspin knockdown can inhibit progression and development of pancreatic cancer in vitro and vivo. Exp Cell Res 2019; 385:111605. [PMID: 31493385 DOI: 10.1016/j.yexcr.2019.111605] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/14/2019] [Accepted: 09/03/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Pancreatic cancer is one of the most aggressive and lethal malignancies and it is the eighth most common cause of death from cancer worldwide. The purpose of this study was to investigate the role of GSG2 (HASPIN) in the development and progression of pancreatic cancer. MATERIAL AND METHODS GSG2 expression was detected by immunohistochemistry in tumor tissue samples, and by qRT-PCR and Western blot assay in human pancreatic cancer cell lines. Cell proliferation was evaluated by MTT assay. Giemsa staining was used for analyzing colony formation. Cell cycle and cell apoptosis were determined using Fluorescence activated Cells Sorting. Wound healing assay and transwell assay were applied for examining cell migration. The molecular mechanism was investigated by human apoptosis antibody array. Tumor-bearing animal model was constructed to verify the effects of GSG2 on pancreatic cancer in vivo. RESULTS GSG2 expression was upregulated in pancreatic cancer tissues and human pancreatic cancer cell lines: PANC-1 and SW1990. Higher expression of GSG2 in tumor samples was associated with poorer prognosis. GSG2 knockdown suppressed cell proliferation, colony formation, metastasis and promoted cell apoptosis, which was also verified in vivo. In addition, GSG2 knockdown blocked the cell cycle in G2. It was also found that downregulation of GSG2 inhibited Bcl-2, Bcl-w, cIAP, HSP60 and Livin expression as well as promoted IGFBP-6 expression. CONCLUSION This study revealed that GSG2 upregulation was associated with pancreatic cancer progression. GSG2 knockdown inhibited cell proliferation, colony formation and migration, blocked cell cycle at G2 phase, and induced cell apoptosis. Therefore, GSG2 might serve as a potential therapeutic target for pancreatic cancer therapy and a market for prognosis.
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Affiliation(s)
- Xu Han
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Tiantao Kuang
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yun Ren
- Department of Anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhufeng Lu
- Department of Anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Qingwu Liao
- Department of Anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Wei Chen
- Department of Anesthesia, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China; Department of Anesthesia, Qingpu Branch of Zhongshan Hospital, Fudan University, No. 1158 Gongyuan East Road, Shanghai, 201700, China.
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20
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Garajová I, Balsano R, Tommasi C, Giovannetti E. Noncoding Rnas Emerging as Novel Biomarkers in Pancreatic Cancer. Curr Pharm Des 2019; 24:4601-4604. [PMID: 30659532 DOI: 10.2174/1381612825666190119125804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/02/2019] [Accepted: 01/11/2019] [Indexed: 02/07/2023]
Abstract
Noncoding RNAs play important regulatory roles in diverse biological processes and their misregulation
might lead to different diseases, including cancer. Previous studies have reported the evolving role of miRNAs
as new potential biomarkers in cancer diagnosis, prognosis, as well as predictive biomarkers of chemotherapy
response or therapeutic targets. In this review, we outline the involvement of noncoding RNA in pancreatic
cancer, providing an overview of known miRNAs in its diagnosis, prognosis and chemoresistance. In addition,
we discuss the influence of non-coding RNAs in the metastatic behavior of pancreatic cancer, as well as the role
of diet in epigenetic regulation of non-coding RNAs in cancer, which can, in turn, lead the development of new
prevention’s techniques or novel targets for cancer therapy.
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Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Chiara Tommasi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
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21
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Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J. The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterol Hepatol 2018; 2018:5389820. [PMID: 30186820 PMCID: PMC6112218 DOI: 10.1155/2018/5389820] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/27/2018] [Accepted: 08/06/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.
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Affiliation(s)
- Lumir Kunovsky
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Pavla Tesarikova
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
| | - Zdenek Kala
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Radek Kroupa
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Petr Kysela
- Department of Surgery, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jiri Dolina
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
| | - Jan Trna
- Department of Gastroenterology, University Hospital Brno Bohunice, Faculty of Medicine, Masaryk University, Czech Republic
- Department of Internal Medicine, Hospital Boskovice, Czech Republic
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22
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Wang L, Wang P, Dong H, Wang S, Chu H, Yan W, Zhang X. Ulk1/FUNDC1 Prevents Nerve Cells from Hypoxia-Induced Apoptosis by Promoting Cell Autophagy. Neurochem Res 2018; 43:1539-1548. [PMID: 29923038 DOI: 10.1007/s11064-018-2568-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 05/28/2018] [Accepted: 05/31/2018] [Indexed: 01/16/2023]
Abstract
Cell autophagy and cell apoptosis are both observed in the process of hypoxia-induced ischemic cerebral infarction (ICI). Unc-51 like autophagy activating kinase 1 (Ulk1) and FUN14 Domain-containing Protein 1 (FUNDC1) are both involved in the regulation of cell autophagy. This study aimed to investigate the regulatory effects of Ulk1 and FUNDC1 on hypoxia-induced nerve cell autophagy and apoptosis. Cell viability was measured using cell counting kit-8 (CCK-8) assay. Cell apoptosis was detected using Annexin V-PE/7-ADD staining assay. qRT-PCR was used to quantify the mRNA levels of Ulk1 and FUNDC1 in PC-12 cells. Cell transfection was performed to up-regulate the expression of Ulk1. 3-Methyladenine (3-MA) was used as autophagy inhibitor and rapamycin was used as autophagy activator in our experiments. SP600125 was used as c-Jun N-terminal kinase (JNK) inhibitor. Western blotting was performed to analyze the expression levels of key factors that are related to cell autophagy, apoptosis and JNK pathway. We found that hypoxia simultaneously induced apoptosis and autophagy of PC-12 cells. The activation of Ulk1 and FUNDC1 were also found in PC-12 cells after hypoxia induction. Overexpression of Ulk1 promoted the activation of FUNDC1 and prevented PC-12 cells from hypoxia-induced apoptosis. Suppression of Ulk1 had opposite effects. Furthermore, we also found that JNK pathway participated in the effects of Ulk1 overexpression on PC-12 cell apoptosis reduction. To conclude, Ulk1/FUNDC1 played critical regulatory roles in hypoxia-induced nerve cell autophagy and apoptosis. Overexpression of Ulk1 prevented nerve cells from hypoxia-induced apoptosis by promoting cell autophagy.
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Affiliation(s)
- Li Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
| | - Peng Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China.
| | - He Dong
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
| | - Shiduan Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
| | - Haichen Chu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
| | - Wei Yan
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
| | - Xue Zhang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266000, China
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23
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Yoshimura H, Matsuda Y, Yamamoto M, Michishita M, Takahashi K, Sasaki N, Ishikawa N, Aida J, Takubo K, Arai T, Ishiwata T. Reduced expression of the H19 long non-coding RNA inhibits pancreatic cancer metastasis. J Transl Med 2018; 98:814-824. [PMID: 29581580 DOI: 10.1038/s41374-018-0048-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 01/23/2018] [Accepted: 01/23/2018] [Indexed: 12/13/2022] Open
Abstract
H19 is an oncofetal RNA expressed in the developing embryo as well as in bladder, breast, gastric, pancreatic, hepatocellular, and prostate cancers. Recent studies have shown that H19 enhances cancer invasion and metastasis; however, its roles in cancer remain controversial. In the current study, H19 exhibited the second largest increase (82.4-fold) and represented the only non-protein coding gene among 11 genes identified that were elevated over 10-fold in lung-metastasis-derived pancreatic cancer cells compared with their parental cells using a mouse metastatic model. Subsequently, we further clarified the roles of H19 in pancreatic cancer growth and metastasis using in vitro and in vivo techniques. In situ hybridization showed that H19 was detected in 23 of 139 invasive ductal carcinomas (17%), and that H19 expression positively correlated with higher histological grades (P < 0.0001). Overexpression of H19 in PANC-1 pancreatic cancer cells induced higher motilities, whereas H19 inhibition using shRNA and siRNA showed opposite results; however, cell growth rates were not impacted. Intravenous injection of H19 shRNA vector-transfected PANC-1 cells yielded marked inhibition of metastasis in the liver and lungs of immunodeficient mice. These findings suggest that H19 has important roles in pancreatic cancer metastasis, and that inhibition of H19 represents a novel candidate for pancreatic cancer therapy.
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Affiliation(s)
- Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan
| | - Masami Yamamoto
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Masaki Michishita
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Kimimasa Takahashi
- Department of Veterinary Pathology, School of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, 180-8602, Japan
| | - Norihiko Sasaki
- Research Team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Naoshi Ishikawa
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Junko Aida
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Kaiyo Takubo
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan
| | - Toshiyuki Ishiwata
- Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan.
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24
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Arriaga-Canon C, De La Rosa-Velázquez IA, González-Barrios R, Montiel-Manríquez R, Oliva-Rico D, Jiménez-Trejo F, Cortés-González C, Herrera LA. The use of long non-coding RNAs as prognostic biomarkers and therapeutic targets in prostate cancer. Oncotarget 2018; 9:20872-20890. [PMID: 29755696 PMCID: PMC5945524 DOI: 10.18632/oncotarget.25038] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 03/15/2018] [Indexed: 12/16/2022] Open
Abstract
Prostate cancer is the most common cancer in men and the second leading cause of cancer-related deaths. The most used biomarker to detect prostate cancer is Prostate Specific Antigen (PSA), whose levels are measured in serum. However, it has been recently established that molecular markers of cancer should not be based solely on genes and proteins but should also reflect other genomic traits; long non-coding RNAs (lncRNAs) serve this purpose. lncRNAs are transcripts of >200 bases that do not encode proteins and that have been shown to display abnormal expression profiles in different types of cancer. Experimental studies have highlighted lncRNAs as potential biomarkers for prognoses and treatments in patients with different types of cancer, including prostate cancer, where the PCA3 lncRNA is currently used as a diagnostic tool and management strategy. With the development of genomic technologies, particularly next-generation sequencing (NGS), several other lncRNAs have been linked to prostate cancer and are currently under validation for their medical use. In this review, we will discuss different strategies for the discovery of novel lncRNAs that can be evaluated as prognostic biomarkers, the clinical impact of these lncRNAs and how lncRNAs can be used as potential therapeutic targets.
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Affiliation(s)
| | - Inti Alberto De La Rosa-Velázquez
- Universidad Nacional Autónoma de México, Laboratorio de Genómica, CIC-Red de Apoyo a la Investigación, INCMNSZ, Colonia Belisario Domínguez Sección XVI, Delegación Tlalpan C.P.14080, CDMX, Mexico
| | - Rodrigo González-Barrios
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan. C.P. 14080, CDMX, Mexico
| | - Rogelio Montiel-Manríquez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan. C.P. 14080, CDMX, Mexico
| | - Diego Oliva-Rico
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan. C.P. 14080, CDMX, Mexico
| | | | - Carlo Cortés-González
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan. C.P. 14080, CDMX, Mexico
| | - Luis A Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Tlalpan. C.P. 14080, CDMX, Mexico
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25
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Zhang X, Shi S, Zhang B, Ni Q, Yu X, Xu J. Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. Am J Cancer Res 2018; 8:332-353. [PMID: 29636993 PMCID: PMC5883088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/25/2018] [Indexed: 06/08/2023] Open
Abstract
Pancreatic cancer (PC) is characterized by extremely high mortality and poor prognosis, which are largely ascribed to difficulties in early diagnosis and limited therapeutics. Although there is a sufficient window for intervention before preneoplastic lesions progress to invasive disease, effective early detection of PC remains difficult using current biomarkers and imaging techniques. Biomarkers with satisfactory diagnostic efficacy and convenient analysis methods are urgently required. In this review, we summarized recent advances in the identification of biomarkers in circulation for early detection of PC. A number of novel circulating biomarkers, such as metabolites, cell-free DNA (cfDNA), noncoding RNA, and exosomes, that show promising diagnostic value have been discovered using advances in sequencing techniques and "omics" analyses. Panels comprising several biomarkers may also exhibit better diagnostic performance. In the future, we need more efficient circulating biomarkers for the identification of noninvasive precursor lesions and early disease. Collaborative large-scale studies are also required to show the clinical validity and applicability of potential biomarkers.
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Affiliation(s)
- Xu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
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26
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Hu P, Qiao O, Wang J, Li J, Jin H, Li Z, Jin Y. rs1859168 A > C polymorphism regulates HOTTIP expression and reduces risk of pancreatic cancer in a Chinese population. World J Surg Oncol 2017; 15:155. [PMID: 28818070 PMCID: PMC5561564 DOI: 10.1186/s12957-017-1218-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 08/05/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are aberrantly expressed in many types of human cancer including pancreatic cancer (PC) and correlated with tumorigenesis and cancer prognosis, whereas knowledge about regulatory mechanism of lncRNA expression is few known. This study aimed to explore whether polymorphisms in lncRNAs genes are associated with PC susceptibility by affecting its expression. METHODS We first genotyped three common single-nucleotide polymorphisms (SNPs) of lncRNA genes (HOTTIP rs1859168, HOTAIR rs4759314, and H19 rs217727) in 416 paired PC patients and controls, and then validated the results in another 505 paired PC patients and controls. The genotype-phenotype correlation was examined in 50 PC tissue samples with different genotypes as well as by luciferase reporter assay. RESULTS In the discovery set, only the HOTTIP rs1859168 A > C showed to be significantly associated with a reduced PC risk (CC vs AA: odds ratio (OR) = 0.71, 95% confidence interval (95%CI) = 0.57-0.88, P = 0.002; recessive model: adjusted OR = 0.51, 95%CI = 0.38-0.68, P < 0.001; additive model: adjusted OR = 0.67, 95%CI = 0.51-0.82, P < 0.001). The results in validation set and pooled population also indicated that the C allele of HOTTIP rs1859168 could significantly decrease the risk of PC. In addition, the genotype-phenotype association analysis suggested that HOTTIP expression level was significantly lower in PC samples with CC genotype than that in samples with AA and AC genotype. Furthermore, the C allele of HOTTIP rs1859168 could significantly decrease the relative luciferase activity compared to the A allele in three PC cell lines. CONCLUSIONS The current findings provided evidence that the functional rs1859168 A > C polymorphism may decrease the PC risk by down-regulating the HOTTIP expression.
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Affiliation(s)
- Pinghai Hu
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Ou Qiao
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Jun Wang
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Jiao Li
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Hao Jin
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Zhaolian Li
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China
| | - Yan Jin
- Department of Hepatobiliary Surgery, First People's Hospital of Yunnan Province, No. 157 Jinbi Rd., Xishan District, Kunming, 6050032, China.
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Bhan A, Soleimani M, Mandal SS. Long Noncoding RNA and Cancer: A New Paradigm. Cancer Res 2017; 77:3965-3981. [PMID: 28701486 DOI: 10.1158/0008-5472.can-16-2634] [Citation(s) in RCA: 2098] [Impact Index Per Article: 262.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 04/05/2017] [Accepted: 05/04/2017] [Indexed: 12/11/2022]
Abstract
In addition to mutations or aberrant expression in the protein-coding genes, mutations and misregulation of noncoding RNAs, in particular long noncoding RNAs (lncRNA), appear to play major roles in cancer. Genome-wide association studies of tumor samples have identified a large number of lncRNAs associated with various types of cancer. Alterations in lncRNA expression and their mutations promote tumorigenesis and metastasis. LncRNAs may exhibit tumor-suppressive and -promoting (oncogenic) functions. Because of their genome-wide expression patterns in a variety of tissues and their tissue-specific expression characteristics, lncRNAs hold strong promise as novel biomarkers and therapeutic targets for cancer. In this article, we have reviewed the emerging functions and association of lncRNAs in different types of cancer and discussed their potential implications in cancer diagnosis and therapy. Cancer Res; 77(15); 3965-81. ©2017 AACR.
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Affiliation(s)
- Arunoday Bhan
- Gene Regulation and Epigenetics Research Lab, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas
| | - Milad Soleimani
- Gene Regulation and Epigenetics Research Lab, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas
| | - Subhrangsu S Mandal
- Gene Regulation and Epigenetics Research Lab, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas.
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Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
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29
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Wu T, Du Y. LncRNAs: From Basic Research to Medical Application. Int J Biol Sci 2017; 13:295-307. [PMID: 28367094 PMCID: PMC5370437 DOI: 10.7150/ijbs.16968] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Accepted: 11/02/2016] [Indexed: 01/17/2023] Open
Abstract
This review aimed to summarize the current research contents about long noncoding RNAs (lncRNAs) and some related lncRNAs as molecular biomarkers or therapy strategies in human cancer and cardiovascular diseases. Following the development of various kinds of sequencing technologies, lncRNAs have become one of the most unknown areas that need to be explored. First, the definition and classification of lncRNAs were constantly amended and supplemented because of their complexity and diversity. Second, several methods and strategies have been developed to study the characteristic of lncRNAs, including new species identifications, subcellular localization, gain or loss of function, molecular interaction, and bioinformatics analysis. Third, based on the present results from basic researches, the working mechanisms of lncRNAs were proved to be different forms of interactions involving DNAs, RNAs, and proteins. Fourth, lncRNA can play different important roles during the embryogenesis and organ differentiations. Finally, because of the tissue-specific expression of lncRNAs, they could be used as biomarkers or therapy targets and effectively applied in different kinds of diseases, such as human cancer and cardiovascular diseases.
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Affiliation(s)
- Tao Wu
- Cardiovascular Department, The Affiliated Hospital of Medical College, Ningbo University, No.247, Renmin Road, Jiangbei District, Ningbo, China
| | - Yantao Du
- Ningbo Institute of Medical Science, No.42-46, Yangshan Road, Jiangbei District, Ningbo, China
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30
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Previdi MC, Carotenuto P, Zito D, Pandolfo R, Braconi C. Noncoding RNAs as novel biomarkers in pancreatic cancer: what do we know? Future Oncol 2016; 13:443-453. [PMID: 27841659 PMCID: PMC5253462 DOI: 10.2217/fon-2016-0253] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is an aggressive cancer of the digestive system, which is becoming a serious health problem worldwide. Overall survival for patients with pancreatic cancer is poor, mainly due to a lack of biomarkers to enable early diagnosis and a lack of prognostic markers that can inform decision-making, facilitating personalized treatment and an optimal clinical outcome. ncRNAs play an important role in pancreatic carcinogenesis. Here we review the literature on the role of ncRNAs as biomarkers in pancreatic cancer. We focus on the significance of ncRNAs as markers for early diagnosis, as prognostic biomarkers able to inform clinical management and as targets for novel therapeutics for patients with pancreatic cancer.
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Affiliation(s)
- Maria C Previdi
- Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, SM2 5NG, UK
| | - Pietro Carotenuto
- Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, SM2 5NG, UK
| | - Domenico Zito
- Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, SM2 5NG, UK
| | - Rosantony Pandolfo
- Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, SM2 5NG, UK
| | - Chiara Braconi
- Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Rd, Sutton, SM2 5NG, UK.,The Royal Marsden NHS Trust London & Surrey, Downs Rd, Sutton, SM2 5NG, UK
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31
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Taucher V, Mangge H, Haybaeck J. Non-coding RNAs in pancreatic cancer: challenges and opportunities for clinical application. Cell Oncol (Dordr) 2016; 39:295-318. [DOI: 10.1007/s13402-016-0275-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2016] [Indexed: 01/17/2023] Open
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32
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Peng JF, Zhuang YY, Huang FT, Zhang SN. Noncoding RNAs and pancreatic cancer. World J Gastroenterol 2016; 22:801-814. [PMID: 26811626 PMCID: PMC4716078 DOI: 10.3748/wjg.v22.i2.801] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Noncoding RNAs (ncRNAs) represent a class of RNA molecules that typically do not code for proteins. Emerging data suggest that ncRNAs play an important role in several physiological and pathological conditions such as cancer. The best-characterized ncRNAs are the microRNAs (miRNAs), which are short, approximately 22-nucleotide sequences of RNA of approximately 22-nucleotide in length that regulate gene expression at the posttranscriptional level, through transcript degradation or translational repression. MiRNAs can function as master gene regulators, impacting a variety of cellular pathways important to normal cellular functions as well as cancer development and progression. In addition to miRNAs, long ncRNAs, which are transcripts longer than 200 nucleotides, have recently emerged as novel drivers of tumorigenesis. However, the molecular mechanisms of their regulation and function, and the significance of other ncRNAs such as piwi-interacting RNAs in pancreas carcinogenesis are largely unknown. This review summarizes the growing body of evidence supporting the vital roles of ncRNAs in pancreatic cancer, focusing on their dysregulation through both genetic and epigenetic mechanisms, and highlighting the promise of ncRNAs in diagnostic and therapeutic applications of pancreatic cancer.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Pancreatic Neoplasms/therapy
- Predictive Value of Tests
- Prognosis
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- RNA, Untranslated/therapeutic use
- Transcription, Genetic
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Abstract
For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non-toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfected tumor cells. In this regard, the suicide gene therapy has demonstrated its potential for efficient tumor eradication. Numerous suicide genes of viral or bacterial origin were isolated, characterized, and extensively tested in vitro and in vivo, demonstrating their therapeutic potential even in clinical trials to treat cancers of different entities. Apart from this, growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard, bacterial toxins are an alternative to the classical GDEPT strategy, which add to the broad spectrum of different suicide approaches. In this context, lytic bacterial toxins, such as streptolysin O (SLO) or the claudin-targeted Clostridium perfringens enterotoxin (CPE) represent attractive new types of suicide oncoleaking genes. They permit as pore-forming proteins rapid and also selective toxicity toward a broad range of cancers. In this chapter, we describe the generation and use of SLO as well as of CPE-based gene therapies for the effective tumor cell eradication as promising, novel suicide gene approach particularly for treatment of therapy refractory tumors.
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Chen X, Fan S, Song E. Noncoding RNAs: New Players in Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 927:1-47. [PMID: 27376730 DOI: 10.1007/978-981-10-1498-7_1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The world of noncoding RNAs (ncRNAs) has gained widespread attention in recent years due to their novel and crucial potency of biological regulation. Noncoding RNAs play essential regulatory roles in a broad range of developmental processes and diseases, notably human cancers. Regulatory ncRNAs represent multiple levels of structurally and functionally distinct RNAs, including the best-known microRNAs (miRNAs), the complicated long ncRNAs (lncRNAs), and the newly identified circular RNAs (circRNAs). However, the mechanisms by which they act remain elusive. In this chapter, we will review the current knowledge of the ncRNA field, discussing the genomic context, biological functions, and mechanisms of action of miRNAs, lncRNAs, and circRNAs. We also highlight the implications of the biogenesis and gene expression dysregulation of different ncRNA subtypes in the initiation and development of human malignancies.
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Affiliation(s)
- Xueman Chen
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China
| | - Siting Fan
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China
| | - Erwei Song
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China.
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Abstract
Metastasis is the primary cause of cancer-related death all over the world. Metastasis is a process by which cancer spreads from the place at which it first arose to distant locations in the body. It is well known that several steps are necessary for this process, including cancer cell epithelial-mesenchymal transition (EMT), cell migration, resistance to anoikis, and angiogenesis. Therefore, investigating the molecular mechanism of regulating cancer metastasis progress may provide helpful insights in the development of efficient diagnosis and therapeutic strategy. Recent studies have indicated that long noncoding RNAs (lncRNAs) play important roles in cancer metastasis. lncRNAs are the nonprotein coding RNAs that have a size longer than 200 nucleotides. More and more studies have indicated that lncRNAs are involved in a broad range of biological processes and are associated with many diseases, such as cancer. The role of lncRNAs in cancer metastasis has been widely studied; however, lncRNAs are mainly involved in the EMT process on the current literature. This review focuses on the mechanisms underlying the role of lncRNAs in cancer metastasis.
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Affiliation(s)
- Juan Li
- Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
| | - Hui Meng
- Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
| | - Yun Bai
- Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
| | - Kai Wang
- Department of Medical Genetics, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China
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Crea F, Clermont PL, Parolia A, Wang Y, Helgason CD. The non-coding transcriptome as a dynamic regulator of cancer metastasis. Cancer Metastasis Rev 2015; 33:1-16. [PMID: 24346158 PMCID: PMC3988524 DOI: 10.1007/s10555-013-9455-3] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered “housekeeping” genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients’ prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms.
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Affiliation(s)
- Francesco Crea
- Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada,
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Malek E, Jagannathan S, Driscoll JJ. Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget 2014; 5:8027-38. [PMID: 25275300 PMCID: PMC4226665 DOI: 10.18632/oncotarget.2469] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/06/2014] [Indexed: 12/31/2022] Open
Abstract
The therapeutic response and clinical outcome of patients diagnosed with the same cancer type and that receive identical treatment is highly variable to reflect the genetic heterogeneity within tumor cells. Non-coding RNAs (ncRNAs) are recently discovered molecules that regulate eukaryotic gene expression and represent a significant advance towards a better understanding of the mechanisms that govern cellular growth. NcRNAs are essential for the proper regulation of cell proliferation and survival under physiologic conditions and are deregulated in many pathologies, e.g., human cancers. NcRNAs have been associated with cancer diagnosis, staging, treatment response, metastasis and survival and include distinct subtypes, e.g., long ncRNAs (lncRNAs) and microRNAs (miRNAs). LncRNAs have been linked to essential growth-promoting activities and their deregulation contributes to tumor cell survival. A prominent example is the Hox transcript antisense intergenic lncRNA, HOTAIR, that cooperates with the polycomb repressive complex to reprogram chromatin organization. HOTAIR expression is deregulated in a spectrum of cancers and HOTAIR expression correlates with patient survival. Here, we highlight emerging evidence that supports a role for lncRNAs in cancer with implications for the development of novel diagnostics and therapeutics.
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Affiliation(s)
- Ehsan Malek
- The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Sajjeev Jagannathan
- The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH
| | - James J. Driscoll
- The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH
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Huang T, Alvarez A, Hu B, Cheng SY. Noncoding RNAs in cancer and cancer stem cells. CHINESE JOURNAL OF CANCER 2014; 32:582-93. [PMID: 24206916 PMCID: PMC3845549 DOI: 10.5732/cjc.013.10170] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In recent years, it has become increasingly apparent that noncoding RNAs (ncRNA) are of crucial importance for human cancer. The functional relevance of ncRNAs is particularly evident for microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). miRNAs are endogenously expressed small RNA sequences that act as post-transcriptional regulators of gene expression and have been extensively studied for their roles in cancers, whereas lncRNAs are emerging as important players in the cancer paradigm in recent years. These noncoding genes are often aberrantly expressed in a variety of human cancers. However, the biological functions of most ncRNAs remain largely unknown. Recently, evidence has begun to accumulate describing how ncRNAs are dysregulated in cancer and cancer stem cells, a subset of cancer cells harboring self-renewal and differentiation capacities. These studies provide insight into the functional roles that ncRNAs play in tumor initiation, progression, and resistance to therapies, and they suggest ncRNAs as attractive therapeutic targets and potentially useful diagnostic tools.
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Affiliation(s)
- Tianzhi Huang
- The Ken & Ruth Davee Department of Neuro-logy, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ,
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Vitiello M, Tuccoli A, Poliseno L. Long non-coding RNAs in cancer: implications for personalized therapy. Cell Oncol (Dordr) 2014; 38:17-28. [PMID: 25113790 DOI: 10.1007/s13402-014-0180-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2014] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs, pseudogenes and circRNAs) have recently come into light as powerful players in cancer pathogenesis and it is becoming increasingly clear that they have the potential of greatly contributing to the spread and success of personalized cancer medicine. In this concise review, we briefly introduce these three classes of long non-coding RNAs. We then discuss their applications as diagnostic and prognostic biomarkers. Finally, we describe their appeal as targets and as drugs, while pointing out the limitations that still lie ahead of their definitive entry into clinical practice.
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Affiliation(s)
- Marianna Vitiello
- Oncogenomics Unit, Core Research Laboratory, Istituto Toscano Tumori c/o IFC-CNR, via Moruzzi 1, 56124, Pisa, Italy
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Giladi M, Schneiderman RS, Porat Y, Munster M, Itzhaki A, Mordechovich D, Cahal S, Kirson ED, Weinberg U, Palti Y. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology 2013; 14:54-63. [PMID: 24555979 DOI: 10.1016/j.pan.2013.11.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 09/30/2013] [Accepted: 11/16/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Tumor Treating Fields (TTFields) are a non-invasive cancer treatment modality approved for the treatment of patients with recurrent glioblastoma. The present study determined the efficacy and mechanism of action of TTFields in preclinical models of pancreatic cancer. METHODS The effect of TTFields in vitro was assessed using cell counts, clonogenic assays, cell cycle analysis and analysis of mitotic figures. The effect in vivo effect was studied in the PC1-0 hamster pancreatic cancer model. RESULTS Application of TTFields in vitro showed a significant decrease in cell count, an increase in cell volume and reduced clonogenicity. Further analysis demonstrated significant increase in the number of abnormal mitotic figures, as well as a decrease in G2-M cell population. In hamsters with orthotopic pancreatic tumors, TTFields significantly reduced tumor volume accompanied by an increase in the frequency of abnormal mitotic events. TTFields efficacy was enhanced both in vitro and in vivo when combined with chemotherapy. CONCLUSIONS These results provide the first evidence that TTFields serve as an effective antimitotic treatment in preclinical pancreatic cancer models and have a long term negative effect on cancer cell survival. These results make TTFields an attractive candidate for testing in the treatment of patients with pancreatic cancer.
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Xia Z, Jiang K, Liu T, Zheng H, Liu X, Zheng X. The protective effect of Cold-inducible RNA-binding protein (CIRP) on testicular torsion/detorsion: an experimental study in mice. J Pediatr Surg 2013; 48:2140-7. [PMID: 24094970 DOI: 10.1016/j.jpedsurg.2013.02.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/19/2013] [Accepted: 02/20/2013] [Indexed: 11/17/2022]
Abstract
PURPOSE To evaluate the expression of Cold-inducible RNA-binding protein (CIRP) in torsion/detorsion of the testes in different phases and demonstrate the protective effect of CIRP on testicular injury after torsion/detorsion (T/D) in an experimental mouse model. METHODS Twenty-four male BALB/c mice were divided randomly into 8 groups: normal control group (N), sham-operated group (S), torsion 2 h group (T2h), torsion/detorsion 12 h group (T/D12h), and T/D24h, T/D48h, T/D72h, and T/D96h groups. The testes were examined for the expression levels of CIRP. Another 32 male BALB/c mice were divided randomly in to 4 groups: normal control group (N), T/D group, T/D+pcDNA3.1 group, and T/D + pcDNA3.1-CIRP group. The plasmids were transfected into testes with in vivo-jetPEI. After 3 days, morphological changes, mean seminiferous tubule diameter (MSTD), and the number of the germ cell layers were observed. Superoxide dismutase (SOD) activity, the levels of malondialdehyde (MDA), and Bcl-2/Bax ratios were studied in the different groups. RESULTS Compared with the N and S groups, the expression of CIRP in the T2h group was down-regulated. In T/D groups, the levels of CIRP were reduced in a time dependent manner. Compared to T/D and T/D+pcDNA3.1 group, the MSTD, number of the germ cell layers, SOD activity, and Bcl-2/Bax ratio increased in T/D + pcDNA3.1-CIRP group, while the level of MDA decreased. CONCLUSIONS The results of our study have shown that down-regulated CIRP is involved in testicular injury after testicular torsion/detorsion. Up-regulation of the expression of CIRP may reduce the damage caused by torsion/detorsion, possibly by preventing germ cell oxidative stress and apoptosis.
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Affiliation(s)
- Zhiping Xia
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P.R. China
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Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol 2013; 34:613-20. [PMID: 23359273 DOI: 10.1007/s13277-013-0658-6] [Citation(s) in RCA: 311] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2012] [Accepted: 01/09/2013] [Indexed: 02/06/2023] Open
Abstract
Recent studies have demonstrated the importance of non-protein coding part of human genome in carcinogenesis and metastasis. Among numerous kinds of non-protein coding RNAs, long noncoding RNAs (lncRNAs) play a key regulatory role in cancer biology. LncRNAs are dysregulated in different kinds of cancer and the expression levels of certain lncRNAs are associated with recurrence, metastasis, and prognosis of cancer. It is also proved that overexpression of certain lncRNAs, behaving like oncogenes, can promote matrix invasion of cancer cells and tumor growth. In this review, we focus our attention on lncRNAs those have been validated in human cancer tissues to suggest reasonable strategies for future research. We introduce an update view of lncRNA, extract cancer-related lncRNAs from literature, and describe the known functions and possible underlying molecular mechanisms of some well investigated lncRNAs (MALAT1, HOX antisense intergenic RNA, and highly upregulated in hepatocellular cancer), as well as their current and potential future application in cancer diagnosis (PCA3) and treatment (H19).
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Sorin V, Ohana P, Gallula J, Birman T, Matouk I, Hubert A, Gilon M, Hochberg A, Czerniak A. H19-promoter-targeted therapy combined with gemcitabine in the treatment of pancreatic cancer. ISRN ONCOLOGY 2012; 2012:351750. [PMID: 22701803 PMCID: PMC3371723 DOI: 10.5402/2012/351750] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 05/01/2012] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is the eighth cancer leading cause of cancer-related death in the world and has a 5-year survival rate of 1–4% only. Gemcitabine is a first line agent for advanced pancreatic therapy; however, its efficacy is limited by its poor intracellular metabolism and chemoresistance. Studies have been conducted in an effort to improve gemcitabine treatment results by adding other chemotherapeutic agents, but none of them showed any significant advantage over gemcitabine monotherapy. We found that 85% of human pancreatic tumors analyzed by in situ hybridization analyses showed moderated to strong expression of the H19 gene. We designed a preclinical study combining gemcitabine treatment and a DNA-based therapy for pancreatic cancer using a non viral vector BC-819 (also known as DTA-H19), expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The experiments conducted either in an orthotopic and heterotopic pancreatic carcinoma animal model showed better antitumor activity following the sequential administration of the vector BC-819 and gemcitabine as compared to the effect of each of them alone. The results presented in the current study indicate that treatment with BC-819 in combination with gemcitabine might be a viable new therapeutic option for patients with advanced pancreatic cancer.
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Affiliation(s)
- Vladimir Sorin
- Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
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Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. Cancer Gene Ther 2012; 19:374-81. [PMID: 22498722 DOI: 10.1038/cgt.2012.10] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BC-819 is a DNA plasmid that was developed to target the expression of diphtheria-toxin gene under the control of H19 regulatory sequences. BC-819 has the potential to treat pancreatic cancer that overexpresses the H19 gene. The objectives were to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of BC-819 administered intratumorally in subjects with unresectable, locally advanced, non-metastatic pancreatic cancer. Nine patients with unresectable pancreatic adenocarcinoma were enrolled in an open-label, dose-escalation trial. Subjects were entered into one out of two cohorts with escalating doses of BC-819. Each cohort received 2 weeks of twice weekly intratumoral injection of BC-819 under computerized tomography (CT) (n = 3) or endoscopic ultrasound (EUS) (n = 6) guidance. Patients were assessed by CT or positron emission tomography (PET)/CT during week 4 for tumor response. The maximum tolerated dose of BC-819 was not reached in this study at the highest dose. Asymptomatic elevation of lipase, which was considered as an adverse event with dose-limiting toxicity, occurred in only one subject in the high-dose group and was resolved spontaneously. The tumors did not increase in size 4 weeks after initiating treatment. Two weeks after completing the treatment, the two subjects who went on to receive subsequent chemotherapy or chemoradiation therapy, pancreatic tumors were downstaged and considered surgically resectable. Remarkably, three of the six subjects in cohort no. 2 evaluated at month 3 had a partial response. BC-819 can be safely administered intratumorally via EUS- or CT-guided injection at a dose of at least 8 mg per injection weekly twice. BC-819 given locally in combination with systemic chemotherapy may provide an additional therapeutic benefit for the treatment of pancreatic cancer.
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Amit D, Matouk IJ, Lavon I, Birman T, Galula J, Abu-Lail R, Schneider T, Siegal T, Hochberg A, Fellig Y. Transcriptional targeting of glioblastoma by diphtheria toxin-A driven by both H19 and IGF2-P4 promoters. Int J Clin Exp Med 2012; 5:124-135. [PMID: 22567173 PMCID: PMC3342706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 02/03/2012] [Indexed: 05/31/2023]
Abstract
BACKGROUND The H19-IGF2 locus is either highly expressed and/or shows aberrant allelic pattern of expression in a large array of human cancers, while rarely expressed in the corresponding normal tissue. Preclinical, clinical studies and human compassionate using a DNA plasmid containing H19 and/or IGF2-P4 regulatory sequences that drive the expression of an intracellular toxin [diphtheria toxin A-fragment (DTA)] have demonstrated promising results in several types of carcinomas. Recently we reported that a single construct that expresses DTA under the control of both H19 and IGF2 P4 promoters showed superior efficacy in vitro as well as in vivo, in comparison to a single promoter construct in bladder carcinoma. Here we extended this approach to glioblastoma and tested the antitumor efficacy of the double promoter DTA-expressing vector (H19-DTA-P4-DTA) in vitro as well as in heterotopic animal model. H19 gene expression was tested by in-situ hybridization (ISH) and by quantitative Real-Time PCR (qRT-PCR) in samples of diffuse glioma. METHODS IGF2-P4 gene expression was tested by qRT-PCR as well. RESULTS Both H19 and IGF2-P4 transcripts were highly expressed in high grade gliomas. Furthermore, significant H19 expression in other types of primary brain tumors as well as in brain metastases was detected by ISH. Both A172 and U87 human glioblastoma cell lines showed high expression of IGF2-P4 while the A172 cell line showed high expression of H19 RNA as well. H19-DTA-P4-DTA exhibited superior cytotoxic activity compared to the single promoter expression vectors, in U87 and A172 glioblastoma cell lines in vitro and showed antitumoral efficacy in heterotopic glioblastoma animal model. CONCLUSIONS Our findings indicate antitumoral efficacy against glioblastoma of the targeted double promoter vector H19-DTA-P4-DTA, both in-vitro and in-vivo. Thus, its test in orthotopic animal model of glioblastoma as well as in clinical trials is warranted.
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Affiliation(s)
- Doron Amit
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Imad J Matouk
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Iris Lavon
- Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Medical CenterIsrael
| | - Tatiana Birman
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Jenifer Galula
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Rasha Abu-Lail
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Tamar Schneider
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Tali Siegal
- Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Medical CenterIsrael
| | - Abraham Hochberg
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
| | - Yakov Fellig
- Department of Biological Chemistry, the Institute of Life Sciences, Hebrew University of JerusalemJerusalem Israel
- Department of Pathology, Hadassah Hebrew University Medical CenterIsrael
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Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer 2011; 10:38. [PMID: 21489289 PMCID: PMC3098824 DOI: 10.1186/1476-4598-10-38] [Citation(s) in RCA: 1335] [Impact Index Per Article: 95.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Accepted: 04/13/2011] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potential roles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressed in a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently, evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function, providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight the emerging functional role of lncRNAs in human cancer.
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Affiliation(s)
- Ewan A Gibb
- British Columbia Cancer Agency Research Centre, Vancouver, Canada.
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Huang Z, Saluja A, Dudeja V, Vickers S, Buchsbaum D. Molecular targeted approaches for treatment of pancreatic cancer. Curr Pharm Des 2011; 17:2221-38. [PMID: 21777178 PMCID: PMC3422746 DOI: 10.2174/138161211796957427] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 06/20/2011] [Indexed: 02/07/2023]
Abstract
Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research. Many targeted therapies are under development. However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models. Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy. Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis. Sensitivity to therapy may also vary for cancer cells at different stages. The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells. In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed. However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge. Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects. These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages. Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy.
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Affiliation(s)
- Z.Q. Huang
- Department of Radiation Oncology, University of Alabama at Birmingham USA
| | - A.K. Saluja
- Department of Surgery, University of Minnesota, USA
| | - V. Dudeja
- Department of Surgery, University of Minnesota, USA
| | - S.M. Vickers
- Department of Surgery, University of Minnesota, USA
| | - D.J. Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham USA
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