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Zare-Mehrjardi MJ, Hatami-Araghi M, Jafari-Khorchani M, Oushyani Roudsari Z, Taheri-Anganeh M, Abdolrahmat M, Ghasemi H, Aiiashi S. RNA biosensors for detection of pancreatic cancer. Clin Chim Acta 2025; 571:120237. [PMID: 40081786 DOI: 10.1016/j.cca.2025.120237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/16/2025]
Abstract
Pancreatic cancer is recognized as one of the most lethal types of cancer globally, characterized by a high mortality rate and a bleak prognosis, which greatly contributes to cancer-related deaths. Forecasts suggest that by 2030, pancreatic cancer will exceed other cancer types in prevalence. The disease presents considerable difficulties owing to the lack of prominent symptoms in its early stages, restricted options for early detection, rapid progression, and unfavorable outcomes. Presently, traditional methods for diagnosing pancreatic cancer primarily rely on imaging techniques. However, these methods often entail significant costs, require considerable time, and necessitate specialized skills for both operating the equipment and interpreting the resulting images. To overcome these obstacles, the use of biosensors has been proposed as a potentially valuable tool for the early detection of pancreatic cancer. MicroRNAs (miRs), a type of small non-coding RNA molecules, have emerged as highly sensitive molecular diagnostic tools that have the potential to function as precise indicators for a range of diseases, including cancer. Biosensors have been suggested as a potential solution for tackling these challenges, offering a promising approach for the early detection of pancreatic cancer. Small non-coding RNA molecules known as MicroRNAs (miRs) have become recognized as extremely sensitive molecular diagnostic tools and can act as precise biomarkers for different diseases, such as cancer. Moreover, this manuscript presents a thorough summary of the latest innovations in nano-biosensors that have been specifically developed for the identification of non-coding RNAs related to pancreatic cancer.
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Affiliation(s)
| | - Mahtab Hatami-Araghi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Majid Jafari-Khorchani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zahra Oushyani Roudsari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mona Abdolrahmat
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hassan Ghasemi
- Research Center for Environmental Contaminants (RCEC), Abadan University of Medical Sciences, Abadan, Iran.
| | - Saleh Aiiashi
- Abadan University of Medical Sciences, Abadan, Iran.
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Shi M, Zhang R, Lyu H, Xiao S, Guo D, Zhang Q, Chen XZ, Tang J, Zhou C. Long non-coding RNAs: Emerging regulators of invasion and metastasis in pancreatic cancer. J Adv Res 2025:S2090-1232(25)00073-6. [PMID: 39933650 DOI: 10.1016/j.jare.2025.02.001] [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: 11/09/2024] [Revised: 01/20/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND The invasion and metastasis of pancreatic cancer (PC) are key factors contributing to disease progression and poor prognosis. This process is primarily driven by EMT, which has been the focus of recent studies highlighting the role of long non-coding RNAs (lncRNAs) as crucial regulators of EMT. However, the mechanisms by which lncRNAs influence invasive metastasis are multifaceted, extending beyond EMT regulation alone. AIM OF REVIEW This review primarily aims to characterize lncRNAs affecting invasion and metastasis in pancreatic cancer. We summarize the regulatory roles of lncRNAs across multiple molecular pathways and highlight their translational potential, considering the implications for clinical applications in diagnostics and therapeutics. KEY SCIENTIFIC CONCEPTS OF REVIEW The review focuses on three principal scientific themes. First, we primarily summarize lncRNAs orchestrate various signaling pathways, such as TGF-β/Smad, Wnt/β-catenin, and Notch, to regulate molecular changes associated with EMT, thereby enhancing cellular motility and invasivenes. Second, we summarize the effects of lncRNAs on autophagy and ferroptosis and discuss the role of exosomal lncRNAs in the tumor microenvironment to regulate the behavior of neighboring cells and promote cancer cell invasion. Third, we emphasize the effects of RNA modifications (such as m6A and m5C methylation) on stabilizing lncRNAs and enhancing their capacity to mediate invasive metastasis in PC. Lastly, we discuss the translational potential of these findings, emphasizing the inherent challenges in using lncRNAs as clinical biomarkers and therapeutic targets, while proposing prospective research strategies.
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Affiliation(s)
- Mengmeng Shi
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Rui Zhang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Hao Lyu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Shuai Xiao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Dong Guo
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Qi Zhang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China
| | - Xing-Zhen Chen
- Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G2R3, Canada
| | - Jingfeng Tang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China.
| | - Cefan Zhou
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China.
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Gong L, Zou C, Zhang H, Yang F, Qi G, Ma Z. Landscape of Noncoding RNA in the Hypoxic Tumor Microenvironment. Genes (Basel) 2025; 16:140. [PMID: 40004471 PMCID: PMC11855738 DOI: 10.3390/genes16020140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/20/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Amidst the prevalent and notable characteristic of a hypoxic microenvironment present in the majority of solid tumors, a burgeoning number of studies have revealed the significance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. The transcriptome of cancers is highly heterogeneous, with noncoding transcripts playing crucial roles. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two distinctive classes of ncRNA that are garnering increasing attention. Biologically, they possess intriguing properties and possess significant regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Additionally, recent research has evaluated the clinical applications of these ncRNAs in RNA-based treatments and noninvasive liquid biopsies. This review provides a comprehensive summary of recent studies on lncRNAs and circRNAs within the hypoxic tumor microenvironment. Furthermore, the clinical significance of lncRNAs and circRNAs in cancer diagnosis and treatment is emphasized, which could pave the way for the development of effective targeted therapies.
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Affiliation(s)
| | | | | | | | | | - Zhaowu Ma
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (L.G.); (C.Z.); (H.Z.); (F.Y.); (G.Q.)
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Qin D, Xi P, Huang K, Jiang L, Yao Z, Wei R, Li S. Nomogram for predicting post-progression-free survival in patients with recurrent pancreatic ductal adenocarcinoma after radical surgery: a retrospective analysis. Front Med (Lausanne) 2024; 11:1486750. [PMID: 39712186 PMCID: PMC11659012 DOI: 10.3389/fmed.2024.1486750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Radical resection is the only curative method for patients with pancreatic adenocarcinoma (PDAC). However, nearly 85% of PDAC patients suffer from local or distant recurrence within 5 years after curative resection. The progression of recurrent lesions accelerates the mortality rate in PDAC patients. However, the influence of clinicopathological factors on post-progression-free survival (PPFS), defined as the period from tumor recurrence to the timing of the progression of recurrent lesions, has rarely been discussed. The present study aimed to explore the independent prognostic factors for PPFS and construct a nomogram for PPFS prediction. MATERIALS AND METHODS The 200 recurrent PDAC patients were divided into training and validation groups by leave-one-out cross-validation. The patients' clinicopathological characteristics were compared through a chi-square test. Meanwhile, these factors were enrolled in the univariate and multivariate COX regression to find the independent prognostic factors of PPFS. Moreover, the Kaplan-Meier survival analysis based on the independent prognostic factors was performed. Finally, we constructed a nomogram model for PPFS prediction, followed by an effectiveness examination. RESULTS PDAC patients who received multi-agent chemotherapy after surgery showed a longer PPFS than the single-agent chemotherapy group. PDAC patients who received multi-agent chemotherapy after recurrence showed a similar PPFS compared to the single-agent chemotherapy group. Local recurrence with distant metastases, early recurrence, lympho-vascular invasion, higher T stage, and higher N stage predicted shorter PPFS in recurrent PDAC patients. Finally, a nomogram to indicate the progression of recurrent lesions was constructed. CONCLUSION Multi-agent chemotherapy is recommended for PDAC patients after surgery. Meanwhile, single-agent chemotherapy also deserves consideration after tumor recurrence. Moreover, the nomogram could be used in PPFS prediction.
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Affiliation(s)
| | | | | | | | | | - Ran Wei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Jafari SH, Lajevardi ZS, Zamani Fard MM, Jafari A, Naghavi S, Ravaei F, Taghavi SP, Mosadeghi K, Zarepour F, Mahjoubin-Tehran M, Rahimian N, Mirzaei H. Imaging Techniques and Biochemical Biomarkers: New Insights into Diagnosis of Pancreatic Cancer. Cell Biochem Biophys 2024; 82:3123-3144. [PMID: 39026059 DOI: 10.1007/s12013-024-01437-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Pancreatic cancer (PaC) incidence is increasing, but our current screening and diagnostic strategies are not very effective. However, screening could be helpful in the case of PaC, as recent evidence shows that the disease progresses gradually. Unfortunately, there is no ideal screening method or program for detecting PaC in its early stages. Conventional imaging techniques, such as abdominal ultrasound, CT, MRI, and EUS, have not been successful in detecting early-stage PaC. On the other hand, biomarkers may be a more effective screening tool for PaC and have greater potential for further evaluation compared to imaging. Recent studies on biomarkers and artificial intelligence (AI)-enhanced imaging have shown promising results in the early diagnosis of PaC. In addition to proteins, non-coding RNAs are also being studied as potential biomarkers for PaC. This review consolidates the current literature on PaC screening modalities to provide an organized framework for future studies. While conventional imaging techniques have not been effective in detecting early-stage PaC, biomarkers and AI-enhanced imaging are promising avenues of research. Further studies on the use of biomarkers, particularly non-coding RNAs, in combination with imaging modalities may improve the accuracy of PaC screening and lead to earlier detection of this deadly disease.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Sadat Lajevardi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Chronic Respiratory Diseases Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soroush Naghavi
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ravaei
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Kimia Mosadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Ye S, Chen S, Yang X, Lei X. Drug resistance in breast cancer is based on the mechanism of exocrine non-coding RNA. Discov Oncol 2024; 15:138. [PMID: 38691224 PMCID: PMC11063018 DOI: 10.1007/s12672-024-00993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 04/22/2024] [Indexed: 05/03/2024] Open
Abstract
Breast cancer (BC) ranks first among female malignant tumors and involves hormonal changes and genetic as well as environmental risk factors. In recent years, with the improvement of medical treatment, a variety of therapeutic approaches for breast cancer have emerged and have strengthened to accommodate molecular diversity. However, the primary way to improve the effective treatment of breast cancer patients is to overcome treatment resistance. Recent studies have provided insights into the mechanisms of resistance to exosome effects in BC. Exosomes are membrane-bound vesicles secreted by both healthy and malignant cells that facilitate intercellular communication. Specifically, exosomes released by tumor cells transport their contents to recipient cells, altering their properties and promoting oncogenic components, ultimately resulting in drug resistance. As important coordinators, non-coding RNAs (ncRNAs) are involved in this process and are aberrantly expressed in various human cancers. Exosome-derived ncRNAs, including microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as crucial components in understanding drug resistance in breast cancer. This review provides insights into the mechanism of exosome-derived ncRNAs in breast cancer drug resistance, thereby suggesting new strategies for the treatment of BC.
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Affiliation(s)
- Simin Ye
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Shiyu Chen
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
- The Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
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Trifylli EM, Kriebardis AG, Koustas E, Papadopoulos N, Fortis SP, Tzounakas VL, Anastasiadi AT, Sarantis P, Vasileiadi S, Tsagarakis A, Aloizos G, Manolakopoulos S, Deutsch M. A Current Synopsis of the Emerging Role of Extracellular Vesicles and Micro-RNAs in Pancreatic Cancer: A Forward-Looking Plan for Diagnosis and Treatment. Int J Mol Sci 2024; 25:3406. [PMID: 38542378 PMCID: PMC10969997 DOI: 10.3390/ijms25063406] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 12/25/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies worldwide, while it persists as the fourth most prevalent cause of cancer-related death in the United States of America. Although there are several novel therapeutic strategies for the approach of this intensely aggressive tumor, it remains a clinical challenge, as it is hard to identify in early stages, due to its asymptomatic course. A diagnosis is usually established when the disease is already in its late stages, while its chemoresistance constitutes an obstacle to the optimal management of this malignancy. The discovery of novel diagnostic and therapeutic tools is considered a necessity for this tumor, due to its low survival rates and treatment failures. One of the most extensively investigated potential diagnostic and therapeutic modalities is extracellular vesicles (EVs). These vesicles constitute nanosized double-lipid membraned particles that are characterized by a high heterogeneity that emerges from their distinct biogenesis route, their multi-variable sizes, and the particular cargoes that are embedded into these particles. Their pivotal role in cell-to-cell communication via their cargo and their implication in the pathophysiology of several diseases, including pancreatic cancer, opens new horizons in the management of this malignancy. Meanwhile, the interplay between pancreatic carcinogenesis and short non-coding RNA molecules (micro-RNAs or miRs) is in the spotlight of current studies, as they can have either a role as tumor suppressors or promoters. The deregulation of both of the aforementioned molecules leads to several aberrations in the function of pancreatic cells, leading to carcinogenesis. In this review, we will explore the role of extracellular vesicles and miRNAs in pancreatic cancer, as well as their potent utilization as diagnostic and therapeutic tools.
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Affiliation(s)
- Eleni Myrto Trifylli
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.M.T.); (S.P.F.)
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece;
- GI-Liver Unit, 2nd Department of Internal Medicine National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.M.T.); (S.P.F.)
| | - Evangelos Koustas
- Oncology Department, General Hospital Evangelismos, 10676 Athens, Greece;
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Nikolaos Papadopoulos
- Second Department of Internal Medicine, 401 General Military Hospital, 11527 Athens, Greece;
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece; (E.M.T.); (S.P.F.)
| | - Vassilis L. Tzounakas
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Alkmini T. Anastasiadi
- Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece; (A.T.A.); (V.L.T.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Sofia Vasileiadi
- GI-Liver Unit, 2nd Department of Internal Medicine National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Ariadne Tsagarakis
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;
| | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece;
| | - Spilios Manolakopoulos
- GI-Liver Unit, 2nd Department of Internal Medicine National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
| | - Melanie Deutsch
- GI-Liver Unit, 2nd Department of Internal Medicine National and Kapodistrian University of Athens, General Hospital of Athens “Hippocratio”, 114 Vas Sofias, 11527 Athens, Greece; (S.V.); (S.M.); (M.D.)
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Jawad SF, Altalbawy FMA, Hussein RM, Fadhil AA, Jawad MA, Zabibah RS, Taraki TY, Mohan CD, Rangappa KS. The strict regulation of HIF-1α by non-coding RNAs: new insight towards proliferation, metastasis, and therapeutic resistance strategies. Cancer Metastasis Rev 2024; 43:5-27. [PMID: 37552389 DOI: 10.1007/s10555-023-10129-8] [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: 02/11/2023] [Accepted: 07/21/2023] [Indexed: 08/09/2023]
Abstract
The hypoxic environment is prominently witnessed in most solid tumors and is associated with the promotion of cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, metabolic reprogramming, therapeutic resistance, and metastasis of tumor cells. All the effects are mediated by the expression of a transcription factor hypoxia-inducible factor-1α (HIF-1α). HIF-1α transcriptionally modulates the expression of genes responsible for all the aforementioned functions. The stability of HIF-1α is regulated by many proteins and non-coding RNAs (ncRNAs). In this article, we have critically discussed the crucial role of ncRNAs [such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), Piwi-interacting RNAs (piRNAs), and transfer RNA (tRNA)-derived small RNAs (tsRNAs)] in the regulation of stability and expression of HIF-1α. We have comprehensively discussed the molecular mechanisms and relationship of HIF-1α with each type of ncRNA in either promotion or repression of human cancers and therapeutic resistance. We have also elaborated on ncRNAs that are in clinical examination for the treatment of cancers. Overall, the majority of aspects concerning the relationship between HIF-1α and ncRNAs have been discussed in this article.
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Affiliation(s)
- Sabrean Farhan Jawad
- Department of Pharmacy, Al-Mustaqbal University College, Hilla, Babylon, 51001, Iraq
| | - Farag M A Altalbawy
- National Institute of Laser Enhanced Sciences, University of Cairo, Giza, 12613, Egypt
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | | | - Ali Abdulhussain Fadhil
- College of Medical Technology, Medical Lab Techniques, Al-Farahidi University, Baghdad, Iraq
| | - Mohammed Abed Jawad
- Department of Medical Laboratories Technology, Al-Nisour University College, Baghdad, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Chakrabhavi Dhananjaya Mohan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, 570006, India.
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226 001, India.
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Li ZW, Yu JF, Han F, Peng J, Lu Y, Ding K. Identifying potential anti-metastasis drugs for prostate cancer through integrative bioinformatics analysis and compound library screening. J Gene Med 2023; 25:e3548. [PMID: 37580943 DOI: 10.1002/jgm.3548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/12/2023] [Accepted: 05/18/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Metastasis poses the greatest threat to the lives of individuals with prostate cancer. Therefore, it is imperative to identify the underlying mechanism driving metastasis. Doing so would facilitate the detection of new diagnostic biomarkers and the advancement of treatment options for patients. METHODS Metastasis-related modules were identified through weighted gene co-expression network analysis based on microarray GSE6919. Hub genes were confirmed by quantitative real-time PCR across different prostate cell lines and clinic samples. Pivotal genes were determined through integration of RNA and transcription factor-target associated interactions. To predict drugs with potential to suppress tumor metastasis, we applied molecular networks using the DrugBank database. Drug repositioning analysis and confirmation of drug screen were conducted using the compound library. Confirmation of selective cytotoxicity of cupric oxide was carried out via invasion, transwell and apoptosis assays. RESULTS We identified five metastasis-related modules. Of these modules, two were identified to represent core dysfunction modules in which five hub genes were determined for each module. Five of these 10 genes correlating with prostate cancer progression. Furthermore, our analysis revealed that there are 36 drugs with the potential to be active against tumor metastasis. Finally, we identified four compounds that have not previously been reported to have any association with cancer therapy. Of these, cupric oxide was determined to have the best chemotherapeutic potential in treating prostate cancer metastasis. CONCLUSIONS By combining bioinformatics methods with compound library screening, this study proposes a valuable approach to drug discovery. Cupric oxide showed the potential in the treatment of prostate cancer metastasis and deserves further study.
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Affiliation(s)
- Zhi Wei Li
- Department of Urology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiang Fan Yu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Feng Han
- Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jingxuan Peng
- Department of Urology, First Affiliated Hospital of Jishou University, Jishou, Hunan, China
| | - Yanxu Lu
- Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, Hunan, China
| | - Ke Ding
- Department of General Surgery Thyroid Specialty, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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Sun Y, Yao L, Man C, Gao Z, He R, Fan Y. Development and validation of cuproptosis-related lncRNAs associated with pancreatic cancer immune microenvironment based on single-cell. Front Immunol 2023; 14:1220760. [PMID: 37822927 PMCID: PMC10563513 DOI: 10.3389/fimmu.2023.1220760] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 09/12/2023] [Indexed: 10/13/2023] Open
Abstract
Background Cuproptosis, a novel mode of cell death associated with the tricarboxylic acid (TCA) cycle, is relevant to the development of cancer. However, the impact of single-cell-based Cuproptosis-associated lncRNAs on the Tumor immune microenvironment (TIME) of Pancreatic adenocarcinoma (PAAD) and its potential value for individualized immunotherapy has not been clarified. Methods 14 immune-related CRGs were screened by exploring the interaction between differentially expressed Immune-Related Genes (IRGs) and Cuproptosis-Related Genes (CRGs) in PAAD. Next, the expression amount and expression distribution of CRGs in single-cell samples were analyzed by focusing on 7-CRGs with significant expressions. On the one hand, MAP2K2, SOD1, and VEGFA, which were significantly differentially expressed between PAAD sites and normal tissues adjacent to them, were subjected to immunohistochemical validation and immune landscape analysis. On the other hand, from these 7-CRGs, prognostic signatures of lncRNAs were established by co-expression and LASSO-COX regression analysis, and their prognostic value and immune relevance were assessed. In addition, this study not only validated the hub CRGs and the lncRNAs constituting the signature in a PAAD animal model treated with immunotherapy-based combination therapy using immunohistochemistry and qRT-PCR but also explored the potential value of the combination of targeted, chemotherapy and immunotherapy. Results Based on the screening of 7-CRGs significantly expressed in a PAAD single-cell cohort and their co-expressed Cuproptosis-Related lncRNAs (CRIs), this study constructed a prognostic signature of 4-CRIs named CIR-score. A Nomogram integrating the CIR-score and clinical risk factors was constructed on this basis to predict the individualized survival of patients. Moreover, high and low-risk groups classified according to the median of signatures exhibited significant differences in clinical prognosis, immune landscape, bioenrichment, tumor burden, and drug sensitivity. And the immunohistochemical and qRT-PCR results of different mouse PAAD treatment strategies were consistent with the trend of inter-group variability in drug sensitivity of hub CRGs and CIR-score. The combination of immunotherapy, targeted therapy, and chemotherapy exhibited a better tumor suppression effect. Conclusion CIR-score, as a Cuproptosis-related TIME-specific prognostic signature based on PAAD single cells, not only predicts the prognosis and immune landscape of PAAD patients but also provides a new strategy for individualized immunotherapy-based combination therapy.
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Affiliation(s)
- Yimeng Sun
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lin Yao
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Changfeng Man
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhenjun Gao
- Department of Gastroenterology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Rong He
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Fan
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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11
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GÜZEL TANOĞLU E, ADIGÜZEL S, TANOĞLU A, AYDIN ZB, HOCAOĞLU G, EBİNÇ S. Long noncoding RNAs in pancreas cancer: from biomarkers to therapeutic targets. Turk J Med Sci 2023; 53:1552-1564. [PMID: 38813489 PMCID: PMC10760575 DOI: 10.55730/1300-0144.5724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 12/12/2023] [Accepted: 09/09/2023] [Indexed: 05/31/2024] Open
Abstract
Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are transcribed by RNA polymerase II, they have properties similar to messenger RNA (mRNA). Contrary to popular belief, the term "ncRNA" originated before the discovery of microRNAs. LncRNA genes are more numerous than protein-coding genes. They are the focus of current molecular research because of their pivotal roles in cancer-related processes such as cell proliferation, differentiation, and migration. The incidence of pancreatic cancer (PC) is increasing around the world and research on the molecular aspects of PC are growing. In this review, it is aimed to provide critical information about lncRNAs in PC, including the biological and oncological behaviors of lncRNAs in PC and their potential application in therapeutic strategies and as diagnostic tumor markers.
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Affiliation(s)
- Esra GÜZEL TANOĞLU
- Department of Molecular Biology and Genetics, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul,
Turkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, İstanbul,
Turkiye
| | - Seyfure ADIGÜZEL
- Department of Molecular Biology and Genetics, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul,
Turkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, İstanbul,
Turkiye
| | - Alpaslan TANOĞLU
- Department of Internal Medicine, Division of Gastroenterology, School of Medicine, Bahçeşehir University, İstanbul,
Turkiye
| | - Zehra Betül AYDIN
- Department of Molecular Biology and Genetics, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul,
Turkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, İstanbul,
Turkiye
| | - Gülizar HOCAOĞLU
- Department of Molecular Biology and Genetics, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul,
Turkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, İstanbul,
Turkiye
| | - Samet EBİNÇ
- Department of Molecular Biology and Genetics, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul,
Turkiye
- Experimental Medicine Research and Application Center, University of Health Sciences, İstanbul,
Turkiye
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12
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Zhang H, Cao K, Xiang J, Zhang M, Zhu M, Xi Q. Hypoxia induces immunosuppression, metastasis and drug resistance in pancreatic cancers. Cancer Lett 2023; 571:216345. [PMID: 37558084 DOI: 10.1016/j.canlet.2023.216345] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/26/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023]
Abstract
Pancreatic cancer is one of the common malignant tumors of the digestive system and is known as the "king of cancers". It is extremely difficult to diagnose at an early stage, the disease progresses rapidly, and the effect of chemotherapy and radiotherapy is poor, so the prognosis of pancreatic cancer patients is very poor. Numerous studies have suggested that hypoxia is closely related to the development and progression of pancreatic cancer. Inadequate blood supply and desmoplasia in the microenvironment of pancreatic cancer can result in its extreme hypoxia. This hypoxic microenvironment can further contribute to angiogenesis and desmoplasia. Hypoxia is mediated by the complex hypoxia inducible factor (HIF) signaling pathway and plays an important role in the formation of a highly immunosuppressive microenvironment and the metastasis of pancreatic cancer. Further work on the hypoxic microenvironment will help clarify the specific mechanisms of the role of hypoxia in pancreatic cancer and provide a basis for the realization of hypoxia-targeted therapeutic and diagnostic strategies.
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Affiliation(s)
- Huan Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Kailei Cao
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Jingrong Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Mengting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Mengxin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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13
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Dalmasso B, Ghiorzo P. Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer. Cancers (Basel) 2023; 15:3486. [PMID: 37444595 PMCID: PMC10340399 DOI: 10.3390/cancers15133486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic adenocarcinoma is a highly aggressive disease with a poor prognosis. The reprogramming of energetic metabolism has long been implicated in pancreatic tumorigenesis and/or resistance to treatment. Considering that long non-coding RNA dysregulation has been described both in cancerogenesis and in the altered homeostasis of several metabolic pathways, metabolism-associated lncRNAs can contribute to pancreatic cancer evolution. The objective of this review is to assess the burden of lncRNA dysregulation in pancreatic cancer metabolic reprogramming, and its effect on this tumor's natural course and response to treatment. Therefore, we reviewed the available literature to assess whether metabolism-associated lncRNAs have been found to be differentially expressed in pancreatic cancer, as well as whether experimental evidence of their role in such pathways can be demonstrated. Specifically, we provide a comprehensive overview of lncRNAs that are implicated in hypoxia-related pathways, as well as in the reprogramming of autophagy, lipid metabolism, and amino acid metabolism. Our review gathers background material for further research on possible applications of metabolism-associated lncRNAs as diagnostic/prognostic biomarkers and/or as potential therapeutic targets in pancreatic adenocarcinoma.
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Affiliation(s)
- Bruna Dalmasso
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy;
| | - Paola Ghiorzo
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy;
- Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
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14
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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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15
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Li J, Li W, Wang H, Ni B, Liu Y. Development and validation of a novel ferroptosis‑related lncRNA prognostic signature for pancreatic adenocarcinoma. Mol Med Rep 2023; 27:56. [PMID: 36660936 PMCID: PMC9879080 DOI: 10.3892/mmr.2023.12943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 11/29/2022] [Indexed: 01/19/2023] Open
Abstract
Long non‑coding RNAs (lncRNAs) serve a pivotal role in the regulation of cancer cell ferroptosis. However, the prognostic value of ferroptosis‑related lncRNAs in pancreatic adenocarcinoma (PAAD) largely remains unclear. We aimed at constructing a lncRNA‑based signature to improve the prognosis prediction of PAAD. In the present study, the transcriptome profiling data and clinical information of patients with PAAD were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Gene Consortium (ICGC) databases. Univariate Cox regression analysis of the TCGA cohort demonstrated that 26 ferroptosis‑related lncRNAs had significant prognostic value for PAAD (all P<0.01). Least absolute shrinkage and selection operator regression and multivariate Cox proportional hazards regression analyses were performed to construct a prognostic ferroptosis‑related lncRNA signature (FRLS) comprising nine ferroptosis‑related lncRNAs. The efficacy of this FRLS was verified in the training (TCGA) and validation (ICGC) cohorts. Based on the risk model, high risk scores were significantly correlated with poor overall survival (OS) (hazard ratio, 1.314; 95% confidence interval, 1.218‑1.418; P<0.001). The receiver operating characteristic curves and principal component analysis further demonstrated the robust prognostic ability of the FRLS. Furthermore, a nomogram with favorable predictive efficacy for the prediction of OS was constructed based on the FRLS and clinical features. Gene set enrichment analysis demonstrated that the genes in the FRLS participated in a number of cancer‑associated immunoregulatory pathways. Importantly, it was demonstrated that immune infiltration and response to cancer immunotherapy differed significantly between the high and low‑risk groups according to the FRLS. In conclusion, the risk signature based on the FRLS has potential for the clinical prediction of prognosis and immunotherapy response in patients with PAAD.
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Affiliation(s)
- Jian Li
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, P.R. China,Department of General Surgery, Air Force Hospital of Western Theater Command, Chengdu, Sichuan 610065, P.R. China,Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Wenhua Li
- Department of Cadre Ward, Air Force Hospital of Western Theater Command, Chengdu, Sichuan 610065, P.R. China
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China
| | - Bing Ni
- Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, P.R. China,Correspondence to: Professor Bing Ni, Department of Pathophysiology, College of High Altitude Military Medicine, Third Military Medical University, 30 Gaotanyan Main Street, Shapingba, Chongqing 400038, P.R. China, E-mail:
| | - Yongkang Liu
- Department of General Surgery, Air Force Hospital of Western Theater Command, Chengdu, Sichuan 610065, P.R. China,Dr Yongkang Liu, Department of General Surgery, Air Force Hospital of Western Theater Command, 18 Shunjiang Street, Jinjiang, Chengdu, Sichuan 610065, P.R. China, E-mail:
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16
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Wei X, Yang M, Pan B, Zhang X, Lin H, Li W, Shu W, Wang K, Khan AR, Zhang X, Cen B, Xu X. Proteomics-based identification of the role of osteosarcoma amplified-9 in hepatocellular carcinoma recurrence. Hepatol Commun 2022; 6:2182-2197. [PMID: 35429130 PMCID: PMC9315138 DOI: 10.1002/hep4.1952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 02/09/2022] [Accepted: 03/03/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies; its recurrence is associated with high mortality and poor recurrence-free survival and is affected by multisystem and multilevel pathological changes. To identify the key proteins associated with tumor recurrence and the underlying mechanisms, proteomic profiling of tumor specimens from early recurrence and nonrecurrence patients was performed in this study. Proteomics was applied to identify differentially expressed proteins during the early recurrence of HCC after surgery. Osteosarcoma amplified-9 (OS-9) was discovered, and the correlation between OS-9 expression and the clinicopathological characteristics of patients was analyzed. Invasion and migration were examined in SMMC-7721 cells with and without OS-9 overexpression. Proteomics was performed once again using SMMC-7721 cells with OS-9 overexpression to further analyze the proteins with altered expression. OS-9 was overexpressed in the early recurrence group, and OS-9 overexpression was associated with high serum alpha-fetoprotein levels and poor recurrence-free survival in 196 patients with HCC. The invasion and migration abilities of SMMC-7721 cells were enhanced in the OS-9 overexpression group. Bioinformatic functional enrichment methods, including Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealed that the hypoxia-inducible factor 1 (HIF-1) and tumor necrosis factor (TNF) signaling pathways were activated in the OS-9 overexpression group. The migration and invasion capacities of OS-9 overexpressed HCC cell line were weakened while treated with HIF-1α or TNF-α inhibitors. Conclusion: Our results suggest that the overexpression of OS-9 is related to HCC recurrence, thereby contributing to the migration and invasion capacities of HCC cell line by regulating the HIF-1 and TNF pathways.
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Affiliation(s)
- Xuyong Wei
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Mengfan Yang
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina.,Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Binhua Pan
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina.,Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaobing Zhang
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Hanchao Lin
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Wangyao Li
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Kun Wang
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Abdul Rehman Khan
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina.,Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xuanyu Zhang
- NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina.,Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Beini Cen
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina.,Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina.,NHC Key Laboratory of Combined Multi-Organ TransplantationHangzhouChina.,Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina.,Zhejiang University Cancer CenterHangzhouChina.,Institute of Organ TransplantationZhejiang UniversityHangzhouChina
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17
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Wu C, Liu Y, Wan K, Lan Y, Jia M, Lin L, Gao S, Chen K, Yang J, Pan HL, Li M, Mao H. Long Non-Coding RNA and mRNA Profiles in the Spinal Cord of Rats with Resiniferatoxin-Induced Neuropathic Pain. J Pain Res 2022; 15:2149-2160. [PMID: 35935680 PMCID: PMC9348574 DOI: 10.2147/jpr.s368599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/15/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose The ultrapotent transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX) induces small-fiber sensory neuropathy, which has been widely used model of postherpetic neuralgia to study mechanisms of neuropathic pain and new analgesics. The long non-coding RNA (lncRNA) and mRNA expression profiles in spinal dorsal horn tissues of rats six weeks after RTX injection to identify new RNAs related to neuropathic pain. Methods Microarray technology was applied to determine lncRNA expressions in spinal dorsal horn samples of adult rats 6 weeks after treatment with RTX or vehicle. The lncNA/mRNA co-expression network was constructed, and differential expression patterns of lncRNA and mRNA in RTX-treated rats were identified. Differential expressions of lncRNAs and mRNAs between RTX-treated samples and control samples were examined by RT-qPCR. Results Microarray analyses showed that 745 mRNA and 139 lncRNAs were upregulated, whereas 590 mRNA and 140 lncRNAs were downregulated in spinal dorsal horn tissues after RTX exposure. TargetScan was used to predict mRNA targets for these lncRNAs, which showed that the transcripts with multiple predicted target sites were related to neurologically important pathways. In addition, differential expressions of lncRNA (ENSRNOG00000022535, ENSRNOG00000042027, NR_027478, NR_030675) and Apobec3b mRNA in spinal cord tissue samples were validated, which confirmed the microarray data. The association between NR_030675 and Apobec3b levels was confirmed, which may be related to neuropathic pain. Conclusion Our study reveals lncRNA and mRNA of molecule targets that are enriched in the spinal cord dorsal horn and provides new information for further investigation on the mechanisms and therapeutics of neuropathic pain.
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Affiliation(s)
- Caihua Wu
- Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Yongmin Liu
- Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Kexing Wan
- Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Yuye Lan
- Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Min Jia
- Clinical Laboratories, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Lixue Lin
- Department of Rehabilitation, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Shan Gao
- Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Ke Chen
- Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Jinmei Yang
- Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Hui-Lin Pan
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Man Li
- Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China
| | - Hongrong Mao
- Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China
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18
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Ma Y, Di Y, Li Q, Zhan Q, He X, Liu S, Zou H, Corpe C, Chen L, Wang J. LncRNAs as epigenetic regulators of epithelial to mesenchymal transition in pancreatic cancer. Discov Oncol 2022; 13:61. [PMID: 35819532 PMCID: PMC9276894 DOI: 10.1007/s12672-022-00522-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/01/2022] [Indexed: 11/04/2022] Open
Abstract
Pancreatic cancer is the leading cause of cancer-related mortality because of tumor metastasis. Activation of the epithelial-to-mesenchymal transition (EMT) pathway has been confirmed to be an important driver of pancreatic cancer progression from initiation to metastasis. Long noncoding RNAs (lncRNAs) have been reported to exert essential physiological functions in pancreatic cancer progression by regulating the EMT program. In this review, we have summarized the role of EMT-related lncRNAs in human pancreatic cancer and the potential molecular mechanisms by which lncRNAs can be vital epigenetic regulators of epithelial to mesenchymal transition. Specifically, EMT-activating transcription factors (EMT-TFs) regulate EMT via TGF-β/Smad, Wnt/β-catenin, and JAK/STAT pathways. In addition, the interaction between lncRNAs and HIF-1α and m6A RNA methylation also have an impact on tumor metastasis and EMT in pancreatic cancer. This review will provide insights into lncRNAs as promising biomarkers for tumor metastasis and potential therapeutic strategies for pancreatic cancer.
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Affiliation(s)
- Yan Ma
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Yang Di
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiuyue Li
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Qilin Zhan
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Xiaomeng He
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Shanshan Liu
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Heng Zou
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China
| | - Christopher Corpe
- King's College London, Nutritional Science Department, 150 Stamford Street, Waterloo, London, SE19NH, UK
| | - Litian Chen
- Department of Hepatobiliary Surgery, Shanghai Jiaotong University School of Medicine Xinhua Hospital, Kongjiang Road 1665, Shanghai, China.
| | - Jin Wang
- Shanghai Public Health Clinical Center, Fudan University, 2901 Caolang Road, Jinshan District, Shanghai, 201508, People's Republic of China.
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19
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Wang BQ, Wang JL, Zhang BQ, Li TT, Wang C, Sun GB. Role of long non-coding RNAs in development and progression of pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2022; 30:274-279. [DOI: 10.11569/wcjd.v30.i6.274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a kind of digestive tract malignant tumor that has high malignancy and is difficult to diagnose and treat. Recent studies have proved that long non-coding RNAs (lncRNAs) can mediate tumor genesis, proliferation, migration, and metastasis by regulating epigenetic modification, alternative splicing, transcription, and protein translation. LncRNAs play an important role in the occurrence and development of pancreatic cancer. In this review, we review the role of lncRNAs in pancreatic cancer to provide possible diagnostic and therapeutic targets for the treatment of this malignancy.
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Affiliation(s)
- Bai-Qing Wang
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Jue-Lei Wang
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Bao-Qin Zhang
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Tian-Tian Li
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Chao Wang
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Guang-Bin Sun
- Department of Gastroenterology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
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20
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Song Y, Liang Y, Zou Q, Zeng S, Lin H, Liu M, Liu X, Du J, Chen G, Zou L, Su W, Niu F. LINC00857 promotes the proliferation of pancreatic cancer via MET, STAT3, and CREB. J Gastrointest Oncol 2021; 12:2622-2630. [PMID: 35070392 PMCID: PMC8748069 DOI: 10.21037/jgo-21-723] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/26/2021] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) LINC00857 promotes cell proliferation in various cancers and is overexpressed in pancreatic cancer (PC). However, the role of LINC00857 in PC is yet to be clarified. METHODS In this study, we used Gene Expression Profiling Interactive Analysis (GEPIA) to investigate transcriptional data of LINC00857 in different cancers. We determined LINC00857 expression in 4 PC cell lines, and one normal pancreatic cell line by quantitative real-time reverse transcription PCR (qRT-PCR). small interfering RNA (siRNA) was employed to specifically knockdown LINC00857 in BxPc3 and PANC1 cells. Cell proliferation was evaluated using WST-1. Western blotting analysis was used to detect the expression levels of downstream proteins of LINC00857. RESULTS We revealed that the knockdown of LINC00857 in PC cell lines inhibited the proliferation of the PC cells. We found that LINC00857 downregulation was followed by the downregulation of oncogenic proteins mesenchymal-epithelial transition (MET), signal transducer and activator of transcription 3 (STAT3), and cAMP response element-binding protein (CREB). CONCLUSIONS Our study indicated that LINC00857 regulated the expression of STAT3 and CREB via regulating the expression of MET, and consequently promoted the growth of PC cells. The results allowed us to deepen our understanding of the pathogenesis of PC and provided a potential target for the clinical treatment of PC.
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Affiliation(s)
- Ye Song
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Yingying Liang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Qingfeng Zou
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | | | - Hanhong Lin
- Guangzhou Medical University, Guangzhou, China
| | - Meiyuan Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Jike Du
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Guoan Chen
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Lei Zou
- Department of Organ Transplant, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wenmei Su
- Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Feiyu Niu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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21
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Takahashi K, Taniue K, Ono Y, Fujiya M, Mizukami Y, Okumura T. Long Non-Coding RNAs in Epithelial-Mesenchymal Transition of Pancreatic Cancer. Front Mol Biosci 2021; 8:717890. [PMID: 34820419 PMCID: PMC8606592 DOI: 10.3389/fmolb.2021.717890] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/25/2021] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs (ncRNAs), or RNA molecules that do not code for proteins, are generally categorized as either small or long ncRNA (lncRNA) and are involved in the pathogenesis of several diseases including many cancers. Identification of a large number of ncRNAs could help to elucidate previously unknown mechanisms in phenotype regulation. Some ncRNAs are encapsulated by extracellular vesicles (EVs) and transferred to recipient cells to regulate cellular processes, including epigenetic and post-transcriptional regulations. Recent studies have uncovered novel molecular mechanisms and functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC), one of the most intractable cancers that is highly invasive and metastatic. As the epithelial-mesenchymal transition (EMT) triggers tumor cell invasion and migration, clarification of the roles of lncRNA in EMT and tumor cell stemness would be critical for improving diagnostic and therapeutic approaches in metastatic cancers. This review provides an overview of relevant studies on lncRNA and its involvement with EMT in PDAC. Emerging knowledge offers evidence for the dysregulated expression of lncRNAs and essential insights into the potential contribution of both lncRNAs and EVs in the pathogenesis of PDAC. Future directions and new clinical applications for PDAC are also discussed.
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Affiliation(s)
- Kenji Takahashi
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kenzui Taniue
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.,Isotope Science Center, The University of Tokyo, Bunkyo, Japan
| | - Yusuke Ono
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Mikihiro Fujiya
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yusuke Mizukami
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.,Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
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22
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Ghafouri-Fard S, Fathi M, Zhai T, Taheri M, Dong P. LncRNAs: Novel Biomarkers for Pancreatic Cancer. Biomolecules 2021; 11:1665. [PMID: 34827663 PMCID: PMC8615627 DOI: 10.3390/biom11111665] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/31/2021] [Accepted: 11/09/2021] [Indexed: 12/31/2022] Open
Abstract
Pancreatic cancer is one of the most deadly neoplasms and the seventh major cause of cancer-related deaths among both males and females. This cancer has a poor prognosis due to the lack of appropriate methods for early detection of cancer. Long non-coding RNAs (lncRNAs) have been recently found to influence the progression and initiation of pancreatic cancer. MACC1-AS1, LINC00976, LINC00462, LINC01559, HOXA-AS2, LINC00152, TP73-AS1, XIST, SNHG12, LUCAT1, and UCA1 are among the oncogenic lncRNAs in pancreatic cancer. On the other hand, LINC01111, LINC01963, DGCR5, MEG3, GAS5, and LINC00261 are among tumor suppressor lncRNAs in this tissue. In the current review, we summarize the roles of these two classes of lncRNAs in pancreatic cancer and discuss their potential as attractive diagnostic and prognostic biomarkers for pancreatic cancer. We also identified that the low expression of MEG3, LINC01963, and LINC00261 and the high expression of MACC1-AS1, LINC00462, LINC01559, and UCA1 were significantly correlated with worse survival in pancreatic cancer patients. Further research on these lncRNAs will provide new clues that could potentially improve the early diagnosis, prognostic prediction, and personalized treatments of patients with pancreatic cancer.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983535511, Iran;
| | - Mohadeseh Fathi
- Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran 1983535511, Iran;
| | - Tianyue Zhai
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Kita-ku, Sapporo 0608638, Japan;
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran 1983535511, Iran
| | - Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, N15, W7, Kita-ku, Sapporo 0608638, Japan;
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23
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Palamaris K, Felekouras E, Sakellariou S. Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance. Cancers (Basel) 2021; 13:cancers13215532. [PMID: 34771695 PMCID: PMC8582651 DOI: 10.3390/cancers13215532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/31/2021] [Accepted: 11/01/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma’s (PDAC) dismal prognosis is associated with its aggressive biological behavior and resistance to chemotherapy. Epithelial to mesenchymal transition (EMT) has been recognized as a key driver of PDAC progression and development of drug resistance. EMT is a transient and reversible process leading to transdifferentiation of epithelial cells into a more mesenchymal phenotype. It is regulated by multiple signaling pathways that control the activity of a transcription factors network. Activation of EMT in pre-invasive stages of PDAC has been accused for early dissemination. Furthermore, it contributes to the development of intratumoral heterogeneity and drug resistance. This review summarizes the available data regarding signaling networks regulating EMT and describes the integral role of EMT in different aspects of PDAC pathogenesis. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.
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Affiliation(s)
- Kostas Palamaris
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Evangelos Felekouras
- 1ST Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stratigoula Sakellariou
- 1ST Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Correspondence:
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24
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Chen X, Liu F, Xue Q, Weng X, Xu F. Metastatic pancreatic cancer: Mechanisms and detection (Review). Oncol Rep 2021; 46:231. [PMID: 34498718 PMCID: PMC8444192 DOI: 10.3892/or.2021.8182] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/19/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PC) is a lethal malignancy. Its prevalence rate remains low but continues to grow each year. Among all stages of PC, metastatic PC is defined as late-stage (stage IV) PC and has an even higher fatality rate. Patients with PC do not have any specific clinical manifestations. Most cases are inoperable at the time-point of diagnosis. Prognosis is also poor even with curative-intent surgery. Complications during surgery, postoperative pancreatic fistula and recurrence with metastatic foci make the management of metastatic PC difficult. While extensive efforts were made to improve survival outcomes, further elucidation of the molecular mechanisms of metastasis poses a formidable challenge. The present review provided an overview of the mechanisms of metastatic PC, summarizing currently known signaling pathways (e.g. epithelial-mesenchymal transition, NF-κB and KRAS), imaging that may be utilized for early detection and biomarkers (e.g. carbohydrate antigen 19-9, prostate cancer-associated transcript-1, F-box/LRR-repeat protein 7 and tumor stroma), giving insight into promising therapeutic targets.
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Affiliation(s)
- Xiangling Chen
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Fangfang Liu
- Department of Art, Art College, Southwest Minzu University, Chengdu, Sichuan 610041, P.R. China
| | - Qingping Xue
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Xiechuan Weng
- Department of Neuroscience, Beijing Institute of Basic Medical Sciences, Beijing 100850, P.R. China
| | - Fan Xu
- Department of Public Health, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
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25
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Seyed Hosseini E, Nikkhah A, Sotudeh A, Alizadeh Zarei M, Izadpanah F, Nikzad H, Haddad Kashani H. The impact of LncRNA dysregulation on clinicopathology and survival of pancreatic cancer: a systematic review and meta-analysis (PRISMA compliant). Cancer Cell Int 2021; 21:447. [PMID: 34425840 PMCID: PMC8383355 DOI: 10.1186/s12935-021-02125-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
Purpose An increasing number of studies have reported a significant association between long non-coding RNAs (lncRNAs) dysregulation and pancreatic cancers. In the present study, we aimed to gather articles to evaluate the prognostic value of long non coding RNA in pancreatic cancer. Experimental design We systematically searched all eligible articles from databases of PubMed, Web of Science, and Scopus to meta-analysis of published articles and screen association of multiple lncRNAs expression with clinicopathology and/or survival of pancreatic cancer. The pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were used to analysis of overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. Results A total of 39 articles were included in the present meta-analysis. Our results showed that dysregulation of lncRNAs were linked to overall survival (39 studies, 4736 patients HR = 0.41, 95% CI 0.25 ± 0.58, random-effects in pancreatic cancer. Moreover, altered lncRNAs were also contributed to progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI (1.35–2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI 1.28–28.78). In addition, our findings revealed the association between dysregulated RNAs and clinicopathological features in this type of cancer. Conclusions In conclusion, dysregulated lncRNAs could be served as promising biomarkers for diagnosis and prognosis of pancreatic cancer.
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Affiliation(s)
- Elahe Seyed Hosseini
- Gametogenesis Research Center, Kashan University of Medical Science, Kashan, Iran.,Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Nikkhah
- Student Research Committee, Kashan University of Medical Science, Kashan, Iran
| | - Amir Sotudeh
- Student Research Committee, Kashan University of Medical Science, Kashan, Iran
| | - Marziyeh Alizadeh Zarei
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Izadpanah
- Food and Drug Laboratory Research Center and Food and Drug Reference Control Laboratories Center, Food & Drug Administration of Iran, MOH & ME, Tehran, Iran
| | - Hossein Nikzad
- Gametogenesis Research Center, Kashan University of Medical Science, Kashan, Iran.,Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Haddad Kashani
- Gametogenesis Research Center, Kashan University of Medical Science, Kashan, Iran. .,Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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26
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Zhu Y, Wu F, Gui W, Zhang N, Matro E, Zhu L, Eserberg DT, Lin X. A positive feedback regulatory loop involving the lncRNA PVT1 and HIF-1α in pancreatic cancer. J Mol Cell Biol 2021; 13:676-689. [PMID: 34245303 PMCID: PMC8648389 DOI: 10.1093/jmcb/mjab042] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 04/15/2021] [Accepted: 04/28/2021] [Indexed: 11/22/2022] Open
Abstract
Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer (PC). Both the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and hypoxic inducible factor-1α (HIF-1α) are highly expressed in PC patients and play a crucial role in disease progression. Reciprocal regulation involving PVT1 and HIF-1α in PC, however, is poorly understood. Here, we report that PVT1 binds to the HIF-1α promoter and activates its transcription. In addition, we found that PVT1 could bind to HIF-1α and increases HIF-1α post-translationally. Our findings suggest that the PVT1‒HIF-1α positive feedback loop is a potential therapeutic target in the treatment of PC.
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Affiliation(s)
- Yiping Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fang Wu
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weiwei Gui
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Nan Zhang
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Erik Matro
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Linghua Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | | | - Xihua Lin
- Department of Endocrinology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
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27
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Mortoglou M, Tabin ZK, Arisan ED, Kocher HM, Uysal-Onganer P. Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy. Transl Oncol 2021; 14:101090. [PMID: 33831655 PMCID: PMC8042452 DOI: 10.1016/j.tranon.2021.101090] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/14/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - Zoey Kathleen Tabin
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - E Damla Arisan
- Institution of Biotechnology, Gebze Technical University, Gebze, Turkey.
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University London, London EC1M 6BQ, UK.
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
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28
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Ramya Devi KT, Karthik D, Mahendran T, Jaganathan MK, Hemdev SP. Long noncoding RNAs: role and contribution in pancreatic cancer. Transcription 2021; 12:12-27. [PMID: 34036896 DOI: 10.1080/21541264.2021.1922071] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Noncoding RNAs are proclaimed to be expressed in various cancer types and one such type is found to be pancreatic ductal adenocarcinoma (PDAC). The long noncoding RNAs (LncRNAs) affect the migration, invasion, and growth of tumor cells by playing important roles in the process of epigenesis, post-transcription, and transcriptional regulation along with the maintenance of apoptosis and cell cycle. It is quite subtle whether the alterations in lncRNAs would impact PDAC progression and development. This review throws a spotlight on the lncRNAs associated with tumor functions: MALAT-1, HOTAIR, HOXA13, H19, LINC01559, LINC00460, SNHG14, SNHG16, DLX6-AS1, MSC-AS1, ABHD11-AS1, DUXAP8, DANCR, XIST, DLEU2, etc. are upregulated lncRNAs whereas GAS5, HMlincRNA717, MIAT, LINC01111, lncRNA KCNK15-AS1, etc. are downregulated lncRNAs inhibiting the invasion and progression of PDAC. These data provided helps in the assessment of lncRNAs in the development, metastasis, and occurrence of PDAC and also play a vital role in the evolution of biomarkers and therapeutic agents for the treatment of PDAC.
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Affiliation(s)
- K T Ramya Devi
- Department of Biotechnology, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Tamil Nadu, India
| | - Dharshene Karthik
- Department of Biotechnology, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Tamil Nadu, India.,Department of Industrial Biotechnology, Sri Venkateswara College of Engineering, Chennai, India
| | - TharunSelvam Mahendran
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - M K Jaganathan
- Department of Biotechnology, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Tamil Nadu, India
| | - Sanjana Prakash Hemdev
- School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, United States
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29
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Li MX, Wang HY, Yuan CH, Ma ZL, Jiang B, Li L, Zhang L, Xiu DR. KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages. Clin Sci (Lond) 2021; 135:629-649. [PMID: 33538300 DOI: 10.1042/cs20201259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 01/13/2021] [Accepted: 02/04/2021] [Indexed: 12/19/2022]
Abstract
Tumor microenvironment (TME) exerts key roles in pancreatic ductal adenocarcinoma (PDAC) development. However, the factors regulating the cross-talk between PDAC cells and TME are largely unknown. In the present study, we identified a long noncoding RNA (lncRNA) KLHDC7B divergent transcript (KLHDC7B-DT), which was up-regulated in PDAC and correlated with poor survival of PDAC patients. Functional assays demonstrated that KLHDC7B-DT enhanced PDAC cell proliferation, migration, and invasion. Mechanistically, KLHDC7B-DT was found to directly bind IL-6 promoter, induce open chromatin structure at IL-6 promoter region, activate IL-6 transcription, and up-regulate IL-6 expression and secretion. The expression of KLHDC7B-DT was positively correlated with IL-6 in PDAC tissues. Via inducing IL-6 secretion, KLHDC7B-DT activated STAT3 signaling in PDAC cells in an autocrine manner. Furthermore, KLHDC7B-DT also activated STAT3 signaling in macrophages in a paracrine manner, which induced macrophage M2 polarization. KLHDC7B-DT overexpressed PDAC cells-primed macrophages promoted PDAC cell proliferation, migration, and invasion. Blocking IL-6/STAT3 signaling reversed the effects of KLHDC7B-DT on macrophage M2 polarization and PDAC cell proliferation, migration, and invasion. In conclusion, KLHDC7B-DT enhanced malignant behaviors of PDAC cells via IL-6-induced macrophage M2 polarization and IL-6-activated STAT3 signaling in PDAC cells. The cross-talk between PDAC cells and macrophages induced by KLHDC7B-DT represents potential therapeutic target for PDAC.
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Affiliation(s)
- Mu-Xing Li
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Hang-Yan Wang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Zhao-Lai Ma
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Bin Jiang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Lei Li
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Li Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing, China
| | - Dian-Rong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, China
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Ma CN, Wo LL, Wang DF, Zhou CX, Li JC, Zhang X, Gong XF, Wang CL, He M, Zhao Q. Hypoxia activated long non-coding RNA HABON regulates the growth and proliferation of hepatocarcinoma cells by binding to and antagonizing HIF-1 alpha. RNA Biol 2021; 18:1791-1806. [PMID: 33478328 DOI: 10.1080/15476286.2020.1871215] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The adaptation of tumour cells to hypoxic microenvironment is one of the most significant characteristics of many malignant tumour diseases including hepatocarcinoma. Recently, long non-coding RNAs (lncRNAs) have been reported to play important roles in the various levels of gene regulation thus functioning in growth and survival of tumour cells. Here, new hypoxia-related lncRNAs in hepatocarcinoma cells were screened and validated by lncRNA chip-array as well as real-time RT-PCR. Among them, a hypoxia-activated lncRNA that we identified and termed Hypoxia-Activated BNIP3 Overlapping Non-coding RNA (HABON), was not only regulated by hypoxic-induced factor-1α (HIF-1α) but its expression increased significantly under hypoxia in tumour cells. We deciphered the biological characteristics of HABON including its cell localization, genomic location, as well as its full-length sequence, and proved HABON could promote growth, proliferation and clone-formation of hepatocarcinoma cells under hypoxia. Then, we revealed that HABON was transcriptionally activated by HIF-1α in hypoxic cells, furthermore, it could interact with HIF-1α and promote its protein degradation, thus affecting transcription of HIF-1α's target genes to exert its effects on cells. Besides, the elevated expression of HABON under hypoxia could promote the transcriptional activation of BNIP3 through HIF-1α, and increasing the expression level of BNIP3. This research provides a novel clue for the adaptive survival and growth mechanism of tumour under hypoxia, and gives a way to reveal the nature of tumour cells' resistance characteristics to harsh microenvironment.
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Affiliation(s)
- Cheng-Ning Ma
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Lu-Lu Wo
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Di-Fei Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Ci-Xiang Zhou
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Jing-Chi Li
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xin Zhang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xiu-Feng Gong
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Chen-Long Wang
- Department of Pathology, Xuzhou Medical University, Xuzhou, China
| | - Ming He
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China
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Wang X, Zhao D, Xie H, Hu Y. Interplay of long non-coding RNAs and HIF-1α: A new dimension to understanding hypoxia-regulated tumor growth and metastasis. Cancer Lett 2020; 499:49-59. [PMID: 33217445 DOI: 10.1016/j.canlet.2020.11.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/11/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022]
Abstract
Hypoxia is a feature of the solid tumor microenvironment that is associated with poor clinical outcomes in multiple tumor types. Hypoxia-induced factor-1 alpha (HIF-1α) is a master regulator of hypoxic adaption, has been demonstrated to modulate hypoxic gene expression profiling and signaling transduction networks, and is thus a potential therapeutic target. Despite hypoxic response signaling having being extensively studied, the involvement of long non-coding RNAs (lncRNAs) in the hypoxic response has become a new focus of attention. Emerging evidence has documented complex interactions between HIF-1α and lncRNAs, which contribute to the acquisition of multiple hallmarks of cancer. In this review, we focus on recent advances in the study of hypoxia and HIF-1α-regulated lncRNAs, and summarize the molecular mechanisms and functional outcomes of the interplay between lncRNAs and HIF-1α, which may provide important insights into cancer diagnosis and prognosis, enabling better control of cancer.
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Affiliation(s)
- Xingwen Wang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China
| | - Dong Zhao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China
| | - Hui Xie
- State Key Laboratory of Robotics and Systems, Harbin Institute of Technology, 2 Yikuang, Harbin, 150001, China
| | - Ying Hu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Provence, 150001, China; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, 518055, China.
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32
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Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
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Research progress on long non-coding RNAs and their roles as potential biomarkers for diagnosis and prognosis in pancreatic cancer. Cancer Cell Int 2020; 20:457. [PMID: 32973402 PMCID: PMC7493950 DOI: 10.1186/s12935-020-01550-y] [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: 06/23/2020] [Accepted: 09/09/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the main causes of tumor-related deaths worldwide because of its low morbidity but extremely high mortality, and is therefore colloquially known as the "king of cancer." Sudden onset and lack of early diagnostic biomarkers directly contribute to the extremely high mortality rate of pancreatic cancer patients, and also make it indistinguishable from benign pancreatic diseases and precancerous pancreatic lesions. Additionally, the lack of effective prognostic biomarkers makes it difficult for clinicians to formulate precise follow-up strategies based on the postoperative characteristics of the patients, which results in missed early diagnosis of recurrent pancreatic cancer. Long non-coding RNAs (lncRNAs) can influence cell proliferation, invasion/migration, apoptosis, and even chemoresistance via regulation of various signaling pathways, leading to pro- or anti-cancer outcomes. Given the versatile effects of lncRNAs on tumor progression, using a single lncRNA or combination of several lncRNAs may be an effective method for tumor diagnosis and prognostic predictions. This review will give a comprehensive overview of the most recent research related to lncRNAs in pancreatic cancer progression, as targeted therapies, and as biomarkers for the diagnosis and prognosis of pancreatic cancer.
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Liu Y, Zhang H, Li Y, Yan L, Du W, Wang S, Zheng X, Zhang M, Zhang J, Qi J, Sun H, Zhang L, Li G, Zhu D. Long Noncoding RNA Rps4l Mediates the Proliferation of Hypoxic Pulmonary Artery Smooth Muscle Cells. Hypertension 2020; 76:1124-1133. [PMID: 32772647 DOI: 10.1161/hypertensionaha.120.14644] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Pulmonary hypertension (PH) is a rare and fatal disorder involving the vascular remodeling of pulmonary arteries mediated by the enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs). Long noncoding RNAs are a subclass of regulatory molecules with diverse cellular functions, but their role in PH remains largely unexplored. We aimed to identify and determine the functions of long noncoding RNAs involved in hypoxia-induced PH and PASMC proliferation. RNA sequencing in a hypoxic mouse model identified hypoxia-regulated long noncoding RNAs, including Rps4l. Rps4l expression was significantly reduced in PH-model mice and hypoxic PASMCs. The subcellular localization of Rps4l was detected by RNA fluorescence in situ hybridization and quantification of nuclear/cytoplasmic RNA. Rps4l overexpression rescued pulmonary arterial hypertension features, as demonstrated by right ventricle hypertrophy, right ventricular systolic pressure, hemodynamics, cardiac function, and vascular remodeling. At the cellular level, Rps4l overexpression weakened cell viability and proliferation and suppressed cell cycle progression. Potential Rps4l-binding proteins were identified via RNA pull-down followed by mass spectrometry, RNA immunoprecipitation, and microscale thermophoresis. These results indicated that Rps4l is associated with and affects the stabilization of ILF3 (interleukin enhancer-binding factor 3). Rps41 further regulates the levels of HIF-1α and consequently leads to hypoxia-induced PASMC proliferation and migration. Our results showed that in hypoxic PASMCs, Rps4l expression decreases due to regulation by hypoxia. This decrease affects the proliferation, migration, and cell cycle progression of PASMCs through ILF3/HIF-1α. These results provide a theoretical basis for further investigations into the pathological mechanism of hypoxic PH and may provide insight for the development of novel treatments.
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Affiliation(s)
- Ying Liu
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Hongyue Zhang
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Yiying Li
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Lixin Yan
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Wei Du
- College of Pharmacy, Harbin University of Commerce, Heilongjiang Province, China (W.D., S.W., D.Z.)
| | - Siqi Wang
- College of Pharmacy, Harbin University of Commerce, Heilongjiang Province, China (W.D., S.W., D.Z.)
| | - Xiaodong Zheng
- Department of Pathophysiology, College of Basic Medicine, Harbin Medical University, Daqing, China (X.Z.)
| | - Min Zhang
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Junting Zhang
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Jing Qi
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Hanliang Sun
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
| | - Lixin Zhang
- Central Laboratory of Harbin Medical University (Daqing), P.R. China (L.Z.)
| | - Guangqun Li
- College of Medical Laboratory Science and Technology, Harbin Medical University, Daqing, Heilongjiang Province, China (G.L.)
| | - Daling Zhu
- From the Biopharmaceutical Key Laboratory of Heilongjiang Province, College of Pharmacy, Harbin Medical University, P.R. China (Y. Liu, H.Z., Y. Li, L. Yan, M.Z., J.Z., J.Q., H.S., D.Z.)
- College of Pharmacy, Harbin University of Commerce, Heilongjiang Province, China (W.D., S.W., D.Z.)
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Qin X, Denton WD, Huiting LN, Smith KS, Feng H. Unraveling the regulatory role of endoplasmic-reticulum-associated degradation in tumor immunity. Crit Rev Biochem Mol Biol 2020; 55:322-353. [PMID: 32633575 DOI: 10.1080/10409238.2020.1784085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
During malignant transformation and cancer progression, tumor cells face both intrinsic and extrinsic stress, endoplasmic reticulum (ER) stress in particular. To survive and proliferate, tumor cells use multiple stress response pathways to mitigate ER stress, promoting disease aggression and treatment resistance. Among the stress response pathways is ER-associated degradation (ERAD), which consists of multiple components and steps working together to ensure protein quality and quantity. In addition to its established role in stress responses and tumor cell survival, ERAD has recently been shown to regulate tumor immunity. Here we summarize current knowledge on how ERAD promotes protein degradation, regulates immune cell development and function, participates in antigen presentation, exerts paradoxical roles on tumorigenesis and immunity, and thus impacts current cancer therapy. Collectively, ERAD is a critical protein homeostasis pathway intertwined with cancer development and tumor immunity. Of particular importance is the need to further unveil ERAD's enigmatic roles in tumor immunity to develop effective targeted and combination therapy for successful treatment of cancer.
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Affiliation(s)
- Xiaodan Qin
- Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA
| | - William D Denton
- Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA
| | - Leah N Huiting
- Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA
| | - Kaylee S Smith
- Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA
| | - Hui Feng
- Departments of Pharmacology and Medicine, Section of Hematology and Medical Oncology, Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA
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36
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Long-Noncoding RNA (lncRNA) in the Regulation of Hypoxia-Inducible Factor (HIF) in Cancer. Noncoding RNA 2020; 6:ncrna6030027. [PMID: 32640630 PMCID: PMC7549355 DOI: 10.3390/ncrna6030027] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/25/2020] [Accepted: 07/03/2020] [Indexed: 02/06/2023] Open
Abstract
Hypoxia is dangerous for oxygen-dependent cells, therefore, physiological adaption to cellular hypoxic conditions is essential. The transcription factor hypoxia-inducible factor (HIF) is the main regulator of hypoxic metabolic adaption reducing oxygen consumption and is regulated by gradual von Hippel-Lindau (VHL)-dependent proteasomal degradation. Beyond physiology, hypoxia is frequently encountered within solid tumors and first drugs are in clinical trials to tackle this pathway in cancer. Besides hypoxia, cancer cells may promote HIF expression under normoxic conditions by altering various upstream regulators, cumulating in HIF upregulation and enhanced glycolysis and angiogenesis, altogether promoting tumor proliferation and progression. Therefore, understanding the underlying molecular mechanisms is crucial to discover potential future therapeutic targets to evolve cancer therapy. Long non-coding RNAs (lncRNA) are a class of non-protein coding RNA molecules with a length of over 200 nucleotides. They participate in cancer development and progression and might act as either oncogenic or tumor suppressive factors. Additionally, a growing body of evidence supports the role of lncRNAs in the hypoxic and normoxic regulation of HIF and its subunits HIF-1α and HIF-2α in cancer. This review provides a comprehensive update and overview of lncRNAs as regulators of HIFs expression and activation and discusses and highlights potential involved pathways.
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Liu S, Zhang J, Yin L, Wang X, Zheng Y, Zhang Y, Gu J, Yang L, Yang J, Zheng P, Jiang Y, Shuai L, Cai X, Wang H. The lncRNA RUNX1-IT1 regulates C-FOS transcription by interacting with RUNX1 in the process of pancreatic cancer proliferation, migration and invasion. Cell Death Dis 2020; 11:412. [PMID: 32487998 PMCID: PMC7265432 DOI: 10.1038/s41419-020-2617-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 02/08/2023]
Abstract
Numerous long noncoding RNAs (lncRNAs) are aberrantly expressed in pancreatic cancer (PC); however, their functions and mechanisms in cancer progression are largely unknown. In this study, we identified a novel PC-associated lncRNA, RUNX1-IT1, that was significantly upregulated in PC patient samples from multiple centers and associated with poor prognosis. In vitro and in vivo, alterations in RUNX1-IT1 expression markedly affected PC proliferation, migration and invasion. RUNX1-IT1 contributed to the progression of PC by interacting with the adjacent gene RUNX1. Rescue experiments showed that RUNX1 reduced the cancer-promoting effect of RUNX1-IT1. RNA-seq analysis after silencing RUNX1-IT1 and RUNX1 highlighted alterations in the common target C-FOS. Mechanistically, we demonstrated that RUNX1-IT1 was a trans-acting factor that participated in the proliferation, migration and invasion of PC by recruiting RUNX1 to the C-FOS gene promoter. Furthermore, RUNX1-IT1 enhanced the transcription of the RUNX1 gene, indicating its potential as a cis-regulatory RNA involved in the upstream regulation of RUNX1. Overall, RUNX1-IT1 is a crucial oncogenic lncRNA that activates C-FOS expression by regulating and recruiting RUNX1 and is a potential prognostic biomarker and therapeutic target for PC.
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Affiliation(s)
- Songsong Liu
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Junfeng Zhang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, P. R. China
| | - Liangyu Yin
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Xianxing Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, P. R. China
| | - Yao Zheng
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, P. R. China
| | - Yujun Zhang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Jianyou Gu
- Department of First Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China
| | - Ludi Yang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Ping Zheng
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Yan Jiang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Ling Shuai
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China
| | - Xiongwei Cai
- Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China.
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China.
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, P. R. China.
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Kuo TC, Kung HJ, Shih JW. Signaling in and out: long-noncoding RNAs in tumor hypoxia. J Biomed Sci 2020; 27:59. [PMID: 32370770 PMCID: PMC7201962 DOI: 10.1186/s12929-020-00654-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023] Open
Abstract
Over the past few years, long non-coding RNAs (lncRNAs) are recognized as key regulators of gene expression at chromatin, transcriptional and posttranscriptional level with pivotal roles in various biological and pathological processes, including cancer. Hypoxia, a common feature of the tumor microenvironment, profoundly affects gene expression and is tightly associated with cancer progression. Upon tumor hypoxia, the central regulator HIF (hypoxia-inducible factor) is upregulated and orchestrates transcription reprogramming, contributing to aggressive phenotypes in numerous cancers. Not surprisingly, lncRNAs are also transcriptional targets of HIF and serve as effectors of hypoxia response. Indeed, the number of hypoxia-associated lncRNAs (HALs) identified has risen sharply, illustrating the expanding roles of lncRNAs in hypoxia signaling cascade and responses. Moreover, through extra-cellular vesicles, lncRNAs could transmit hypoxia responses between cancer cells and the associated microenvironment. Notably, the aberrantly expressed cellular or exosomal HALs can serve as potential prognostic markers and therapeutic targets. In this review, we provide an update of the current knowledge about the expression, involvement and potential clinical impact of lncRNAs in tumor hypoxia, with special focus on their unique molecular regulation of HIF cascade and hypoxia-induced malignant progression.
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Affiliation(s)
- Tse-Chun Kuo
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan, ROC
| | - Hsing-Jien Kung
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, 35053, Taiwan, ROC.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.,Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.,Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA, 95817, USA.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC
| | - Jing-Wen Shih
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC. .,Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan, ROC. .,Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan, ROC.
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39
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Wang W, Xing H, Huang C, Pan H, Li D. Identification of pancreatic cancer type related factors by Weighted Gene Co-Expression Network Analysis. Med Oncol 2020; 37:33. [PMID: 32200436 DOI: 10.1007/s12032-020-1339-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/22/2020] [Indexed: 12/12/2022]
Abstract
This study aims to identify the core modules associated with pancreatic cancer (PC) types and the ncRNAs and transcription factors (TFs) that regulate core module genes by weighted gene co-expression network analysis (WGCNA). WGCNA was used to analyze the union of genes related to PC in NCBI and OMIM databases and the differentially expressed genes screened by TCGA-PAAD database. Samples were clustered according to gene expression in gene modules and Fisher exact method was performed. GO and KEGG were used for enrichment analysis to visually display module genes and screen driver genes. Hypergeometric test method was used to calculate pivot nodes among ncRNAs, TFs and mRNA based on RAID 2.0 and TRRUST v2 databases. The blue and yellow modules were identified as the core modules associated with PC types. MST1R, TMPRSS, MIR198, SULF1, COL1A1 and FAP were the core genes in the modules. Hypergeometric test results showed that ANCR, miR-3134, MT1DP, LOC154449, LOC28329 and other ncRNAs were key factors driving blue module genes, while LINC-ROR, UCA1, SNORD114-4, HEIH, SNORD114-6 and other ncRNAs were key factors driving yellow module genes. TFs with significant regulatory effect on blue module included LCOR, PIAS4, ZEB1, SNAI2, SMARCA4, etc. and on yellow module included HOXC6, PER2, HOXD3, TWIST2, VHL, etc. The core modules associated with PC types were proved as yellow and blue modules, and important ncRNAs and TFs regulating yellow and blue modules were found. This study provides relevant evidence for further identification of PC types.
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Affiliation(s)
- Wei Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3# Eastern Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China
| | - Haibo Xing
- Department of ICU, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Xiasha Campus, 368# Xiasha Road, Hangzhou, 310019, Zhejiang, People's Republic of China
| | - Changxin Huang
- Department of Medical Oncology, Hangzhou Normal University Affiliated Hospital, Hangzhou, 310000, Zhejiang, People's Republic of China
| | - Hong Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Xiasha Campus, 368# Xiasha Road, Hangzhou, 310019, Zhejiang, People's Republic of China.
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3# Eastern Qingchun Road, Hangzhou, 310016, Zhejiang, People's Republic of China.
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40
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Gong R, Jiang Y. Non-coding RNAs in Pancreatic Ductal Adenocarcinoma. Front Oncol 2020; 10:309. [PMID: 32257946 PMCID: PMC7089935 DOI: 10.3389/fonc.2020.00309] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
Non-coding RNAs (ncRNAs) are reported to be expressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). These ncRNAs affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as playing important roles in epigenetic processes, transcription and post-transcriptional regulation. It is still unclear whether alterations in ncRNAs influence PDAC development and progression. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for future research on PDAC. Here, we summarize ncRNAs with tumor-promoting functions: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3, and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarize the functions of ncRNAs in the occurrence, development and metastasis of PDAC, with the goal to provide guidance in the clinical diagnosis and treatment of PDAC.
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Affiliation(s)
- Ruining Gong
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yueping Jiang
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
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41
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Zhou W, Chen L, Li C, Huang R, Guo M, Ning S, Ji J, Guo X, Lou G, Jia X, Zhao J, Luo F, Li C, Qu Z, Yu S, Tai S. The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know. Cancer Cell Int 2020; 20:41. [PMID: 32042268 PMCID: PMC7003405 DOI: 10.1186/s12935-020-1126-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide. Due to the shortage of effective biomarkers for predicting survival and diagnosing PC, the underlying mechanism is still intensively investigated but poorly understood. Long noncoding RNAs (lncRNAs) provide biological functional diversity and complexity in protein regulatory networks. Scientific studies have revealed the emerging functions and regulatory roles of lncRNAs in PC behaviors. It is worth noting that some in-depth studies have revealed that lncRNAs are significantly associated with the initiation and progression of PC. As lncRNAs have good properties for both diagnostic and prognostic prediction due to their translation potential, we herein address the current understanding of the multifaceted roles of lncRNAs as regulators in the molecular mechanism of PC. We also discuss the possibility of using lncRNAs as survival biomarkers and their contributions to the development of targeted therapies based on the literature. The present review, based on what we know about current research findings, may help us better understand the roles of lncRNAs in PC.
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Affiliation(s)
- Wenjia Zhou
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Lu Chen
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Chao Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Huang
- Department of Colorectal Surgery, The second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mian Guo
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shangwei Ning
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jingjing Ji
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Xiaorong Guo
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Ge Lou
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Xinqi Jia
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Junjie Zhao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Feng Luo
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Chunlong Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Zhaowei Qu
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
| | - Sheng Tai
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People’s Republic of China
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Peng X, Gao H, Xu R, Wang H, Mei J, Liu C. The interplay between HIF-1α and noncoding RNAs in cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:27. [PMID: 32014012 PMCID: PMC6998277 DOI: 10.1186/s13046-020-1535-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia is a classic characteristic of the tumor microenvironment with a significant impact on cancer progression and therapeutic response. Hypoxia-inducible factor-1 alpha (HIF-1α), the most important transcriptional regulator in the response to hypoxia, has been demonstrated to significantly modulate hypoxic gene expression and signaling transduction networks. In past few decades, growing numbers of studies have revealed the importance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. These hypoxia-responsive ncRNAs (HRNs) play pivotal roles in regulating hypoxic gene expression at the transcriptional, posttranscriptional, translational and posttranslational levels. In addition, as a significant gene expression regulator, ncRNAs exhibit promising roles in regulating HIF-1α expression at multiple levels. In this review, we briefly elucidate the reciprocal regulation between HIF-1α and ncRNAs, as well as their effect on cancer cell behaviors. We also try to summarize the complex feedback loop existing between these two components. Moreover, we evaluated the biomarker potential of HRNs for the diagnosis and prognosis of cancer, as well as the potential clinical utility of shared regulatory mechanisms between HIF-1α and ncRNAs in cancer treatment, providing novel insights into tumorigenicity, which may lead to innovative clinical applications.
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Affiliation(s)
- Xiafeng Peng
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.,The First Clinical Medicine School, Nanjing Medical University, Nanjing, 211166, China
| | - Han Gao
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Rui Xu
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China
| | - Huiyu Wang
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China
| | - Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
| | - Chaoying Liu
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
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43
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Hypoxia and lncRNAs in gastrointestinal cancers. Pathol Res Pract 2019; 215:152687. [DOI: 10.1016/j.prp.2019.152687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/27/2019] [Accepted: 10/06/2019] [Indexed: 01/17/2023]
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44
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Han D, Fang Y, Guo Y, Hong W, Tu J, Wei W. The emerging role of long non-coding RNAs in tumor-associated macrophages. J Cancer 2019; 10:6738-6746. [PMID: 31777603 PMCID: PMC6856883 DOI: 10.7150/jca.35770] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 08/24/2019] [Indexed: 12/18/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are an important cellular component of the tumor microenvironment (TME) and play an essential role in tumor immunity. Recently, numerous studies have indicated that long non-coding RNAs (lncRNAs) can affect several functions of TAMs. In the present review, we summarize the versatile role of lncRNAs in the polarization, epigenetic modulation, and classic signaling pathways of TAMs, which represent a potential target for tumor diagnosis or treatment.
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Affiliation(s)
- Dafei Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Yilong Fang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Yawei Guo
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Wenming Hong
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Jiajie Tu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China
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45
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Tax G, Lia A, Santino A, Roversi P. Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells? JOURNAL OF ONCOLOGY 2019; 2019:8384913. [PMID: 31662755 PMCID: PMC6791201 DOI: 10.1155/2019/8384913] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/27/2019] [Indexed: 12/21/2022]
Abstract
Endoplasmic reticulum glycoprotein folding quality control (ERQC) and ER-associated degradation (ERAD) preside over cellular glycoprotein secretion and maintain steady glycoproteostasis. When cells turn malignant, cancer cell plasticity is affected and supported either by point mutations, preferential isoform selection, altered expression levels, or shifts to conformational equilibria of a secreted glycoprotein. Such changes are crucial in mediating altered extracellular signalling, metabolic behavior, and adhesion properties of cancer cells. It is therefore conceivable that interference with ERQC and/or ERAD can be used to selectively damage cancers. Indeed, inhibitors of the late stages of ERAD are already in the clinic against cancers such as multiple myeloma. Here, we review recent advances in our understanding of the complex relationship between glycoproteostasis and cancer biology and discuss the potential of ERQC and ERAD modulators for the selective targeting of cancer cell plasticity.
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Affiliation(s)
- Gábor Tax
- Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, UK
| | - Andrea Lia
- Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, UK
- Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy
| | - Angelo Santino
- Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy
| | - Pietro Roversi
- Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, UK
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Zhang Y, Yang H, Du Y, Liu P, Zhang J, Li Y, Shen H, Xing L, Xue X, Chen J, Zhang X. Long noncoding RNA TP53TG1 promotes pancreatic ductal adenocarcinoma development by acting as a molecular sponge of microRNA-96. Cancer Sci 2019; 110:2760-2772. [PMID: 31325400 PMCID: PMC6726832 DOI: 10.1111/cas.14136] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 06/29/2019] [Accepted: 07/10/2019] [Indexed: 01/01/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)-96 and effectively function as a sponge for miR-96, thus antagonizing the functions of miR-96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-96 and regulate KRAS expression, which highlights the importance of the complicated miRNA-lncRNA network in modulating the progression of PDAC.
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Affiliation(s)
- Yufeng Zhang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Haiyan Yang
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Du
- Department of Stomatology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Pingping Liu
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Jing Zhang
- Department of Molecular, Cellular and Development Biology, University of Colorado Boulder, Boulder, USA
| | - Yue Li
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Haitao Shen
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Lingxiao Xing
- Laboratory of Pathology, Hebei Medical University, Shijiazhuang, China
| | - Xiaoying Xue
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianghong Zhang
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Ling J, Wang F, Liu C, Dong X, Xue Y, Jia X, Song W, Li Q. FOXO1-regulated lncRNA LINC01197 inhibits pancreatic adenocarcinoma cell proliferation by restraining Wnt/β-catenin signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:179. [PMID: 31027497 PMCID: PMC6485178 DOI: 10.1186/s13046-019-1174-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
Background Recent studies have revealed that numerous oncogenic long non-coding RNAs (lncRNAs) play pivotal roles in pancreatic ductal adenocarcinoma (PDAC) progression, but little is known about tumor-suppressive lncRNAs in PDAC. This study was conducted to evaluate the function of tumor-suppressive LINC01197 in PDAC progression and investigate the detailed mechanisms. Methods LncRNA microarray was used to identify differentially expressed lncRNAs in FOXO1-overexpressing PANC1 cells. LINC01197 expression was evaluated by quantitative PCR, Northern blotting, and fluorescence in situ hybridization. The Cancer Genome Atlas database was used to analyze the prognostic role of LNC01197 in PDAC. A luciferase reporter assay was performed to confirm the interaction between LNC01197 and FOXO1. The biological function of LINC01197 was evaluated by colony formation assay in vitro and in an animal subcutaneous tumorigenesis experiment and Ki67 staining in vivo. RNA-pulldown, western blotting, RNA immunoprecipitation assay, and co-immunoprecipitation were further performed to determine the molecular mechanism of LNC01197 and β-catenin in the Wnt pathway. Results We found that a FOXO1-related lncRNA, LINC01197, was significantly decreased in PDAC malignant tissues and that its low expression predicted poor prognosis. Moreover, LINC01197 was mainly localized in the nucleus and inhibited PDAC cell proliferation both in vitro and in vivo. Mechanistically, LINC01197 was found to bind to β-catenin and inhibit Wnt/β-catenin signaling activity by disrupting β-catenin binding to TCF4 in PDAC cells. Conclusions The novel FOXO1/LINC01197/β-catenin axis was dysregulated during PDAC progression. Our study provides insight into the mechanisms of LINC01197 in PDAC and reveal a potential target for PDAC clinical therapy and prognostic prediction.
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Affiliation(s)
- Jing Ling
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Chuan Liu
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Xiao Dong
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Ying Xue
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Xuebing Jia
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Weifeng Song
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. .,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai, 200080, China.
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Liang R, Liu Z, Chen Z, Yang Y, Li Y, Cui Z, Chen A, Long Z, Chen J, Lu J, Huang B, Li Q. Long noncoding RNA DNAJC3-AS1 promotes osteosarcoma progression via its sense-cognate gene DNAJC3. Cancer Med 2019; 8:761-772. [PMID: 30652414 PMCID: PMC6382712 DOI: 10.1002/cam4.1955] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 12/04/2018] [Accepted: 12/08/2018] [Indexed: 12/19/2022] Open
Abstract
Long noncoding RNAs have been proved to play essential roles in tumor development and progression. In this study, we focused on DNAJC3-AS1 and investigated its biological function and clinical significance in osteosarcoma. We detected the expression of DNAJC3-AS1 in 30 pairs of matched osteosarcoma and adjacent nontumorous specimens and osteosarcoma cell lines and analyzed association between DNAJC3-AS1 levels and clinicopathological factors. We found that DNAJC3-AS1 expression was up-regulated in osteosarcoma. High level of DNAJC3-AS1 was correlated with high differentiated degree (P = 0.018) and advanced Enneking stage (P = 0.016). Mechanistically, DNAJC3-AS1 enhanced cell proliferation, migration, and invasion in vitro and in vivo and reduced sensitivity of osteosarcoma to cisplatin. These effects of DNAJC3-AS1 were reversed by down-regulation of its sense-cognate gene DNAJC3. Thus, DNAJC3-AS1 promotes osteosarcoma development and progression by regulating DNAJC3 and might be a biomarker and therapeutic target for osteosarcoma.
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Affiliation(s)
- Ridong Liang
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Zezheng Liu
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Zhixu Chen
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Yang Yang
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Yuejun Li
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Zhifei Cui
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Ajuan Chen
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Zhenxue Long
- Department of Orthopedics, The People's Hospital of Baise, Baise, China
| | - Jinbin Chen
- The First Affiliated Hospital, The School of Public Health, The Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
| | - Jiachun Lu
- The First Affiliated Hospital, The School of Public Health, The Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
| | - Bin Huang
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
| | - Qingchu Li
- Department of Orthopedics, The Third Affiliated Hospital, Academy of Orthopedics, Southern Medical University, Guangzhou, China
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Mungamuri SK. Targeting the epigenome as a therapeutic strategy for pancreatic tumors. THERANOSTIC APPROACH FOR PANCREATIC CANCER 2019:211-244. [DOI: 10.1016/b978-0-12-819457-7.00011-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
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Wang J, Shen J, Zhao K, Hu J, Dong J, Sun J. STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression. Cancer Biol Med 2019; 16:100-108. [PMID: 31119050 PMCID: PMC6528447 DOI: 10.20892/j.issn.2095-3941.2018.0304] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective Stromal interaction molecule 1 (STIM1) overexpression has been reported to play an important role in progression of several cancers. However, the mechanism of STIM1 overexpression and its relationship with hypoxia in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Methods STIM1 and HIF-1α expression was tested using immunohistochemistry in tissue microarray (TMA) including pancreatic cancer and matched normal pancreatic tissues, and their relationships with clinicopathological parameters were statistically analyzed. q-PCR, Western blot, ChIP, and luciferase assay were employed to 030 analyze transcriptional regulation between HIF-1α and STIM1 in pancreatic cancer PANC-1 cells. Results Both STIM1 and HIF-1α showed higher positive rates and up-regulated expression in cancer tissues compared to that of normal tissues (P < 0.05). The Kaplan–Meier method revealed that higher HIF-1α and STIM1 expression levels were significantly correlated with decreased disease-free survival ( P = 0.025 and P = 0.029, respectively). The expression of HIF-1α showed a significant positive correlation with that of STIM1 in cancer tissues (rs = 0.3343, P = 0.0011) and pancreatic cancer cell lines. Furthermore, ChIP and luciferase assays confirmed that HIF-1α bound to the STIM1 promoter and regulated its expression in PANC-1 cells.
Conclusions In hypoxia microenvironment, up-regulated expression of STIM1 mediated by HIF-1α promotes PDAC progression. HIF-1α and STIM1 are potential prognostic markers and/or therapeutic targets for PDAC treatment.
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Affiliation(s)
- Jian Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Junling Shen
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650091, China
| | - Kaili Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jinmeng Hu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jiuxing Dong
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jianwei Sun
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650091, China
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