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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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Ding M, Wang W, Huo K, Song Y, Chen X, Xiang Z, Chen P, Liu L. The Role of lncRNA FEZF1-AS1 in Colorectal Cancer Progression Via the P53 Signaling Pathway. DNA Cell Biol 2025; 44:32-45. [PMID: 39503758 DOI: 10.1089/dna.2024.0184] [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] [Indexed: 01/30/2025] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as critical regulators in the development of colorectal cancer (CRC). Previous studies indicate that lncRNA FEZF1-AS1 is highly expressed in CRC, but its role in modulating CRC via the P53 signaling pathway remains unclear. In this study, we found that FEZF1-AS1 promotes the growth of the CRC cell line (HCT116) and drives epithelial-mesenchymal transition (EMT) through the P53 signaling pathway. Our data showed that FEZF1-AS1 expression is significantly upregulated in HCT116, and elevated levels of FEZF1-AS1 are associated with poor prognosis in patients with CRC. In addition, the knockdown of FEZF1-AS1 markedly inhibited the proliferation of HCT116 by inducing cell cycle arrest. Knockdown of FEZF1-AS1 depletion also led to apoptosis in CRC cells by suppressing the P53 signaling pathway and EMT, thereby reducing their viability, proliferation, migration, and invasion. In summary, this study confirmed that FEZF1-AS1 regulates the growth of junction HCT116 through P53 signaling pathway and inhibiting EMT, providing new insights for the potential therapeutic strategies against CRC.
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Affiliation(s)
- Minglu Ding
- Mudanjiang Medical University, Mudanjiang, China
| | - Wanyao Wang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Keyuan Huo
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Yidan Song
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaojie Chen
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Zihan Xiang
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Lantao Liu
- School of Basic Medicine, Mudanjiang Medical University, Mudanjiang, China
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Dibaj M, Haghi M, Safaralizadeh R, Saberi A. The role of EZH2 and its regulatory lncRNAs as a serum-based biomarker in Alzheimer's disease. Mol Biol Rep 2024; 51:866. [PMID: 39073683 DOI: 10.1007/s11033-024-09802-0] [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: 02/21/2024] [Accepted: 07/17/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) have become a hot topic in the human nervous system. Moreover, circulating lncRNAs have been suggested as possible biomarkers for central nervous system processes and neurodegenerative diseases. The present research aimed to highlight the role of plasma lncRNAs TUG1, FEZF1-AS1, and EZH2 gene as diagnostic biomarkers in Alzheimer's disease (AD). METHODS Plasma samples for the study were provided by 100 AD patients and 100 matched controls. Real-time quantitative reverse transcriptase PCR was used to determine the plasma level of the aforementioned lncRNAs. Furthermore, the plasma level of EZH2 protein in the participants' blood was determined using the ELISA technique. RESULTS In contrast to controls, down-regulation of the EZH2 gene and protein was reported in the plasma of patients with AD. Additionally, plasma samples from AD patients showed up-and-down-regulation of the lncRNAs TUG1 and FEZF1-AS1, respectively. CONCLUSION Our new findings suggest that the EZH2 gene, plasma lncRNA TUG1, and FEZF1-AS1 may contribute, as valuable biomarkers, to AD diagnosis.
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Affiliation(s)
- Mohsen Dibaj
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mehdi Haghi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Alia Saberi
- Neurology Department, School of Medicine, Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran
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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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Al-Noshokaty TM, Mansour A, Abdelhamid R, Abdellatif N, Alaaeldien A, Reda T, Abdelmaksoud NM, Doghish AS, Abulsoud AI, Elshaer SS. Role of long non-coding RNAs in pancreatic cancer pathogenesis and treatment resistance- A review. Pathol Res Pract 2023; 245:154438. [PMID: 37043965 DOI: 10.1016/j.prp.2023.154438] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/14/2023]
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers associated with poor prognosis. The lack of reliable means of early cancer detection contributes to this disease's dismal prognosis. Long non-coding RNAs (LncRNAs) are protein-free RNAs produced by genome transcription; they play critical roles in gene expression regulation, epigenetic modification, cell proliferation, differentiation, and reproduction. Recent research has shown that lncRNAs play important regulatory roles in PC behaviors, in addition to their recently found functions. Several in-depth investigations have shown that lncRNAs are strongly linked to PC development and progression. Here, we discuss how lncRNAs, which are often overlooked, play many roles as regulators in the molecular mechanism underlying PC. This review also discusses the involved LncRNAs in PC pathogenesis and treatment resistance.
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Affiliation(s)
- Tohada M Al-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Abdallah Mansour
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan Abdellatif
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ayat Alaaeldien
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Tasnim Reda
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr, Cairo, Egypt
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El Sharkawi FZ, El Sabah M, Atya HB, Khaled HM. Urinary BLACAT1 as a non-invasive biomarker for bladder cancer. Mol Biol Rep 2023; 50:4339-4345. [PMID: 36939965 PMCID: PMC10147806 DOI: 10.1007/s11033-023-08370-z] [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: 10/14/2022] [Accepted: 03/02/2023] [Indexed: 03/21/2023]
Abstract
BACKGROUND Bladder cancer (BC) is recorded as the fifth most common cancer worldwide with high morbidity and mortality. The most urgent problem in BCs is the high recurrence rate as two-thirds of non-muscle-invasive bladder cancer (NMIBC) will develop into muscle-invasive bladder cancer (MIBC), which retains a feature of rapid progress and metastasis. In addition, only a limited number of biomarkers are available for diagnosing BC compared to other cancers. Hence, finding sensitive and specific biomarkers for predicting the diagnosis and prognosis of patients with BC is critically needed. Therefore, this study aimed to determine the expression and clinical significance of urinary lncRNA BLACAT1 as a non-invasively diagnostic and prognostic biomarker to detect and differentiate BCs stages. METHODS AND RESULTS The expression levels of urinary BLACAT1 were detected by qRT-PCR assay in seventy (70) BC patients with different TNM grades (T0-T3) and twelve (12) healthy subjects as control. BLACAT1 was downregulated in superficial stages (T0 = 0.09 ± 0.02 and T1 = 0.5 ± 0.1) compared to healthy control. Furthermore, in the invasive stages, its levels started to elevate in the T2 stage (1.2 ± 0. 2), and higher levels were detected in the T3 stage with a mean value of (5.2 ± 0.6). This elevation was positively correlated with disease progression. Therefore, BLACAT1 can differentiate between metastatic and non-metastatic stages of BCs. Furthermore, its predictive values are not like to be influenced by schistosomal infection. CONCLUSIONS Upregulation of BLACAT1 in invasive stages predicted an unfavorable prognosis for patients with BCs, as it contributes to the migration and metastasis of BCs. Therefore, we can conclude that urinary BLACAT1 may be considered a non-invasive promising metastatic biomarker for BCs.
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Affiliation(s)
- Fathia Z El Sharkawi
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt
| | - Mahmoud El Sabah
- Department of Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University, Cairo, Egypt
| | - Hanaa B Atya
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Cairo, Egypt.
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Ghafouri-Fard S, Hussen BM, Shoorei H, Abak A, Poornajaf Y, Taheri M, Samadian M. Interactions between non-coding RNAs and HIF-1α in the context of cancer. Eur J Pharmacol 2023; 943:175535. [PMID: 36731723 DOI: 10.1016/j.ejphar.2023.175535] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/03/2023]
Abstract
Hypoxia-inducible factor 1α (HIF-1α) is a subunit of the HIF-1 transcription factor which is encoded by the HIF1A gene. This transcription factor is the main modulator of the cell response to hypoxia. Hypoxia-induced up-regulation of HIF-1α is involved in the pathogenesis of cancer. Recently, the interactions of several long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) with HIF-1α have been reported. These ncRNAs regulate the expression of HIF-1α through different mechanisms. The regulatory roles of ncRNAs on HIF-1α are involved in the response of cancer cells to a wide range of anticancer drugs such as sorafenib, cisplatin, propofol, doxorubicin, and paclitaxel. Therefore, identification of the complex network between ncRNAs and HIF-1α not only facilitates the design of novel therapies but also promotes the efficacy of conventional anticancer treatments. This review aims to explain the interactions between these classes of ncRNAs and HIF-1α in the context of cancer.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran; Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Atefe Abak
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yadollah Poornajaf
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Samadian
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ray SK, Mukherjee S. Interaction Among Noncoding RNAs, DNA Damage Reactions, and Genomic Instability in the Hypoxic Tumor: Is it Therapeutically Exploitable Practice? Curr Mol Med 2023; 23:200-215. [PMID: 35048804 DOI: 10.2174/1566524022666220120123557] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/30/2021] [Accepted: 12/07/2021] [Indexed: 02/08/2023]
Abstract
Hypoxia is a classical function of the tumor's microenvironment with a substantial effect on the development and therapeutic response of cancer. When put in hypoxic environments, cells undergo several biological reactions, including activation of signaling pathways that control proliferation, angiogenesis, and death. These pathways have been adapted by cancer cells to allow tumors to survive and even develop in hypoxic conditions, and poor prognosis is associated with tumor hypoxia. The most relevant transcriptional regulator in response to hypoxia, Hypoxia-inducible factor-1 alpha (HIF-1α), has been shown to modulate hypoxic gene expression and signaling transduction networks significantly. The significance of non-coding RNAs in hypoxic tumor regions has been revealed in an increasing number of studies over the past few decades. In regulating hypoxic gene expression, these hypoxia-responsive ncRNAs play pivotal roles. Hypoxia, a general characteristic of the tumor's microenvironment, significantly affects the expression of genes and is closely associated with the development of cancer. Indeed, the number of known hypoxia-associated lncRNAs has increased dramatically, demonstrating the growing role of lncRNAs in cascades and responses to hypoxia signaling. Decades of research have helped us create an image of the shift in hypoxic cancer cells' DNA repair capabilities. Emerging evidence suggests that hypoxia can trigger genetic instability in cancer cells because of microenvironmental tumor stress. Researchers have found that critical genes' expression is coordinately repressed by hypoxia within the DNA damage and repair pathways. In this study, we include an update of current knowledge on the presentation, participation, and potential clinical effect of ncRNAs in tumor hypoxia, DNA damage reactions, and genomic instability, with a specific emphasis on their unusual cascade of molecular regulation and malignant progression induced by hypoxia.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020. India
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Cheng C, Liu D, Liu Z, Li M, Wang Y, Sun B, Kong R, Chen H, Wang G, Li L, Hu J, Li Y, Chen H, Zhao Z, Zhang T, Zhu S, Pan S. Positive feedback regulation of lncRNA TPT1-AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer. Cancer Sci 2022; 113:2986-3001. [PMID: 35534983 PMCID: PMC9459417 DOI: 10.1111/cas.15388] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/08/2022] [Accepted: 04/18/2022] [Indexed: 11/29/2022] Open
Abstract
Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin β3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.
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Affiliation(s)
- Chundong Cheng
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Danxi Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zonglin Liu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Mengyang Li
- Department of Medical OncologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yongwei Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Bei Sun
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Rui Kong
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hua Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Gang Wang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Le Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Jisheng Hu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Yilong Li
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Hongze Chen
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Zhongjie Zhao
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Tao Zhang
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Siqiang Zhu
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
| | - Shangha Pan
- Department of Pancreatic and Biliary SurgeryThe First Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Key Laboratory of Hepatosplenic SurgeryMinistry of EducationHarbinChina
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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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11
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Yang T, He F, Zhang M, Ai L, He M, Liu X, Li Y. MiR-142-3p as an Indicator of OSA Severity Predicts Prognosis in Lung Adenocarcinoma with OSA. Nat Sci Sleep 2022; 14:2047-2054. [PMID: 36394065 PMCID: PMC9656355 DOI: 10.2147/nss.s385755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/25/2022] [Indexed: 11/10/2022] Open
Abstract
PURPOSE The aim was to explore the correlation between Obstructive sleep apnea (OSA) and Lung adenocarcinoma malignant prognosis and evaluate the miR-142-3p was used as an OSA severity indicator to predict the prognosis of Lung adenocarcinoma patients. METHODS This study comprised of 21 diagnosed lung adenocarcinoma patients with or without OSA. The sleep-related variables and tumor pathology were recorded. Hypoxia-inducible factor-1α (HIF1α) and ki67 expression were analyzed by immunohistochemistry in tumor samples. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess the level of miR-142-3p. RESULTS Lung adenocarcinoma with OSA showed higher apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and the lower lowest pulse oxygen saturation (LSPO2) compared to Lung adenocarcinoma without OSA (P<0.05), and patients with severer OSA have an advanced TNM stage (P=0.004) and metastasis rate (p=0.032). In addition, OSA may down-regulate the miR-142-3p expression in patients with Lung adenocarcinoma, and the patients with low miR-142-3p expression exhibited severe OSA. MiR-142-3p levels significantly decreased in the advanced TNM stage (p=0.015), and the expression of miR-142-3p was negatively associated with AHI (r= -0.505, p=0.020), ODI (r= -0.513, p=0.017). CONCLUSION OSA severity may increase Lung adenocarcinoma malignant prognosis. OSA may down-regulate the expression of miR-42-3p. The expression of miR-142-3p was inversely correlated with AHI and ODI as a surrogate of OSA severity. Additionally, the low miR-142-3p expression level was significantly associated with advanced TNM stage in Lung adenocarcinoma patients.
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Affiliation(s)
- Ting Yang
- Department of Respiratory, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Fang He
- Department of Respiratory, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Mingxiang Zhang
- Department of Cardiothoracic Surgery, Children's Hospital affiliated to Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Li Ai
- Department of Respiratory, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Meng He
- Department of Thoracic Surgery, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Xin Liu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
| | - Yongxia Li
- Department of Respiratory, The Second Affiliated Hospital of Kunming Medical University, Yunnan, 650000, People's Republic of China
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12
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Xiong G, Pan S, Jin J, Wang X, He R, Peng F, Li X, Wang M, Zheng J, Zhu F, Qin R. Long Noncoding Competing Endogenous RNA Networks in Pancreatic Cancer. Front Oncol 2021; 11:765216. [PMID: 34760707 PMCID: PMC8573238 DOI: 10.3389/fonc.2021.765216] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease characterized by insidious onset, rapid progress, and poor therapeutic effects. The molecular mechanisms associated with PC initiation and progression are largely insufficient, hampering the exploitation of novel diagnostic biomarkers and development of efficient therapeutic strategies. Emerging evidence recently reveals that noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs) and microRNAs (miRNAs), extensively participate in PC pathogenesis. Specifically, lncRNAs can function as competing endogenous RNAs (ceRNAs), competitively sequestering miRNAs, therefore modulating the expression levels of their downstream target genes. Such complex lncRNA/miRNA/mRNA networks, namely, ceRNA networks, play crucial roles in the biological processes of PC by regulating cell growth and survival, epithelial-mesenchymal transition and metastasis, cancer stem cell maintenance, metabolism, autophagy, chemoresistance, and angiogenesis. In this review, the emerging knowledge on the lncRNA-associated ceRNA networks involved in PC initiation and progression will be summarized, and the potentials of the competitive crosstalk as diagnostic, prognostic, and therapeutic targets will be comprehensively discussed.
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Affiliation(s)
- Guangbing Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shutao Pan
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jikuan Jin
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoxiang Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruizhi He
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Peng
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu Li
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianwei Zheng
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Zhu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Peng PH, Hsu KW, Chieh-Yu Lai J, Wu KJ. The role of hypoxia-induced long noncoding RNAs (lncRNAs) in tumorigenesis and metastasis. Biomed J 2021; 44:521-533. [PMID: 34654684 PMCID: PMC8640553 DOI: 10.1016/j.bj.2021.03.005] [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: 01/12/2021] [Revised: 02/23/2021] [Accepted: 03/18/2021] [Indexed: 12/11/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are noncoding RNAs with length greater than 200 nt. The biological roles and mechanisms mediated by lncRNAs have been extensively investigated. Hypoxia is a proven microenvironmental factor that promotes solid tumor metastasis. Epithelial-mesenchymal transition (EMT) is one of the major mechanisms induced by hypoxia to contribute to metastasis. Many lncRNAs have been shown to be induced by hypoxia and their roles have been delineated. In this review, we focus on the hypoxia-inducible lncRNAs that interact with protein/protein complex and chromatin/epigenetic factors, and the mechanisms that contribute to metastasis. The role of a recently discovered lncRNA RP11-390F4.3 in hypoxia-induced EMT is discussed. Whole genome approaches to delineating the association between lncRNAs and histone modifications are discussed. Other topics related to hypoxia-induced tumor progression but require further investigation are also mentioned. The clinical significance and treatment strategy targeted against lncRNAs are discussed. The review aims to identify suitable lncRNA targets that may provide feasible therapeutic venues for hypoxia-involved cancers.
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Affiliation(s)
- Pei-Hua Peng
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Kai-Wen Hsu
- Research Center for Cancer Biology, Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | | | - Kou-Juey Wu
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
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14
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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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15
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Son SW, Yun BD, Song MG, Lee JK, Choi SY, Kuh HJ, Park JK. The Hypoxia-Long Noncoding RNA Interaction in Solid Cancers. Int J Mol Sci 2021; 22:ijms22147261. [PMID: 34298879 PMCID: PMC8307739 DOI: 10.3390/ijms22147261] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer.
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Affiliation(s)
- Seung Wan Son
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Ba Da Yun
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Mun Gyu Song
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Jin Kyeong Lee
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Soo Young Choi
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Jong Kook Park
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
- Correspondence: ; Tel.: +82-33-248-2114
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16
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Yao J, Yang Z, Yang J, Wang ZG, Zhang ZY. Long non-coding RNA FEZF1-AS1 promotes the proliferation and metastasis of hepatocellular carcinoma via targeting miR-107/Wnt/β-catenin axis. Aging (Albany NY) 2021; 13:13726-13738. [PMID: 34023817 PMCID: PMC8202841 DOI: 10.18632/aging.202960] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 04/06/2021] [Indexed: 12/18/2022]
Abstract
Hepatocellular carcinoma (HCC) is a public health problem around the world, with the molecular mechanisms being still incompletely clear. This study was carried out to explore the role and mechanism of long-noncoding RNA (lncRNA) FEZF1-AS1 in HCC progression. RNA sequencing and quantitative real time polymerase chain reaction (qRT- PCR) were applied to identify differently expressed lncRNAs in HCC tissues and adjacent normal tissues. CCK8 assay was adopted to test cell proliferation and flow cytometry was taken to detect cell apoptosis. Wound healing assay and transwell experiment were performed to determine cell migration and invasion. To validate the function of lncRNA FEZF1-AS1 in vivo, tumor-burdened models were established. The results showed that lncRNA FEZF1-AS1 level was prominently enhanced in HCC tumor specimens and overexpression of FEZF1-AS1 promoted the proliferation, migration and invasion of HCC cells. In mechanism, overexpression of FEZF1-AS1 reduced the expression of miR-107 which inhibited the activation of Wnt/β-catenin signaling. Overexpression of β-catenin promoted cell proliferation, migration and invasion which were inhibited by FEZF1-AS1 downregulation. In conclusion, our study demonstrated that FEZF1-AS1 promoted HCC progression through activating Wnt/β-catenin signaling by targeting miR-107, which provided a novel target for the therapy of HCC.
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Affiliation(s)
- Jing Yao
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Zhe Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Jun Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Zhi-Gang Wang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
| | - Zheng-Yun Zhang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
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17
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Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T, Zhao Y. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol 2021; 14:14. [PMID: 33436044 PMCID: PMC7805044 DOI: 10.1186/s13045-020-01030-w] [Citation(s) in RCA: 242] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.
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Affiliation(s)
- Jinxin Tao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenchuan Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
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18
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Hua YT, Xu WX, Li H, Xia M. Emerging roles of MiR-133a in human cancers. J Cancer 2021; 12:198-206. [PMID: 33391416 PMCID: PMC7738817 DOI: 10.7150/jca.48769] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) can post-transcriptionally regulate the expression of cancer-relevant genes via binding to the 3'-untranslated region (3'-UTR) of the target mRNAs. MiR-133a, as a miRNA, participate in tumorigenesis, progression, autophagy and drug-resistance in various malignancies. Based on the recent insights, we discuss the functions of miR-133a in physiological and pathological processes and its potential effects on cancer diagnosis, prognosis and therapy.
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Affiliation(s)
- Yu-Ting Hua
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu 214023, China
| | - Wen-Xiu Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China
| | - Hui Li
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu 214023, China
| | - Min Xia
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, Jiangsu 214023, 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: 29] [Impact Index Per Article: 5.8] [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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20
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Geismann C, Arlt A. Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer. Cells 2020; 9:cells9112353. [PMID: 33113836 PMCID: PMC7694089 DOI: 10.3390/cells9112353] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/17/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
With a five-year survival rate under 9%, pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest tumors. Although the treatment options are slightly improving, PDAC is the second leading cause of cancer related death in 2020 in the US. In addition to a pronounced desmoplastic stroma reaction, pancreatic cancer is characterized by one of the lowest levels of oxygen availability within the tumor mass and these hypoxic conditions are known to contribute to tumor development and progression. In this context, the major hypoxia associated transcription factor family, HIF, regulates hundreds of genes involved in angiogenesis, metabolism, migration, invasion, immune escape and therapy resistance. Current research implications show, that hypoxia also modulates diverse areas of epigenetic mechanisms like non-coding RNAs, histone modifications or DNA methylation, which cooperate with the hypoxia-induced transcription factors as well as directly regulate the hypoxic response pathways. In this review, we will focus on hypoxia-mediated epigenetic alterations and their impact on pancreatic cancer.
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Affiliation(s)
- Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany;
| | - Alexander Arlt
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany;
- Department for Gastroenterology, European Medical School (EMS), Klinikum Oldenburg AöR, 26133 Oldenburg, Germany
- Correspondence: ; Tel.: +49-441-403-2581
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21
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Ye T, Yang X, Liu H, Lv P, Ye Z. Long Non-Coding RNA BLACAT1 in Human Cancers. Onco Targets Ther 2020; 13:8263-8272. [PMID: 32903916 PMCID: PMC7445530 DOI: 10.2147/ott.s261461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are a cluster of RNAs with more than 200 nucleotides in length, which lack protein-coding capacity. They are important regulators of numerous cellular processes, including gene transcription, translation, and posttranslational modification, especially in tumor initiation and progression. Aberrant expression of lncRNA bladder cancer-associated transcript 1 (BLACAT1) has been reported in various human cancers and was usually associated with unfavorable prognosis. Previous studies have revealed that dysregulation of BLACAT1 could promote the proliferation and metastasis of cancer cells. In this review, we summarize the present understanding of the functions and underlying mechanisms of BLACAT1 in the occurrence and development of various human cancers and discuss the roles of this lncRNA in cancers, including its promising application as a prognostic biomarker or a novel therapeutic target for malignancies.
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Affiliation(s)
- Tao Ye
- Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Xiaoqi Yang
- Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Haoran Liu
- Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650000, People's Republic of China
| | - Peng Lv
- Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Zhangqun Ye
- Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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Tan Z, Xu J, Zhang B, Shi S, Yu X, Liang C. Hypoxia: a barricade to conquer the pancreatic cancer. Cell Mol Life Sci 2020; 77:3077-3083. [PMID: 31907561 PMCID: PMC11104901 DOI: 10.1007/s00018-019-03444-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/22/2019] [Accepted: 12/27/2019] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer (PC) remains one of the most extremely lethal malignancies worldwide due to late diagnosis and early metastasis, with a 1-year overall survival rate of approximately 20%. The hypoxic microenvironment, induced by intratumoral hypoxia, promotes tumor invasion and progression, leading to chemotherapy or radiotherapy resistance and eventual mortality after treatment of PC. However, the role of the hypoxic microenvironment in PC is complicated and requires further investigation. In this article, we review recent advances regarding the regulation of malignant behaviors in PC, which provide insight into the potential of hypoxic microenvironment activation therapy for the therapeutic agents.
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Affiliation(s)
- Zhen Tan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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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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24
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Jin X, Dai L, Ma Y, Wang J, Liu Z. Implications of HIF-1α in the tumorigenesis and progression of pancreatic cancer. Cancer Cell Int 2020; 20:273. [PMID: 32587480 PMCID: PMC7313137 DOI: 10.1186/s12935-020-01370-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide and is characterized by highly hypoxic tumor microenvironment. Hypoxia-inducible factor-1 alpha (HIF-1α) is a major regulator of cellular response to changes in oxygen concentration, supporting the adaptation of tumor cells to hypoxia in an oxygen-deficient tumor microenvironment. Numerous studies revealed the central role of HIF-1α in the carcinogenesis and progression of pancreatic cancer. This article reviewed the molecular mechanisms of how HIF-1α regulated tumorigenesis and progression of pancreatic cancer and suggested that targeting HIF-1α and its signaling pathways could be promising therapeutics for pancreatic cancer.
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Affiliation(s)
- Xiao Jin
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, 210011 Jiangsu China
| | - Lu Dai
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, 210011 Jiangsu China
| | - Yilan Ma
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, 210011 Jiangsu China
| | - Jiayan Wang
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, 210011 Jiangsu China
| | - Zheng Liu
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, 210011 Jiangsu China
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25
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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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26
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Liu J, Feng G, Li Z, Li R, Xia P. Long Non-Coding RNA FEZF1-AS1 Modulates CXCR4 to Promote Cell Proliferation, Warburg Effect and Suppress Cell Apoptosis in Osteosarcoma by Sponging miR-144. Onco Targets Ther 2020; 13:2899-2910. [PMID: 32308422 PMCID: PMC7147627 DOI: 10.2147/ott.s235970] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 01/10/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Osteosarcoma (OS) is a common bone tumor among children, adolescents, and young adults. Long non-coding RNA (lncRNA) FEZF1 antisense RNA 1 (FEZF1-AS1) has been reported as an oncogene in diverse tumors including colorectal cancer, pancreatic cancer and hepatocellular carcinoma, as well as in osteosarcoma. This study focused on the functions and mechanism of lncRNA FEZF1-AS1 in osteosarcoma. METHODS The levels of FEZF1-AS1, microRNA miR-144 and CXC motif chemokine receptor 4 (CXCR4) in OS tissues and cells (Saos-2 and HOS) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot assay. The interactions between miR-144 and FEZF1-AS1 or CXCR4 were predicted by DIANA tools online database. Then, the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to validate the interactions. Moreover, the cell viability and apoptotic rate in transferred Saos-2 and HOS cells were assessed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry, respectively. The levels of glucose and lactate productions were measured by glucose uptake and lactate production assay. In addition, the protein levels of Warburg-effect-related protein hexokinase 2 (HK2) and apoptosis-related proteins Bcl-2 or Bax in transferred Saos-2 and HOS cells were detected via Western blot assay. RESULTS The levels of FEZF1-AS1 and CXCR4 were strikingly up-regulated, and miR-144 was notably down-regulated in OS tissues and cells. DIANA tools online database exhibited that miR-144 was a direct target of FEZF1-AS1 and CXCR4 was a direct target of miR-144. Then the interactions were validated by dual-luciferase reporter assay and RIP assay. Functionally, FEZF1-AS1 silencing or miR-144 overexpression inhibited cell viability, the glucose and lactate productions and promoted cell apoptosis in Saos-2 and HOS cells. Furthermore, miR-144 inhibitor mitigated the inhibitory effects on cell viability, the glucose and lactate productions and the promoted effect on cell apoptosis rate in Saos-2 and HOS cells induced by FEZF1-AS1 depletion. Mechanistically, FEZF1-AS1 regulated CXCR4 in Saos-2 and HOS cells by sponging miR-144. CONCLUSION We verified that FEZF1-AS1, CXCR4 were up-regulated, and miR-144 was downregulated in OS tissues and cells. Furthermore, FEZF1-AS1 promoted cell proliferation, Warburg effect and suppressed cell apoptosis in osteosarcoma via miR-144/CXCR4 axis, this novel pathway may provide a basis for the further study of osteosarcoma.
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Affiliation(s)
- Jun Liu
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Guang Feng
- The Fourth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Zhengwei Li
- Department of Orthopaedics, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Rui Li
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
| | - Peng Xia
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China
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Ou ZL, Luo Z, Lu YB. Long non-coding RNA HULC as a diagnostic and prognostic marker of pancreatic cancer. World J Gastroenterol 2019; 25:6728-6742. [PMID: 31857775 PMCID: PMC6920662 DOI: 10.3748/wjg.v25.i46.6728] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/18/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) is abnormally expressed in various malignant tumors. In recent years, it has been found that IncRNA HULC is increasingly expressed in pancreatic cancer tissues and is involved in the development and progression of pancreatic cancer. However, the clinical value of serum HULC in pancreatic cancer remains unclear, and there are few studies on how HULC regulates the biological function of pancreatic cancer cells.
AIM To determine the value of lncRNA HULC in the diagnosis and prognosis of pancreatic cancer, and its possible biological potential.
METHODS Sixty patients with pancreatic cancer and sixty patients with benign pancreatic diseases admitted to Xiangya Hospital, Central South University were assigned to the pancreatic cancer group and the benign disease group, respectively, and another 60 healthy subjects were enrolled as the normal group during the same period. HULC-siRNA and NC-siRNA were transfected into pancreatic cancer cells. Quantitative real-time polymerase chain reaction was performed to determine the expression of HULC in tissues, serum, and cells. Western Blot was carried out to determine the expression of β-catenin, c-myc, and cyclin D1 in cells, and the cell counting kit-8, flow cytometry, and Transwell assay were conducted to determine the proliferation, apoptosis and invasion of cells.
RESULTS Highly expressed in the tissues and serum of pancreatic cancer patients, HULC showed good clinical value in distinguishing between patients with pancreatic cancer, patients with benign pancreatic diseases and healthy subjects. HULC was related to pathological parameters including tumor size, T staging, M staging and vascular invasion, and the area-under-the-curve for evaluating these four parameters was 0.844, 0.834, 0.928 and 0.818, respectively. Patients with low expression of HULC had a significantly higher 3-year overall survival (OS) and 5-year OS than those with high expression. T staging, M staging, vascular invasion, and HULC were independent prognostic factors affecting the 3-year OS of patients with pancreatic cancer. Inhibition of HULC expression prevented the proliferation and invasion of pancreatic cancer cells, promoted apoptosis, and inhibited the expression of Wnt/β-catenin signaling pathway-related proteins, β-catenin, c-myc, and cyclin D1. The Wnt/β-catenin signaling pathway agonist (LiCl) restored proliferation, apoptosis, and invasion of pancreatic cancer cells with inhibited expression of HULC.
CONCLUSION HULC is an effective marker for the diagnosis and prognosis of pancreatic cancer, which may affect the biological function of pancreatic cancer cells through the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Zheng-Lin Ou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Zhen Luo
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Ye-Bin Lu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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28
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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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29
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Li J, Zhao LM, Zhang C, Li M, Gao B, Hu XH, Cao J, Wang GY. The lncRNA FEZF1-AS1 Promotes the Progression of Colorectal Cancer Through Regulating OTX1 and Targeting miR-30a-5p. Oncol Res 2019; 28:51-63. [PMID: 31270006 PMCID: PMC7851540 DOI: 10.3727/096504019x15619783964700] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) participate in and regulate the biological process of colorectal cancer (CRC) progression. Our previous research identified differentially expressed lncRNAs in 10 CRC tissues and 10 matched nontumor tissues by next-generation sequencing (NGS). In this study, we identified an lncRNA, FEZF1 antisense RNA 1 (FEZF1-AS1), and further explored its function and mechanism in CRC. We verified that FEZF1-AS1 is highly expressed in CRC tissues and cell lines. Through functional experiments, we found that reduced levels of FEZF1-AS1 significantly suppressed CRC cell migration, invasion, and proliferation and inhibited tumor growth in vivo. Mechanistically, we discovered that reduced levels of the lncRNA FEZF1-AS1 inhibited the activation of epithelial-mesenchymal transition (EMT); the overexpression of orthodenticle homeobox 1 (OTX1) partially rescued the FEZF1-AS1-induced inhibition of protein expression. It indicated that FEZF1-AS1 may play a role in the occurrence and development of CRC by regulating the FEZF1-AS1/OTX1/EMT pathway. Furthermore, it was reported that FEZF1-AS1 is located in both the nucleus and cytoplasm of HCT116 cells. Dual-luciferase reporter assays verified that FEZF1-AS1 directly binds miR-30a-5p and negatively regulated each other. Further, we showed that 5'-nucleotidase ecto (NT5E) is a direct target of miR-30a-5p, and the inhibition of miR-30a-5p expression partially rescued the inhibitory effect of FEZF1-AS1 on NT5E. Our results indicated that the mechanism by which FEZF1-AS1 positively regulates the expression of NT5E is through sponging miR-30a-5p. Our study demonstrated that lncRNA FEZF1-AS1 is involved in the development of CRC and may serve as a diagnostic and therapeutic target for CRC patients.
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Affiliation(s)
- Jing Li
- Medical Examination Center, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Lian-Mei Zhao
- Research Center, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Cong Zhang
- Research Center, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Meng Li
- Pediatric Surgery, The Second Hospital of Hebei Medical UniversityShijiazhuang, HebeiP.R. China
| | - Bo Gao
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Xu-Hua Hu
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Jian Cao
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
| | - Gui-Ying Wang
- The Second General Surgery, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor HospitalShijiazhuang, HebeiP.R. China
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FEZF1-AS1: a novel vital oncogenic lncRNA in multiple human malignancies. Biosci Rep 2019; 39:BSR20191202. [PMID: 31175144 PMCID: PMC6591563 DOI: 10.1042/bsr20191202] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/06/2019] [Accepted: 06/07/2019] [Indexed: 12/24/2022] Open
Abstract
Long noncoding RNAs (LncRNAs) refer to the RNA with a length of >200 nucleotides, which lack or have no open reading coding frame and have higher tissue and organ specificity compared with the protein coding genes. A surging number of studies have shown that lncRNA is involved in numerous essential regulatory processes, such as X chromosome silencing, genomic imprinting, chromatin modification, transcriptional activation, transcriptional interference and nuclear transport, which are closely related to the occurrence and development of human malignancies. FEZ family Zinc Finger 1-Antisense RNA 1 (FEZF1-AS1) of FEZ family is a recently discovered lncRNA. FEZF1-AS1 is highly expressed in pancreatic cancer, colorectal cancer, lung adenocarcinoma and other human malignancies, and is associated with poor prognosis. As an oncogene, it plays crucial role in the proliferation, migration, invasion and Warburg effect of various tumor cells. In addition, FEZF1-AS1 is also involved in the regulation of multiple signal pathways such as epithelial–mesenchymal transition (EMT), signal transducer and activator of transcription 3 (STAT3) and Wnt/ β-catenin. In this paper, the recent research progress of FEZF1-AS1 in tumorigenesis and development is reviewed systematically.
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FEZF1-AS1 functions as an oncogenic lncRNA in retinoblastoma. Biosci Rep 2019; 39:BSR20190754. [PMID: 31076545 PMCID: PMC6542757 DOI: 10.1042/bsr20190754] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/28/2019] [Accepted: 05/01/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNA (lncRNA) FEZF1 antisense RNA 1 (FEZF1-AS1) has been shown to be up-regulated in tumor tissues and cells, and exerts oncogenic effects on various types of malignancies. However, the expression and function of FEZF1-AS1 was still fully unclear in retinoblastoma. The purpose of our study was to investigate the expression and clinical value of FEZF1-AS1 in retinoblastoma patients, and explore the effect of FEZF1-AS1 on retinoblastoma cell proliferation, migration and invasion. In our results, levels of FEZF1-AS1 expression were elevated in retinoblastoma tissue specimens and cell lines compared with adjacent normal retina tissue specimens and human retinal pigment epithelial cell line, respectively. The correlation analysis indicated that high FEZF1-AS1 expression was significantly correlated with present choroidal invasion and optic nerve invasion. Survival analysis suggested that retinoblastoma patients in high FEZF1-AS1 expression group had obviously short disease-free survival (DFS) compared with retinoblastoma patients in low FEZF1-AS1 expression group, and high FEZF1-AS1 expression was an independent unfavorable prognostic factor for DFS in retinoblastoma patients. Loss-of-function study indicated silencing FEZF1-AS1 expression inhibited retinoblastoma cell proliferation, invasion and migration. In conclusion, FEZF1-AS1 functions as an oncogenic lncRNA in retinoblastoma.
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