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Cui Y, Wen H, Tang J, Chen J, Zhou J, Hou M, Rong X, Lan Y, Wu Q. ELAVL1 regulates glycolysis in nasopharyngeal carcinoma cells through the HMGB3/β-catenin axis. Mol Med 2024; 30:172. [PMID: 39390359 PMCID: PMC11468264 DOI: 10.1186/s10020-024-00941-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/23/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND The role of ELAVL1 in the progression of various tumors has been demonstrated. Our research aims to investigate how ELAVL1 controls the glycolytic process in nasopharyngeal carcinoma cells through the HMGB3/β-catenin pathway. METHODS The expression of ELAVL1 was detected in clinical tumor samples and nasopharyngeal carcinoma cell lines. A subcutaneous tumor model was established in nude mice to investigate the role of ELAVL1 in tumor progression. The relationship between HMGB3 and ELAVL1 was validated by RNA pull down and RIP assays. TOPFlash/FOPFlash reporter assay was used to detect β-catenin activity. Assay kits were utilized to measure glucose consumption, lactate production, and G6PD activity in nasopharyngeal carcinoma cells. Western blot was conducted to detect the expression of glycolysis-related proteins. The glycolytic capacity was analyzed through extracellular acidification rate (ECAR). RESULTS In both clinical samples and nasopharyngeal carcinoma cell lines, the expression levels of ELAVL1 mRNA and protein were found to be upregulated. Knockdown of ELAVL1 significantly inhibited the in vivo proliferation of nasopharyngeal carcinoma and suppressed the glycolytic capacity of nasopharyngeal carcinoma cells. ELAVL1 interacts with HMGB3, leading to an increase in the stability of HMGB3 mRNA. Overexpression of HMGB3 elevated the reduced β-catenin activity caused by sh-ELAVL1 and reversed the inhibitory effect of sh-ELAVL1 on cellular glycolytic capacity. Treatment with β-catenin inhibitor (FH535) effectively suppressed the promotion of glycolytic capacity induced by HMGB3 overexpression. CONCLUSIONS ELAVL1 promotes glycolysis in nasopharyngeal carcinoma cells by interacting with HMGB3 to stabilize HMGB3 mRNA, thereby activating β-catenin pathway. Therefore, targeting the ELAVL1-HMGB3-β-catenin axis has the potential to be a novel approach for treating nasopharyngeal carcinoma.
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Affiliation(s)
- Yi Cui
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Haojie Wen
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Jinyong Tang
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Jiawen Chen
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Juan Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Minghua Hou
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, 423000, P.R. China
| | - Xiaohan Rong
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
| | - Yuanzhao Lan
- Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), Chenzhou, Hunan, 423000, P.R. China
| | - Qiong Wu
- Department of Nephrology, The First People's Hospital of Chenzhou (Affiliated Chenzhou Hospital, Southern Medical University), No. 102, luojiajing, beihu District, Chenzhou, Hunan, 423000, P.R. China.
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Yang G, Li T, Liu J, Quan Z, Liu M, Guo Y, Wu Y, Ou L, Wu X, Zheng Y. lncRNA MAGI2-AS3 suppresses castration-resistant prostate cancer proliferation and migration via the miR-106a-5p/RAB31 axis. Genomics 2023; 115:110599. [PMID: 36889366 DOI: 10.1016/j.ygeno.2023.110599] [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: 11/01/2022] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
Prostate cancer (PCa) is a common malignant cancer in elderly males in Western countries. Whole-genome sequencing confirmed that long non-coding RNAs (lncRNAs) are frequently altered in castration-resistant prostate cancer (CRPC) and promote drug resistance to cancer therapy. Therefore, elucidating the prospective role of lncRNAs in PCa oncogenesis and progression is of remarkable clinical significance. In this study, gene expression in prostate tissues was determined using RNA-sequencing datasets, and the gene diagnostic and prognostic values of CRPC were analyzed using bioinformatics. Further, the expression levels and clinical significance of MAGI2 Antisense RNA 3 (MAGI2-AS3) in PCa clinical specimens were evaluated. The tumor-suppressive activity of MAGI2-AS3 was functionally explored in PCa cell lines and animal xenograft models. MAGI2-AS3 was found to be aberrantly decreased in CRPC and was negatively correlated with Gleason score and lymph node status. Notably, low MAGI2-AS3 expression positively correlated with poorer survival in patients with PCa. The overexpression of MAGI2-AS3 significantly inhibited the proliferation and migration of PCa in vitro and in vivo. Mechanistically, MAGI2-AS3 could play a tumor suppressor function in CRPC through a novel miR-106a-5p/RAB31 regulatory network and could be a target for future cancer therapy.
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Affiliation(s)
- Guo Yang
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China
| | - Ting Li
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, 400016 Chongqing, China
| | - Jiayu Liu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China
| | - Zhen Quan
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China
| | - Miao Liu
- Gastrointestinal Cancer Center, Chongqing University Cancer Hospital, 400030 Chongqing, China
| | - Yuan Guo
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China
| | - Yingying Wu
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, 400016 Chongqing, China
| | - Liping Ou
- Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing Medical University, 400016 Chongqing, China
| | - Xiaohou Wu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China.
| | - Yongbo Zheng
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 400042 Chongqing, China.
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Mehta M, Raguraman R, Ramesh R, Munshi A. RNA binding proteins (RBPs) and their role in DNA damage and radiation response in cancer. Adv Drug Deliv Rev 2022; 191:114569. [PMID: 36252617 PMCID: PMC10411638 DOI: 10.1016/j.addr.2022.114569] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 01/24/2023]
Abstract
Traditionally majority of eukaryotic gene expression is influenced by transcriptional and post-transcriptional events. Alterations in the expression of proteins that act post-transcriptionally can affect cellular signaling and homeostasis. RNA binding proteins (RBPs) are a family of proteins that specifically bind to RNAs and are involved in post-transcriptional regulation of gene expression and important cellular processes such as cell differentiation and metabolism. Deregulation of RNA-RBP interactions and any changes in RBP expression or function can lead to various diseases including cancer. In cancer cells, RBPs play an important role in regulating the expression of tumor suppressors and oncoproteins involved in various cell-signaling pathways. Several RBPs such as HuR, AUF1, RBM38, LIN28, RBM24, tristetrapolin family and Musashi play critical roles in various types of cancers and their aberrant expression in cancer cells makes them an attractive therapeutic target for cancer treatment. In this review we provide an overview of i). RBPs involved in cancer progression and their mechanism of action ii). the role of RBPs, including HuR, in breast cancer progression and DNA damage response and iii). explore RBPs with emphasis on HuR as therapeutic target for breast cancer therapy.
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Affiliation(s)
- Meghna Mehta
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA; Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA
| | - Rajeswari Raguraman
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA; Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA
| | - Rajagopal Ramesh
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA; Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA
| | - Anupama Munshi
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA; Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73013, USA.
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Majumder M, Chakraborty P, Mohan S, Mehrotra S, Palanisamy V. HuR as a molecular target for cancer therapeutics and immune-related disorders. Adv Drug Deliv Rev 2022; 188:114442. [PMID: 35817212 DOI: 10.1016/j.addr.2022.114442] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/12/2022] [Accepted: 07/05/2022] [Indexed: 11/19/2022]
Abstract
The control of eukaryotic gene expression occurs at multiple levels, from transcription to messenger RNA processing, transport, localization, turnover, and translation. RNA-binding proteins control gene expression and are involved in different stages of mRNA processing, including splicing, maturation, turnover, and translation. A ubiquitously expressed RBP Human antigen R is engaged in the RNA processes mentioned above but, most importantly, controls mRNA stability and turnover. Dysregulation of HuR is linked to many diseases, including cancer and other immune-related disorders. HuR targets mRNAs containing AU-rich elements at their 3'untranslated region, which encodes proteins involved in cell growth, proliferation, tumor formation, angiogenesis, immune evasion, inflammation, invasion, and metastasis. HuR overexpression has been reported in many tumor types, which led to a poor prognosis for patients. Hence, HuR is considered an appealing drug target for cancer treatment. Therefore, multiple attempts have been made to identify small molecule inhibitors for blocking HuR functions. This article reviews the current prospects of drugs that target HuR in numerous cancer types, their mode of action, and off-target effects. Furthermore, we will summarize drugs that interfered with HuR-RNA interactions and established themselves as novel therapeutics. We will also highlight the significance of HuR overexpression in multiple cancers and discuss its role in immune functions. This review provides evidence of a new era of HuR-targeted small molecules that can be used for cancer therapeutics either as a monotherapy or in combination with other cancer treatment modalities.
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Affiliation(s)
- Mrinmoyee Majumder
- Department of Biochemistry and Molecular Biology, Charleston, SC 29425, USA
| | - Paramita Chakraborty
- Department of Surgery, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sarumathi Mohan
- Department of Biochemistry and Molecular Biology, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Department of Surgery, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Wu X, Xu L. The RNA-binding protein HuR in human cancer: A friend or foe? Adv Drug Deliv Rev 2022; 184:114179. [PMID: 35248670 PMCID: PMC9035123 DOI: 10.1016/j.addr.2022.114179] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/26/2022] [Accepted: 02/27/2022] [Indexed: 12/12/2022]
Abstract
The RNA-binding proteins (RBPs) are critical trans factors that associate with specific cis elements present in mRNAs whose stability and translation are subject to regulation. The RBP Hu antigen R (HuR) is overexpressed in a wide variety of human cancers and serves as a prognostic factor of poor clinical outcome. HuR promotes tumorigenesis by interacting with a subset of oncogenic mRNAs implicated in different cancer hallmarks, and resistance to therapy. Reduction of HuR levels in cancer cells leads to tumor regression in mouse xenograft models. These findings prompt a working model whereby cancer cells use HuR, a master switch of multiple oncogenic mRNAs, to drive drug resistance and promote cell survival and metastasis, thus rendering the tumor cells with high cytoplasmic HuR more progressive and resistant to therapy. This review summarizes the roles of HuR in cancer and other diseases, therapeutic potential of HuR inhibition, and the current status of drug discovery on HuR.
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Affiliation(s)
- Xiaoqing Wu
- Higuchi Biosciences Center, The University of Kansas, Lawrence, KS, USA; The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, USA.
| | - Liang Xu
- The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, USA; Department of Molecular Biosciences, The University of Kansas, Lawrence, KS, USA; Department of Radiation Oncology, The University of Kansas Medical Center, Kansas City, KS, USA.
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Cai H, Zheng D, Yao Y, Yang L, Huang X, Wang L. Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond. Front Cell Dev Biol 2022; 10:847761. [PMID: 35465324 PMCID: PMC9019298 DOI: 10.3389/fcell.2022.847761] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/04/2022] [Indexed: 12/31/2022] Open
Abstract
Embryonic lethal abnormal vision-like (ELAVL) proteins are RNA binding proteins that were originally discovered as indispensable regulators of the development and functioning of the nervous system. Subsequent studies have shown that ELAVL proteins not only exist in the nervous system, but also have regulatory effects in other tissues. ELAVL proteins have attracted attention as potential therapeutic targets because they stabilize multiple mRNAs by binding within the 3′-untranslated region and thus promote the development of tumors, including hepatocellular carcinoma, pancreatic cancer, ovarian cancer, breast cancer, colorectal carcinoma and lung cancer. Previous studies have focused on these important relationships with downstream mRNAs, but emerging studies suggest that ELAVL proteins also interact with non-coding RNAs. In this review, we will summarize the relationship of the ELAVL protein family with mRNA and non-coding RNA and the roles of ELAVL protein family members in a variety of physiological and pathological processes.
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Affiliation(s)
| | | | | | - Lehe Yang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
| | - Xiaoying Huang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
| | - Liangxing Wang
- *Correspondence: Lehe Yang, ; Xiaoying Huang, ; Liangxing Wang,
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7
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Ma Q, Xu C, Han X, Wang X, Zhang W, Liu Z, Wu R, Wu F, Liu X, Zhang T, Su Y, Zheng K, Wang Y. The effects of modified RNA-binding proteins HuR on the biological behavior of the bladder cancer T24 cell line. Transl Androl Urol 2022; 11:348-357. [PMID: 35402198 PMCID: PMC8984971 DOI: 10.21037/tau-22-123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/14/2022] [Indexed: 11/24/2022] Open
Abstract
Background In tumors, the role of human antigen R (HuR) includes regulating tumor cell proliferation, differentiation, apoptosis, angiogenesis, and lymphangiogenesis. Previous studies have revealed that the expression of HuR can be detected in bladder cancer, and is related to the biological behavior of malignancy. Methods T24 cells were transfected by HuR overexpression and HuR knockdown vectors, and divided into the control group, the overexpression-HuR group, and the cas9-HuR group. Cell viability was detected after 48 h by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, apoptosis was detected by Annexin V-allophycocyanin (APC)/7-aminoactinomycin D (7-AAD) double staining, cell migration was detected by Transwell assays, and the expression levels of HuR, cyclin D1, and apoptosis-related factors [i.e., B-cell lymphoma 2 (Bcl-2)] were detected by fluorescence quantitative polymerase chain reaction (PCR) and Western blot. Results Compared to the control group, cell viability after 48 h increased significantly in the overexpression-HuR group, and decreased significantly in the cas9-HuR group (P<0.05). The number of migrating cells increased significantly in the overexpression-HuR group, and decreased significantly in the cas9-HuR group (P<0.05). The apoptosis rate was significantly decreased in the overexpression-HuR group, and significantly increased in the cas9-HuR group (P<0.05). The messenger ribonucleic acid and protein expression levels of HuR, cyclin D1, and Bcl-2 were significantly increased in the overexpression-HuR group, and significantly decreased in the cas9-HuR group (P<0.05). Conclusions HuR promotes the proliferation and migration of T24 cells, and inhibits cell apoptosis. The mechanism may be related to the expression of cyclin D and the apoptosis-related protein, Bcl-2.
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Affiliation(s)
- Qiang Ma
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Blood Conservation Institute, Baotou Medical College, Baotou, China
- Department of Pharmacy, Southern University of Science and Technology Hospital, Shenzhen, China
| | - Chen Xu
- Department of Gynecology, The First Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Xiaomin Han
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Xinxin Wang
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Wei Zhang
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Zhi Liu
- Blood Conservation Institute, Baotou Medical College, Baotou, China
| | - Rihan Wu
- Department of Oncology, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Fei Wu
- Blood Conservation Institute, Baotou Medical College, Baotou, China
| | - Xiaohui Liu
- Blood Conservation Institute, Baotou Medical College, Baotou, China
| | - Tengteng Zhang
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Yan Su
- Blood Conservation Institute, Baotou Medical College, Baotou, China
- School of Basic and Forensic Medicine, Baotou Medical College, Baotou, China
| | - Kewen Zheng
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- The First Clinical College, Wenzhou Medical University, Wenzhou, China
| | - Yukun Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Pharmacy, Southern University of Science and Technology Hospital, Shenzhen, China
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Zhang W, Liu L, Zhao S, Chen L, Wei Y, Chen W, Ge F. Research progress on RNA‑binding proteins in breast cancer (Review). Oncol Lett 2022; 23:121. [PMID: 35261635 PMCID: PMC8867207 DOI: 10.3892/ol.2022.13241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/03/2022] [Indexed: 11/28/2022] Open
Abstract
Breast cancer is the most common malignancy among women, and the abnormal regulation of gene expression serves an important role in its occurrence and development. However, the molecular mechanisms underlying gene expression are highly complex and heterogeneous, and RNA-binding proteins (RBPs) are among the key regulatory factors. RBPs bind targets in an environment-dependent or environment-independent manner to influence mRNA stability and the translation of genes involved in the formation, progression, metastasis and treatment of breast cancer. Due to the growing interest in these regulators, the present review summarizes the most influential studies concerning RBPs associated with breast cancer to elucidate the role of RBPs in breast cancer and to assess how they interact with other key pathways to provide new molecular targets for the diagnosis and treatment of breast cancer.
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Affiliation(s)
- Wenzhu Zhang
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Linlin Liu
- School of Forensic Medicine, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Shengdi Zhao
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Liang Chen
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yuxian Wei
- Department of Endocrine Breast Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenlin Chen
- Third Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, P.R. China
| | - Fei Ge
- Department of Breast Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
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Assoni G, La Pietra V, Digilio R, Ciani C, Licata NV, Micaelli M, Facen E, Tomaszewska W, Cerofolini L, Pérez-Ràfols A, Varela Rey M, Fragai M, Woodhoo A, Marinelli L, Arosio D, Bonomo I, Provenzani A, Seneci P. HuR-targeted agents: An insight into medicinal chemistry, biophysical, computational studies and pharmacological effects on cancer models. Adv Drug Deliv Rev 2022; 181:114088. [PMID: 34942276 DOI: 10.1016/j.addr.2021.114088] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 10/07/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022]
Abstract
The Human antigen R (HuR) protein is an RNA-binding protein, ubiquitously expressed in human tissues, that orchestrates target RNA maturation and processing both in the nucleus and in the cytoplasm. A survey of known modulators of the RNA-HuR interactions is followed by a description of its structure and molecular mechanism of action - RRM domains, interactions with RNA, dimerization, binding modes with naturally occurring and synthetic HuR inhibitors. Then, the review focuses on HuR as a validated molecular target in oncology and briefly describes its role in inflammation. Namely, we show ample evidence for the involvement of HuR in the hallmarks and enabling characteristics of cancer, reporting findings from in vitro and in vivo studies; and we provide abundant experimental proofs of a beneficial role for the inhibition of HuR-mRNA interactions through silencing (CRISPR, siRNA) or pharmacological inhibition (small molecule HuR inhibitors).
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Affiliation(s)
- Giulia Assoni
- Chemistry Department, University of Milan, Via Golgi 19, I-20133 Milan, Italy; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Valeria La Pietra
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
| | - Rosangela Digilio
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Caterina Ciani
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Nausicaa Valentina Licata
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Mariachiara Micaelli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Elisa Facen
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Weronika Tomaszewska
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Linda Cerofolini
- Magnetic Resonance Center (CERM), University of Florence and Interuniversity Consortium for Magnetic Resonance of Metalloproteins (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino (FI), Italy
| | - Anna Pérez-Ràfols
- Giotto Biotech S.R.L., Via Madonna del Piano 6, 50019 Sesto Fiorentino (FI), Italy
| | - Marta Varela Rey
- Gene Regulatory Control in Disease Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Marco Fragai
- Magnetic Resonance Center (CERM), University of Florence and Interuniversity Consortium for Magnetic Resonance of Metalloproteins (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino (FI), Italy
| | - Ashwin Woodhoo
- Gene Regulatory Control in Disease Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, Spain; Department of Functional Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain; Center for Cooperative Research in Biosciences (CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain
| | - Luciana Marinelli
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
| | - Daniela Arosio
- Istituto di Scienze e Tecnologie Chimiche "G. Natta" (SCITEC), National Research Council (CNR), Via C. Golgi 19, I-20133 Milan, Italy
| | - Isabelle Bonomo
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy
| | - Alessandro Provenzani
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, via Sommarive 9, 38123 Trento, Italy.
| | - Pierfausto Seneci
- Chemistry Department, University of Milan, Via Golgi 19, I-20133 Milan, Italy.
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Circular RNA circE2F2 promotes malignant progression of ovarian cancer cells by upregulating the expression of E2F2 protein via binding to HuR protein. Cell Signal 2021; 84:110014. [PMID: 33894314 DOI: 10.1016/j.cellsig.2021.110014] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/20/2021] [Accepted: 04/20/2021] [Indexed: 12/14/2022]
Abstract
Ovarian cancer (OC) is a gynecological malignancy with a poor prognosis and low survival rate. E2F2 is a transcription activator that plays an indispensable role in cell proliferation and cell cycle progression. The preliminary analysis indicated that the E2F2 gene could produce three circular RNAs (circRNAs). This study aimed to investigate whether these circRNAs would be involved in OC tumorigenesis. The results showed that one of the circRNAs (termed circE2F2) was significantly upregulated in OC tissues and cell lines, and high circE2F2 expression was associated with poor survival in OC patients. The knockdown of circE2F2 in OC cells suppressed cell proliferation, migration, invasion, and cellular glucose metabolism. In circE2F2-deficient cells, the half-life of the E2F2 mRNA was significantly shorter than that in the control group, indicating that sufficient circE2F2 expression could strengthen the stability of the E2F2 mRNA. Further analysis revealed that circE2F2 could bind to RNA-binding protein Hu antigen R (HuR). Moreover, circE2F2 enhanced the stability of the E2F2 mRNA via binding to the HuR protein. Also, E2F2 overexpression significantly enhanced the mobility, invasiveness, and glucose metabolism of OC cells with insufficient circE2F2 expression, suggesting that circE2F2 induced OC cell growth and metastasis by upregulating E2F2. In conclusion, circE2F2 promoted OC cell proliferation, metastasis, and glucose metabolism by stabilizing the E2F2 mRNA via binding to the HuR protein. These findings suggest a novel regulatory mechanism for the oncogenic effects of circE2F2, E2F2, and HuR on ovarian carcinogenesis.
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11
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Rashidi S, Kalantar K, Fernandez-Rubio C, Anvari E, Nguewa P, Hatam G. Chitin binding protein as a possible RNA binding protein in Leishmania parasites. Pathog Dis 2020; 78:5735439. [PMID: 32053190 DOI: 10.1093/femspd/ftaa007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 02/12/2020] [Indexed: 12/17/2022] Open
Abstract
Leishmaniasis includes a broad spectrum of pathological outcomes in humans caused by protozoan parasites from the genus Leishmania. In recent years, proteomic techniques have introduced novel proteins with critical functions in Leishmania parasites. Based on our report of a Chitin binding protein (CBP) in our previous immunoproteomic study, this article suggests that CBP might be an RNA binding protein (RBP) in Leishmania parasites. RBPs, as key regulatory factors, have a role in post-transcriptional gene regulation. The presence of RBPs in Leishmania parasites has not been considered so far; however, this study aims to open a new venue regarding RBPs in Leishmania parasites. Confirming CBP as an RBP in Leishmania parasites, exploring other RBPs and their functions might lead to interesting issues in leishmaniasis. In fact, due to the regulatory role of RBPs in different diseases including cancers and their further classification as therapeutic targets, the emerging evaluation of CBP and RBPs from Leishmania parasites may allow the discovery of novel and effective drugs against leishmaniasis.
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Affiliation(s)
- Sajad Rashidi
- Department of Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Celia Fernandez-Rubio
- University of Navarra, ISTUN Instituto de Salud Tropical, IdiSNa, Department of Microbiology and Parasitology. c/ Irunlarrea 1, 31008 Pamplona, Spain
| | - Enayat Anvari
- Department of Physiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Paul Nguewa
- University of Navarra, ISTUN Instituto de Salud Tropical, IdiSNa, Department of Microbiology and Parasitology. c/ Irunlarrea 1, 31008 Pamplona, Spain
| | - Gholamreza Hatam
- Basic Sciences in Infectious Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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12
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Wu M, Tong CWS, Yan W, To KKW, Cho WCS. The RNA Binding Protein HuR: A Promising Drug Target for Anticancer Therapy. Curr Cancer Drug Targets 2020; 19:382-399. [PMID: 30381077 DOI: 10.2174/1568009618666181031145953] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/24/2018] [Accepted: 10/18/2018] [Indexed: 02/07/2023]
Abstract
The stability of mRNA is one of the key factors governing the regulation of eukaryotic gene expression and function. Human antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm shuttling of its target mRNAs. While HuR is normally localized within the nucleus, it has been shown that HuR binds mRNAs in the nucleus and then escorts the mRNAs to the cytoplasm where HuR protects them from degradation. It contains several RNA recognition motifs, which specifically bind to adenylate and uridylate-rich regions within the 3'-untranslated region of the target mRNA to mediate its effect. Many of the HuR target mRNAs encode proteins important for cell growth, tumorigenesis, angiogenesis, tumor inflammation, invasion and metastasis. HuR overexpression is known to correlate well with high-grade malignancy and poor prognosis in many tumor types. Thus, HuR has emerged as an attractive drug target for cancer therapy. Novel small molecule HuR inhibitors have been identified by high throughput screening and new formulations for targeted delivery of HuR siRNA to tumor cells have been developed with promising anticancer activity. This review summarizes the significant role of HuR in cancer development, progression, and poor treatment response. We will discuss the potential and challenges of targeting HuR therapeutically.
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Affiliation(s)
- Mingxia Wu
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Christy W S Tong
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Wei Yan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong
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13
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Wu JI, Lin YP, Tseng CW, Chen HJ, Wang LH. Crabp2 Promotes Metastasis of Lung Cancer Cells via HuR and Integrin β1/FAK/ERK Signaling. Sci Rep 2019; 9:845. [PMID: 30696915 PMCID: PMC6351595 DOI: 10.1038/s41598-018-37443-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/30/2018] [Indexed: 01/31/2023] Open
Abstract
Increased Crabp2 levels have been found in various types of cancer, and are associated with poor patients’ survival. Although Crabp2 is found to be overexpressed in lung cancer, its role in metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin β1/FAK/ERK signaling. Inhibition of HuR or integrin β1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis.
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Affiliation(s)
- Jun-I Wu
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan.,Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Yi-Pei Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan.,Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan
| | - Chien-Wei Tseng
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Hui-Jane Chen
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Lu-Hai Wang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan. .,Department of Life Sciences, National Central University, Taoyuan, Taiwan. .,Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan. .,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. .,Chinese Medical Research Center, China Medical University, Taichung, Taiwan.
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14
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D'Agostino VG, Sighel D, Zucal C, Bonomo I, Micaelli M, Lolli G, Provenzani A, Quattrone A, Adami V. Screening Approaches for Targeting Ribonucleoprotein Complexes: A New Dimension for Drug Discovery. SLAS DISCOVERY 2019; 24:314-331. [PMID: 30616427 DOI: 10.1177/2472555218818065] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
RNA-binding proteins (RBPs) are pleiotropic factors that control the processing and functional compartmentalization of transcripts by binding primarily to mRNA untranslated regions (UTRs). The competitive and/or cooperative interplay between RBPs and an array of coding and noncoding RNAs (ncRNAs) determines the posttranscriptional control of gene expression, influencing protein production. Recently, a variety of well-recognized and noncanonical RBP domains have been revealed by modern system-wide analyses, underlying an evolving classification of ribonucleoproteins (RNPs) and their importance in governing physiological RNA metabolism. The possibility of targeting selected RNA-protein interactions with small molecules is now expanding the concept of protein "druggability," with new implications for medicinal chemistry and for a deeper characterization of the mechanism of action of bioactive compounds. Here, taking SF3B1, HuR, LIN28, and Musashi proteins as paradigmatic case studies, we review the strategies applied for targeting RBPs, with emphasis on the technological advancements to study protein-RNA interactions and on the requirements of appropriate validation strategies to parallel high-throughput screening (HTS) efforts.
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Affiliation(s)
- Vito Giuseppe D'Agostino
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Denise Sighel
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Chiara Zucal
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Isabelle Bonomo
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Mariachiara Micaelli
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Graziano Lolli
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Alessandro Provenzani
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Alessandro Quattrone
- 1 University of Trento, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
| | - Valentina Adami
- 2 University of Trento, HTS Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), Trento, Italy
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Panneerdoss S, Eedunuri VK, Yadav P, Timilsina S, Rajamanickam S, Viswanadhapalli S, Abdelfattah N, Onyeagucha BC, Cui X, Lai Z, Mohammad TA, Gupta YK, Huang THM, Huang Y, Chen Y, Rao MK. Cross-talk among writers, readers, and erasers of m 6A regulates cancer growth and progression. SCIENCE ADVANCES 2018; 4:eaar8263. [PMID: 30306128 PMCID: PMC6170038 DOI: 10.1126/sciadv.aar8263] [Citation(s) in RCA: 265] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 08/30/2018] [Indexed: 05/23/2023]
Abstract
The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m6A levels by silencing either N 6-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m6A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor-β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m6A modifications, as altered m6A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m6A status of target genes by controlling each other's expression and by inhibiting m6A reader YTHDF3 (YTH N 6-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m6A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m6A in cancer and shows that the collaboration among writers-erasers-readers sets up the m6A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m6A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.
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Affiliation(s)
- Subbarayalu Panneerdoss
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Vijay K. Eedunuri
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Pooja Yadav
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Santosh Timilsina
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Subapriya Rajamanickam
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Nourhan Abdelfattah
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Benjamin C. Onyeagucha
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Xiadong Cui
- Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Tabrez A. Mohammad
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Yogesh K. Gupta
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Tim Hui-Ming Huang
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Yufei Huang
- Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Manjeet K. Rao
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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Fus ŁP, Pihowicz P, Koperski Ł, Marczewska JM, Górnicka B. High cytoplasmic HuR expression is associated with advanced pT stage, high grade and increased microvessel density in urothelial bladder carcinoma. Ann Diagn Pathol 2017; 33:40-44. [PMID: 29566946 DOI: 10.1016/j.anndiagpath.2017.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/15/2017] [Accepted: 12/09/2017] [Indexed: 11/17/2022]
Abstract
PURPOSE HuR (human antigen R) protein is a RNA binding protein that stabilizes the mRNA and controls the translation of genes involved in cell proliferation, differentiation, and carcinogenesis. Overexpression of HuR was reported in a variety of cancers, however its clinical significance in urothelial bladder cancer (UBC) is still unknown. Our aim is to investigate the association between HuR expression and selected histopathological factors, such as tumor grade, pT stage, regional lymph nodes status and microvessel density (MVD). METHODS We studied expression of HuR protein in 119 patients with UBC in stages pTis and pTa-pT4 using immunohistochemistry (IHC). Tumor MVD was evaluated immunohistochemically using anti-CD31 antibody. RESULTS We observed no association between nuclear HuR immunoreactivity and tumor grade, stage or MVD. We found a significant association between cytoplasmic HuR positivity and high tumor grade, pT stage and MVD (p<0,001). We also observed significantly higher MVD values in cases with positive cytoplasmic HuR expression (p<0,001). No association between HuR immunoreactivity and lymph nodes status was found. CONCLUSIONS Our results may suggest that HuR is involved in the process of acquiring malignant histopathological features and ability to invade the muscularis propria by UBC cells. Considering frequent difficulties in diagnosing UBC in specimens obtained from transurethral tumor resection and the risk of understaging, cytoplasmic HuR expression would suggest an advanced disease and necessitate serial sectioning of the specimen in search of muscle invasion. Association between HuR expression and MVD could suggest HuR involvement in the process of angiogenesis in UBC.
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Affiliation(s)
- Łukasz Piotr Fus
- Department of Pathology, Medical University of Warsaw, Pawińskiego 7, 02-106 Warsaw, Poland.
| | - Paweł Pihowicz
- Department of Pathology, Medical University of Warsaw, Pawińskiego 7, 02-106 Warsaw, Poland
| | - Łukasz Koperski
- Department of Pathology, Medical University of Warsaw, Pawińskiego 7, 02-106 Warsaw, Poland
| | - Janina Maja Marczewska
- Department of Pathology, Medical University of Warsaw, Pawińskiego 7, 02-106 Warsaw, Poland
| | - Barbara Górnicka
- Department of Pathology, Medical University of Warsaw, Pawińskiego 7, 02-106 Warsaw, Poland
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Kotzsch M, Kirchner T, Soelch S, Schäfer S, Friedrich K, Baretton G, Magdolen V, Luther T. Inverse association of rab31 and mucin-1 (CA15-3) antigen levels in estrogen receptor-positive (ER+) breast cancer tissues with clinicopathological parameters and patients' prognosis. Am J Cancer Res 2017; 7:1959-1970. [PMID: 28979817 PMCID: PMC5622229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 06/13/2017] [Indexed: 06/07/2023] Open
Abstract
Dysregulated expression of rab31, a member of the large Rab protein family of the Ras superfamily of small GTPases, has been observed in several types of cancer, including breast cancer. Rab31, depending on its expression level, may regulate the switch between an invasive versus proliferative phenotype of breast cancer cells in vitro. Moreover, gene expression of rab31 is induced by the C-terminal subunit of mucin-1 (MUC1-C) and estrogen receptors (ER). To gain further insights into the clinical relevance of rab31 and mucin-1 expression in breast cancer, we analyzed the relation between rab31 and mucin-1 (CA15-3) antigen levels in detergent tissue extracts of ER-positive (ER+) tumors and clinicopathological parameters as well as patients' prognosis. No significant correlation was observed between rab31 and CA15-3 antigen levels. Elevated rab31 antigen levels in tumor tissue extracts were significantly associated with higher tumor grade (P = 0.021). Strikingly, an inverse significant association was observed for CA15-3 with tumor grade (P = 0.032). Furthermore, high rab31 antigen levels were significantly associated with a high S-phase fraction (SPF, P = 0.047), whereas a trend for lower CA15-3 antigen levels in tumor tissue displaying higher SPF was observed. High rab31 antigen levels were significantly associated with poor 5-year disease-free survival (DFS) of ER+ breast cancer patients in univariate Cox regression analysis (HR = 1.91, 95% CI = 1.14-3.17, P = 0.013). In contrast, high levels of CA15-3 antigen levels were associated with better patients' prognosis (HR = 0.56, 95% CI = 0.33-0.95, P = 0.031). In multivariable analysis, rab31 antigen levels contributed independent prognostic information for DFS when adjusted for prognostically relevant clinicopathological parameters with a HR for high versus low values of 1.97 (95% CI = 1.09-3.54, P = 0.024), whereas CA15-3 antigen levels were not significant. Our results strongly suggest that rab31 antigen levels in tumor tissue are associated with the proliferative status, and rab31 represents an independent biomarker for prognosis in ER+ breast cancer patients. Total mucin-1 (CA 15-3) levels are rather inversely associated with tumor grade and SPF, and elevated levels even indicate prolonged DFS in ER+ breast cancer patients.
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Affiliation(s)
- Matthias Kotzsch
- Medizinisches Labor OstsachsenD-02526 Bautzen, Germany
- Institut für Pathologie, Technische Universität DresdenD-01307 Dresden, Germany
| | | | - Susanne Soelch
- Klinische Forschergruppe, Klinik für Frauenheilkunde und Geburtshilfe, Technische Universität MünchenD-81675 München, Germany
| | - Sonja Schäfer
- Klinische Forschergruppe, Klinik für Frauenheilkunde und Geburtshilfe, Technische Universität MünchenD-81675 München, Germany
| | - Katrin Friedrich
- Institut für Pathologie, Technische Universität DresdenD-01307 Dresden, Germany
| | - Gustavo Baretton
- Institut für Pathologie, Technische Universität DresdenD-01307 Dresden, Germany
| | - Viktor Magdolen
- Klinische Forschergruppe, Klinik für Frauenheilkunde und Geburtshilfe, Technische Universität MünchenD-81675 München, Germany
| | - Thomas Luther
- Medizinisches Labor OstsachsenD-02526 Bautzen, Germany
- Institut für Pathologie, Technische Universität DresdenD-01307 Dresden, Germany
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Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients. Pathol Oncol Res 2017; 24:631-640. [DOI: 10.1007/s12253-017-0288-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 08/09/2017] [Indexed: 01/04/2023]
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19
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Kotta-Loizou I, Vasilopoulos SN, Coutts RHA, Theocharis S. Current Evidence and Future Perspectives on HuR and Breast Cancer Development, Prognosis, and Treatment. Neoplasia 2016; 18:674-688. [PMID: 27764700 PMCID: PMC5071540 DOI: 10.1016/j.neo.2016.09.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/14/2016] [Accepted: 09/19/2016] [Indexed: 12/20/2022] Open
Abstract
Hu-antigen R (HuR) is an RNA-binding posttranscriptional regulator that belongs to the Hu/ELAV family. HuR expression levels are modulated by a variety of proteins, microRNAs, chemical compounds, or the microenvironment, and in turn, HuR affects mRNA stability and translation of various genes implicated in breast cancer formation, progression, metastasis, and treatment. The aim of the present review is to critically summarize the role of HuR in breast cancer development and its potential as a prognosticator and a therapeutic target. In this aspect, all the existing English literature concerning HuR expression and function in breast cancer cell lines, in vivo animal models, and clinical studies is critically presented and summarized. HuR modulates many genes implicated in biological processes crucial for breast cancer formation, growth, and metastasis, whereas the link between HuR and these processes has been demonstrated directly in vitro and in vivo. Additionally, clinical studies reveal that HuR is associated with more aggressive forms of breast cancer and is a putative prognosticator for patients' survival. All the above indicate HuR as a promising drug target for cancer therapy; nevertheless, additional studies are required to fully understand its potential and determine against which types of breast cancer and at which stage of the disease a therapeutic agent targeting HuR would be more effective.
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Affiliation(s)
- Ioly Kotta-Loizou
- Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom; First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece.
| | - Spyridon N Vasilopoulos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Robert H A Coutts
- Geography, Environment and Agriculture Division, Department of Biological and Environmental Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, United Kingdom
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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20
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Neoplastic extracellular matrix environment promotes cancer invasion in vitro. Exp Cell Res 2016; 344:229-40. [PMID: 27090016 DOI: 10.1016/j.yexcr.2016.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 04/07/2016] [Indexed: 11/21/2022]
Abstract
The invasion of carcinoma cells is a crucial feature in carcinogenesis. The penetration efficiency not only depends on the cancer cells, but also on the composition of the tumor microenvironment. Our group has developed a 3D invasion assay based on human uterine leiomyoma tissue. Here we tested whether human, porcine, mouse or rat hearts as well as porcine tongue tissues could be similarly used to study carcinoma cell invasion in vitro. Three invasive human oral tongue squamous cell carcinoma (HSC-3, SCC-25 and SCC-15), melanoma (G-361) and ductal breast adenocarcinoma (MDA-MB-231) cell lines, and co-cultures of HSC-3 and carcinoma-associated or normal oral fibroblasts were assayed. Myoma tissue, both native and lyophilized, promoted invasion and growth of the cancer cells. However, the healthy heart or tongue matrices were unable to induce the invasion of any type of cancer cells tested. Moreover, when studied in more detail, small molecular weight fragments derived from heart tissue rinsing media inhibited HSC-3 horizontal migration. Proteome analysis of myoma rinsing media, on the other hand, revealed migration enhancing factors. These results highlight the important role of matrix composition for cancer invasion studies in vitro and further demonstrate the unique properties of human myoma organotypic model.
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Huang YH, Peng W, Furuuchi N, Gerhart J, Rhodes K, Mukherjee N, Jimbo M, Gonye GE, Brody JR, Getts RC, Sawicki JA. Delivery of Therapeutics Targeting the mRNA-Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth. Cancer Res 2016; 76:1549-59. [PMID: 26921342 DOI: 10.1158/0008-5472.can-15-2073] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/08/2016] [Indexed: 11/16/2022]
Abstract
Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor-bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo-targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer.
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Affiliation(s)
- Yu-Hung Huang
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Weidan Peng
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
| | - Narumi Furuuchi
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania
| | | | | | - Neelanjan Mukherjee
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Masaya Jimbo
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Jonathan R Brody
- Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Janet A Sawicki
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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22
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Salo T, Sutinen M, Hoque Apu E, Sundquist E, Cervigne NK, de Oliveira CE, Akram SU, Ohlmeier S, Suomi F, Eklund L, Juusela P, Åström P, Bitu CC, Santala M, Savolainen K, Korvala J, Paes Leme AF, Coletta RD. A novel human leiomyoma tissue derived matrix for cell culture studies. BMC Cancer 2015; 15:981. [PMID: 26673244 PMCID: PMC4682271 DOI: 10.1186/s12885-015-1944-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 11/19/2015] [Indexed: 01/29/2023] Open
Abstract
Background The composition of the matrix molecules is important in in vitro cell culture experiments of e.g. human cancer invasion and vessel formation. Currently, the mouse Engelbreth-Holm-Swarm (EHS) sarcoma -derived products, such as Matrigel®, are the most commonly used tumor microenvironment (TME) mimicking matrices for experimental studies. However, since Matrigel® is non-human in origin, its molecular composition does not accurately simulate human TME. We have previously described a solid 3D organotypic myoma disc invasion assay, which is derived from human uterus benign leiomyoma tumor. Here, we describe the preparation and analyses of a processed, gelatinous leiomyoma matrix, named Myogel. Methods A total protein extract, Myogel, was formulated from myoma. The protein contents of Myogel were characterized and its composition and properties compared with a commercial mouse Matrigel®. Myogel was tested and compared to Matrigel® in human cell adhesion, migration, invasion, colony formation, spheroid culture and vessel formation experiments, as well as in a 3D hanging drop video image analysis. Results We demonstrated that only 34 % of Myogel’s molecular content was similar to Matrigel®. All test results showed that Myogel was comparable with Matrigel®, and when mixed with low-melting agarose (Myogel-LMA) it was superior to Matrigel® in in vitro Transwell® invasion and capillary formation assays. Conclusions In conclusion, we have developed a novel Myogel TME matrix, which is recommended for in vitro human cell culture experiments since it closely mimics the human tumor microenvironment of solid cancers. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1944-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tuula Salo
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland. .,Department of Oral and Maxillofacial Diseases, University of Helsinki, FI-00014, Helsinki, Finland.
| | - Meeri Sutinen
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | - Ehsanul Hoque Apu
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | - Elias Sundquist
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | - Nilva K Cervigne
- Clinical Department, Faculty of Medicine of Jundiai (FMJ), Jundiai, São Paulo, SP-13202-550, Brazil. .,Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, SP-13414-903, Brazil.
| | - Carine Ervolino de Oliveira
- Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, SP-13414-903, Brazil.
| | - Saad Ullah Akram
- Center for Machine Vision Research, University of Oulu, FI-90014, Oulu, Finland. .,Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland.
| | - Steffen Ohlmeier
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014, Oulu, Finland. .,Proteomics Core Facility, Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland.
| | - Fumi Suomi
- Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland. .,Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014, Oulu, Finland.
| | - Lauri Eklund
- Biocenter Oulu, University of Oulu, FI-90014, Oulu, Finland. .,Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014, Oulu, Finland.
| | - Pirjo Juusela
- Department of Oral and Maxillofacial Diseases, University of Helsinki, FI-00014, Helsinki, Finland.
| | - Pirjo Åström
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | - Carolina Cavalcante Bitu
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | - Markku Santala
- Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, FI-90029, Oulu, Finland.
| | - Kalle Savolainen
- Department of Obstetrics and Gynecology, Tampere University Hospital and University of Tampere, FI-33521, Tampere, Finland.
| | - Johanna Korvala
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, PO Box 5281, FI-90014, Oulu, Finland. .,Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FI-90014, Oulu, Finland.
| | | | - Ricardo D Coletta
- Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, SP-13414-903, Brazil.
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23
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Zhang X, Devany E, Murphy MR, Glazman G, Persaud M, Kleiman FE. PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells. Nucleic Acids Res 2015; 43:10925-38. [PMID: 26400160 PMCID: PMC4678859 DOI: 10.1093/nar/gkv959] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/13/2015] [Indexed: 01/10/2023] Open
Abstract
mRNA deadenylation is under the control of cis-acting regulatory elements, which include AU-rich elements (AREs) and microRNA (miRNA) targeting sites, within the 3' untranslated region (3' UTRs) of eukaryotic mRNAs. Deadenylases promote miRNA-induced mRNA decay through their interaction with miRNA-induced silencing complex (miRISC). However, the role of poly(A) specific ribonuclease (PARN) deadenylase in miRNA-dependent mRNA degradation has not been elucidated. Here, we present evidence that not only ARE- but also miRNA-mediated pathways are involved in PARN-mediated regulation of the steady state levels of TP53 mRNA, which encodes the tumor suppressor p53. Supporting this, Argonaute-2 (Ago-2), the core component of miRISC, can coexist in complexes with PARN resulting in the activation of its deadenylase activity. PARN regulates TP53 mRNA stability through not only an ARE but also an adjacent miR-504/miR-125b-targeting site in the 3' UTR. More importantly, we found that miR-125b-loaded miRISC contributes to the specific recruitment of PARN to TP53 mRNA, and that can be reverted by the ARE-binding protein HuR. Together, our studies provide new insights into the role of PARN in miRNA-dependent control of mRNA decay and into the mechanisms behind the regulation of p53 expression.
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Affiliation(s)
- Xiaokan Zhang
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA
| | - Emral Devany
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA Department of Biological Sciences, Kingsborough Community College, City University of New York, 2001 Oriental Boulevard, Brooklyn, NY 11235, USA
| | - Michael R Murphy
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA
| | - Galina Glazman
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA
| | - Mirjana Persaud
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA
| | - Frida E Kleiman
- Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA
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24
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Yu C, Xin W, Zhen J, Liu Y, Javed A, Wang R, Wan Q. Human antigen R mediated post-transcriptional regulation of epithelial-mesenchymal transition related genes in diabetic nephropathy. J Diabetes 2015; 7:562-72. [PMID: 25265983 DOI: 10.1111/1753-0407.12220] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 06/04/2014] [Accepted: 09/08/2014] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein that modulates gene expression at the post-transcriptional level. While cytoplasmic HuR expression was identified as a marker in epithelial-mesenchymal transition (EMT) process of several types of cancer, its role in diabetic nephropathy (DN) remains unclear. METHODS Renal biopsies from Type 2 diabetic patients and STZ-induced DN rats were stained for HuR and EMT markers. Redistribution of HuR was detected by immunostaining and western blot in high glucose stimulated cells. RNAi was used to supress HuR expression. The binding affinity for EMT-related genes was evaluated by immunoprecipitation. RESULTS Cytoplasmic HuR expression was elevated in human and rat DN specimens along with EMT changes compared to normal controls. HuR shuttling between nucleus and cytoplasm facilitated epithelial to mesenchymal transition in renal epithelial cells. The suppression of HuR partially inhibited EMT of high glucose stimulated HK-2 cells. Furthermore, HuR bound to 3'-UTRs of critical cytokines or transcription factors mRNA involved in EMT process. CONCLUSION Acquired phenotypic traits of EMT were partially through the enhanced HuR-binding proteins and its post-transcriptional regulation role in DN.
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Affiliation(s)
- Che Yu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Wei Xin
- Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Junhui Zhen
- Department of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan, China
| | - Yi Liu
- Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Akhtar Javed
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Qiang Wan
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China
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25
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Griseri P, Pagès G. Control of pro-angiogenic cytokine mRNA half-life in cancer: the role of AU-rich elements and associated proteins. J Interferon Cytokine Res 2015; 34:242-54. [PMID: 24697202 DOI: 10.1089/jir.2013.0140] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Control of mRNA half-life plays a central role in normal development and disease. Several pathological conditions, such as inflammation and cancer, tightly correlate with deregulation in mRNA stability of pro-inflammatory genes. Among these, pro-angiogenesis cytokines, which play a crucial role in the formation of new blood vessels, normally show rapid mRNA decay patterns. The mRNA half-life of these genes appears to be regulated by mRNA-binding proteins that interact with AU-rich elements (AREs) in the 3'-untranslated region of mRNAs. Some of these RNA-binding proteins, such as tristetraprolin (TTP), ARE RNA-binding protein 1, and KH-type splicing regulatory protein, normally promote mRNA degradation. Conversely, other proteins, such as embryonic lethal abnormal vision-like protein 1 (HuR) and polyadenylate-binding protein-interacting protein 2, act as antagonists, stabilizing the mRNA. The steady state levels of mRNA-binding proteins and their relative ratio is often perturbed in human cancers and associated with invasion and aggressiveness. Compelling evidence also suggests that underexpression of TTP and overexpression of HuR may be a useful prognostic and predictive marker in breast, colon, prostate, and brain cancers, indicating a potential therapeutic approach for these tumors. In this review, we summarize the main mechanisms involved in the regulation of mRNA decay of pro-angiogenesis cytokines in different cancers and discuss the interactions between the AU-rich-binding proteins and their mRNA targets.
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Affiliation(s)
- Paola Griseri
- 1 U.O.C Medical Genetics, Institute Giannina Gaslini , Genoa, Italy
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26
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Chua CEL, Tang BL. The role of the small GTPase Rab31 in cancer. J Cell Mol Med 2014; 19:1-10. [PMID: 25472813 PMCID: PMC4288343 DOI: 10.1111/jcmm.12403] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 07/18/2014] [Indexed: 12/28/2022] Open
Abstract
Members of the small GTPase family Rab are emerging as potentially important factors in cancer development and progression. A good number of Rabs have been implicated or associated with various human cancers, and much recent excitement has been associated with the roles of the Rab11 subfamily member Rab25 and its effector, the Rab coupling protein (RCP), in tumourigenesis and metastasis. In this review, we focus on a Rab5 subfamily member, Rab31, and its implicated role in cancer. Well recognized as a breast cancer marker with good prognostic value, recent findings have provided some insights as to the mechanism underlying Rab31's influence on oncogenesis. Levels of Oestrogen Receptor α (ERα)- responsive Rab31 could be elevated through stabilization of its transcript by the RNA binding protein HuR, or though activation by the oncoprotein mucin1-C (MUC1-C), which forms a transcriptional complex with ERα. Elevated Rab31 stabilizes MUC1-C levels in an auto-inductive loop that could lead to aberrant signalling and gene expression associated with cancer progression. Rab31 and its guanine nucleotide exchange factor GAPex-5 have, however, also been shown to enhance early endosome-late endosome transport and degradation of the epidermal growth factor receptor (EGFR). The multifaceted action and influences of Rab31 in cancer is discussed in the light of its new interacting partners and pathways.
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Affiliation(s)
- Christelle En Lin Chua
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
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27
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Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol 2014; 31:161. [PMID: 25112469 DOI: 10.1007/s12032-014-0161-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 08/01/2014] [Indexed: 12/28/2022]
Abstract
Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of target mRNAs. The aim of the present review was to summarize and present the currently available information in the English literature on HuR expression in various human tumors, verifying its possible clinical significance. HuR function is directly linked to its subcellular localization. In normal cells, HuR is mostly localized in the nucleus, while in malignant cells, an increase in cytoplasmic HuR levels has been noted, in both cell lines and tissue samples. Moreover, in malignancy, elevated HuR expression levels and cytoplasmic immunohistochemical pattern have been correlated with advanced clinicopathological parameters and altered expression levels of proteins implicated in neoplasia. Additionally, elevated HuR expression levels and mainly cytoplasmic immunohistochemical pattern were correlated with decreased patients' survival rate in various human tumors. HuR is a putative drug target for cancer therapy, since it is expressed ubiquitously in malignant clinical samples and has an apparently consistent role in tumor formation and progression.
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Affiliation(s)
- Ioly Kotta-Loizou
- Division of Cell and Molecular Biology, Imperial College London, London, UK
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28
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Griseri P, Pagès G. Regulation of the mRNA half-life in breast cancer. World J Clin Oncol 2014; 5:323-334. [PMID: 25114848 PMCID: PMC4127604 DOI: 10.5306/wjco.v5.i3.323] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/31/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
The control of the half-life of mRNA plays a central role in normal development and in disease progression. Several pathological conditions, such as breast cancer, correlate with deregulation of the half-life of mRNA encoding growth factors, oncogenes, cell cycle regulators and inflammatory cytokines that participate in cancer. Substantial stability means that a mRNA will be available for translation for a longer time, resulting in high levels of protein gene products, which may lead to prolonged responses that subsequently result in over-production of cellular mediators that participate in cancer. The stability of these mRNA is regulated at the 3’UTR level by different mechanisms involving mRNA binding proteins, micro-RNA, long non-coding RNA and alternative polyadenylation. All these events are tightly inter-connected to each other and lead to steady state levels of target mRNAs. Compelling evidence also suggests that both mRNA binding proteins and regulatory RNAs which participate to mRNA half-life regulation may be useful prognostic markers in breast cancers, pointing to a potential therapeutic approach to treatment of patients with these tumors. In this review, we summarize the main mechanisms involved in the regulation of mRNA decay and discuss the possibility of its implication in breast cancer aggressiveness and the efficacy of targeted therapy.
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29
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Korvala J, Harjula T, Siirilä K, Almangush A, Aro K, Mäkitie AA, Grénman R, Karttunen TJ, Leivo I, Kauppila JH, Salo T. Toll-like receptor 9 expression in mucoepidermoid salivary gland carcinoma may associate with good prognosis. J Oral Pathol Med 2014; 43:530-7. [DOI: 10.1111/jop.12160] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2013] [Indexed: 12/29/2022]
Affiliation(s)
- Johanna Korvala
- Department of Dentistry; University of Oulu; Oulu Finland
- Medical Research Center Oulu; Oulu Finland
| | - Teresa Harjula
- Department of Dentistry; University of Oulu; Oulu Finland
| | | | - Alhadi Almangush
- Institute of Dentistry; University of Helsinki; Helsinki Finland
| | - Katri Aro
- Department of Otorhinolaryngology; Helsinki University Central Hospital and University of Helsinki; Helsinki Finland
| | - Antti A. Mäkitie
- Department of Otorhinolaryngology; Helsinki University Central Hospital and University of Helsinki; Helsinki Finland
| | - Reidar Grénman
- Department of Otorhinolaryngology, Head and Neck Surgery; Turku University Hospital and University of Turku; Turku Finland
| | - Tuomo J. Karttunen
- Medical Research Center Oulu; Oulu Finland
- Department of Pathology; University of Oulu; Oulu Finland
- Oulu University Hospital; Oulu Finland
| | - Ilmo Leivo
- Department of Otorhinolaryngology, Head and Neck Surgery; Turku University Hospital and University of Turku; Turku Finland
| | - Joonas H. Kauppila
- Medical Research Center Oulu; Oulu Finland
- Department of Pathology; University of Oulu; Oulu Finland
- Oulu University Hospital; Oulu Finland
- Department of Surgery; University of Oulu; Oulu Finland
| | - Tuula Salo
- Department of Dentistry; University of Oulu; Oulu Finland
- Medical Research Center Oulu; Oulu Finland
- Institute of Dentistry; University of Helsinki; Helsinki Finland
- Oulu University Hospital; Oulu Finland
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30
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Storci G, Bertoni S, De Carolis S, Papi A, Nati M, Ceccarelli C, Pirazzini C, Garagnani P, Ferrarini A, Buson G, Delledonne M, Fiorentino M, Capizzi E, Gruppioni E, Taffurelli M, Santini D, Franceschi C, Bandini G, Bonifazi F, Bonafé M. Slug/β-catenin-dependent proinflammatory phenotype in hypoxic breast cancer stem cells. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:1688-1697. [PMID: 24036252 DOI: 10.1016/j.ajpath.2013.07.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 06/16/2013] [Accepted: 07/30/2013] [Indexed: 11/26/2022]
Abstract
Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.
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Affiliation(s)
- Gianluca Storci
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy.
| | - Sara Bertoni
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Sabrina De Carolis
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Alessio Papi
- Department of Biological, Geological and Environmental Sciences, Functional Genomics Center, University of Verona, Verona, Italy
| | - Marina Nati
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Claudio Ceccarelli
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Chiara Pirazzini
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Paolo Garagnani
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Alberto Ferrarini
- Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy
| | - Genny Buson
- Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy
| | - Massimo Delledonne
- Department of Biotechnologies, Functional Genomics Center, University of Verona, Verona, Italy
| | - Michelangelo Fiorentino
- Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Elisa Capizzi
- Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Elisa Gruppioni
- Pathology Unit, Addarii Institute of Oncology, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Mario Taffurelli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Donatella Santini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Claudio Franceschi
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Giuseppe Bandini
- Institute of Haematology "L & A Seragnoli", St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Francesca Bonifazi
- Institute of Haematology "L & A Seragnoli", St. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Massimiliano Bonafé
- Department of Experimental, Diagnostic and Specialty Medicine, St. Orsola-Malpighi University Hospital, Bologna, Italy; Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy.
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31
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Zhang C, Xue G, Bi J, Geng M, Chu H, Guan Y, Wang J, Wang B. Cytoplasmic expression of the ELAV-like protein HuR as a potential prognostic marker in esophageal squamous cell carcinoma. Tumour Biol 2013; 35:73-80. [PMID: 23873103 DOI: 10.1007/s13277-013-1008-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 07/08/2013] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most frequent cancers and a leading cause of death from cancer in China. The human ELAV-like protein HuR has been found to contribute to cancer development and progression through stabilizing a group of cellular mRNAs of cancer-related genes. In this study, we investigated the expression of HuR in a cohort of ESCC patients using immunohistochemical staining. HuR detected in the cytoplasm of cancer cells was positive in 46.6% of 58 ESCC specimens; 75.9% of these specimens had nuclear immunoreactivity for HuR. Cytoplasmic HuR expression was higher in cancer tissues compared to 20 matched adjacent noncancerous tissues. A clinicopathological study showed that cytoplasmic HuR expression was positively associated with lymph node metastasis, depth of tumor invasion, and advanced stage, whereas nuclear HuR expression was not correlated with any clinicopathological factors. Patients positive for cytoplasmic HuR expression had a cumulative 5-year survival rate of 25.3%, whereas it was 43.8% for patients negative for cytoplasmic HuR expression. In a multivariate analysis, cytoplasmic HuR expression was an independent prognostic factor, whereas nuclear positivity for HuR was not. Our results indicate that high cytoplasmic HuR expression is associated with positive lymph node metastasis, deep tumor invasion, high stage, and poor survival in ESCC. Thus, HuR is the first mRNA stability protein whose expression is associated with poor survival in esophageal cancer.
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Affiliation(s)
- Cong Zhang
- Department of Oncology, General Hospital, Jinan Command of the People's Liberation Army, Shifan Street 25, Tianqiao District, Jinan, 250031, China
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Aparicio LA, Abella V, Valladares M, Figueroa A. Posttranscriptional regulation by RNA-binding proteins during epithelial-to-mesenchymal transition. Cell Mol Life Sci 2013; 70:4463-77. [PMID: 23715860 PMCID: PMC3827902 DOI: 10.1007/s00018-013-1379-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 05/10/2013] [Accepted: 05/16/2013] [Indexed: 12/22/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT), one of the crucial steps for carcinoma cells to acquire invasive capacity, results from the disruption of cell–cell contacts and the acquisition of a motile mesenchymal phenotype. Although the transcriptional events controlling EMT have been extensively studied, in recent years, several posttranscriptional mechanisms have emerged as critical in the regulation of EMT during tumor progression. In this review, we highlight the regulation of posttranscriptional events in EMT by RNA-binding proteins (RBPs). RBPs are responsible for controlling pre-mRNA splicing, capping, and polyadenylation, as well as mRNA export, turnover, localization, and translation. We discuss the most relevant aspects of RBPs controlling the metabolism of EMT-related mRNAs, and describe the implication of novel posttranscriptional mechanisms regulating EMT in response to different signaling pathways. Novel insight into posttranscriptional regulation of EMT by RBPs is uncovering new therapeutic targets in cancer invasion and metastasis.
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Affiliation(s)
- Luis A Aparicio
- Servizo de Oncología Médica, Complejo Hospitalario Universitario A Coruña (CHUAC), SERGAS, A Coruña, Spain
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Wang J, Guo Y, Chu H, Guan Y, Bi J, Wang B. Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis. Int J Mol Sci 2013; 14:10015-41. [PMID: 23665903 PMCID: PMC3676826 DOI: 10.3390/ijms140510015] [Citation(s) in RCA: 218] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 04/22/2013] [Accepted: 04/25/2013] [Indexed: 12/16/2022] Open
Abstract
The human embryonic lethal abnormal vision-like protein, HuR, is a member of the Hu family of RNA-binding proteins. Over the past decade, this ubiquitously expressed protein has been extensively investigated in cancer research because it is involved in the regulation of mRNA stability and translation in many cell types. HuR activity and function is associated with its subcellular distribution, transcriptional regulation, translational and post-translational modifications. HuR regulation of target mRNAs is based on the interaction between the three specific domains of HuR protein and one or several U- or AU-rich elements (AREs) in the untranslated region of target mRNAs. A number of cancer-related transcripts containing AREs, including mRNAs for proto-oncogenes, cytokines, growth factors, and invasion factors, have been characterized as HuR targets. It has been proposed that HuR has a central tumorigenic activity by enabling multiple cancer phenotypes. In this review, we comprehensively survey the existing evidence with regard to the diverse functions of HuR in caner development and progression. The current data also suggest that HuR might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation.
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Affiliation(s)
- Jun Wang
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86-531-5166-5336; Fax: +86-531-5166-6649
| | - Yan Guo
- Department of Outpatient, Military Command of Shandong Province, Jinan 250013, China; E-Mail:
| | - Huili Chu
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Yaping Guan
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Jingwang Bi
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
| | - Baocheng Wang
- Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan 250031, China; E-Mails: (H.C.); (Y.G.); (J.B.); (B.W.)
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Sorting out functions of sirtuins in cancer. Oncogene 2013; 33:1609-20. [PMID: 23604120 DOI: 10.1038/onc.2013.120] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Revised: 02/11/2013] [Accepted: 02/18/2013] [Indexed: 12/21/2022]
Abstract
The sirtuins (SIRT 1-7) comprise a family of NAD⁺-dependent protein-modifying enzymes with activities in lysine deacetylation, adenosinediphospho(ADP)-ribosylation, and/or deacylation. These enzymes are involved in the cell's stress response systems and in regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins have complex roles in both promoting and/or suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional loss of sirtuin genes, particularly SIRT1, involved in maintaining genome integrity and DNA repair will promote tumorigenesis because of genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cell's genome maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions.
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Zhu Z, Wang B, Bi J, Zhang C, Guo Y, Chu H, Liang X, Zhong C, Wang J. Cytoplasmic HuR expression correlates with P-gp, HER-2 positivity, and poor outcome in breast cancer. Tumour Biol 2013; 34:2299-308. [PMID: 23605320 DOI: 10.1007/s13277-013-0774-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 03/25/2013] [Indexed: 12/18/2022] Open
Abstract
HuR is an ubiquitously expressed RNA-binding protein that stabilizes messenger RNA and regulates translation. This protein has been shown to play an important role in carcinogenesis and cancer progression. P-glycoprotein (P-gp) is the product of the multidrug resistance 1 gene, and the overexpression of P-gp induces multidrug resistance and represents a major obstacle in cancer chemotherapy. The purpose of this study was to determine the expression of HuR and P-gp in human breast cancer tissues and analyze the relationship between HuR or P-gp expression and the clinical-pathological variables and patient outcomes. Immunohistochemistry was used to determine HuR and P-gp expression in 82 human breast cancer tissues and 20 matched adjacent noncancerous tissues. Additionally, 16 benign breast tumor samples were used as controls. The overexpression of cytoplasmic HuR was found in breast cancer but not in the matched adjacent noncancerous tissues or benign breast tumors. The expression levels of cytoplasmic HuR were significantly associated with increased age, high nuclear grade, and the positive expression of the ER, PR, and HER-2/neu. HuR was also associated with the expression of P-gp protein. Furthermore, univariate analysis indicates that patients with high expression levels of cytoplasmic HuR or P-gp had significantly reduced survival compared to patients with low expression levels. A multivariate analysis showed that age at diagnosis, nuclear grade, and cytoplasmic HuR positivity were independent indicators for disease-free survival and overall survival in patients with breast cancer. In conclusion, cytoplasmic HuR expression detected by immunohistochemical staining is a negative prognostic indicator for survival in patients with breast cancer.
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Affiliation(s)
- Zhongpeng Zhu
- Department of Oncology, General Hospital, Jinan Command of People's Liberation Army, Shifan Street 25, Tianqiao District, Jinan, 250031, China
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Al-Ahmadi W, Al-Ghamdi M, Al-Souhibani N, Khabar KSA. miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer. J Pathol 2013; 230:28-38. [PMID: 23401122 PMCID: PMC3732382 DOI: 10.1002/path.4178] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Revised: 01/02/2013] [Accepted: 02/04/2013] [Indexed: 12/23/2022]
Abstract
The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that increased stabilization and subsequent over-expression of HuR mRNA were coupled to TTP deficiency. These findings were observed in breast cancer cell lines with an invasive phenotype and were further confirmed in ZFP36-knockout mouse fibroblasts. We show that TTP–HuR imbalance correlated with increased expression of AU-rich element (ARE) mRNAs that code for cancer invasion genes. The microRNA miR-29a was abundant in invasive breast cancer cells when compared to non-tumourigenic cell types. When normal breast cells were treated with miR-29a, HuR mRNA and protein expression were up-regulated. MiR-29a recognized a seed target in the TTP 3′ UTR and a cell-permeable miR-29a inhibitor increased TTP activity towards HuR 3′ UTR. This led to HuR mRNA destabilization and restoration of the aberrant TTP–HuR axis. Subsequently, the cancer invasion factors uPA, MMP-1 and MMP-13, and cell invasiveness, were decreased. The TTP:HuR mRNA ratios were also perturbed in samples from invasive breast cancer patients when compared with normal tissues, and were associated with invasion gene expression. This study demonstrates that an aberrant ARE-mediated pathway in invasive cancer can be normalized by targeting the aberrant and functionally coupled TTP–HuR axis, indicating a potential therapeutic approach. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Wijdan Al-Ahmadi
- Molecular Biomedicine Programme, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Grismayer B, Sölch S, Seubert B, Kirchner T, Schäfer S, Baretton G, Schmitt M, Luther T, Krüger A, Kotzsch M, Magdolen V. Rab31 expression levels modulate tumor-relevant characteristics of breast cancer cells. Mol Cancer 2012; 11:62. [PMID: 22920728 PMCID: PMC3499445 DOI: 10.1186/1476-4598-11-62] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 08/16/2012] [Indexed: 11/12/2022] Open
Abstract
Background Rab proteins constitute a large family of monomeric GTP-binding proteins that regulate intracellular vesicle transport. Several Rab proteins, including rab31, have been shown to affect cancer progression and are related with prognosis in various types of cancer including breast cancer. Recently, the gene encoding rab31 was found to be overexpressed in estrogen receptor-positive breast cancer tissue. In a previous study we found a significant association of high rab31 mRNA expression with poor prognosis in node-negative breast cancer patients. In the present study, we aimed to investigate the impact of rab31 (over)-expression on important aspects of tumor progression in vitro and in vivo. Methods Breast cancer cells displaying low (MDA-MB-231) or no (CAMA-1) endogenous rab31 expression were stably transfected with a rab31 expression plasmid. Batch-transfected cells as well as selected cell clones, expressing different levels of rab31 protein, were analyzed with regard to proliferation, cell adhesion, the invasive capacity of tumor cells, and in vivo in a xenograft tumor model. Polyclonal antibodies directed to recombinantly expressed rab31 were generated and protein expression analyzed by immunohistochemistry, Western blot analysis, and a newly developed sensitive ELISA. Results Elevated rab31 protein levels were associated with enhanced proliferation of breast cancer cells. Interestingly, weak to moderate overexpression of rab31 in cell lines with no detectable endogenous rab31 expression was already sufficient to elicit distinct effects on cell proliferation. By contrast, increased expression of rab31 in breast cancer cells led to reduced adhesion towards several extracellular matrix proteins and decreased invasive capacity through MatrigelTM. Again, the rab31-mediated effects on cell adhesion and invasion were dose-dependent. Finally, in a xenograft mouse model, we observed a significantly impaired metastatic dissemination of rab31 overexpressing MDA-MB-231 breast cancer cells to the lung. Conclusions Overexpression of rab31 in breast cancer cells leads to a switch from an invasive to a proliferative phenotype as indicated by an increased cell proliferation, reduced adhesion and invasion in vitro, and a reduced capacity to form lung metastases in vivo.
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Affiliation(s)
- Bettina Grismayer
- Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Ismaninger Str, 22, Munich 81675, Germany
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Brewster BL, Rossiello F, French JD, Edwards SL, Wong M, Wronski A, Whiley P, Waddell N, Chen X, Bove B, Hopper JL, John EM, Andrulis I, Daly M, Volorio S, Bernard L, Peissel B, Manoukian S, Barile M, Pizzamiglio S, Verderio P, Spurdle AB, Radice P, Godwin AK, Southey MC, Brown MA, Peterlongo P. Identification of fifteen novel germline variants in the BRCA1 3'UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Hum Mutat 2012; 33:1665-75. [PMID: 22753153 DOI: 10.1002/humu.22159] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Accepted: 06/20/2012] [Indexed: 01/05/2023]
Abstract
Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in noncoding and untranslated regions (UTR). As 3'UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3'UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases, and controls. Fifteen novel BRCA1 3'UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.* 528G>C, c.* 718A>G, and c.* 1271T>C and four found in controls, c.* 309T>C, c.* 379G>A, c.* 823C>T, and c.* 264C>T, reduced 3'UTR activity (P < 0.02), whereas two variants found in cases, c.* 291C>T and c.* 1139G>T, increased 3'UTR activity (P < 0.01). Three case variants, c.* 718A>G, c.* 800T>C, and c.* 1340_1342delTGT, were predicted to create new miRNA binding sites and c.* 1340_1342delTGT caused a reduction (25%, P = 0.0007) in 3'UTR reporter activity when coexpressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3'UTR variants published to date.
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Affiliation(s)
- Brooke L Brewster
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia.
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