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Hou X, Chen Y, Carrillo ND, Cryns VL, Anderson RA, Sun J, Wang S, Chen M. Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics. Cell Death Dis 2025; 16:296. [PMID: 40229242 PMCID: PMC11997203 DOI: 10.1038/s41419-025-07616-x] [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: 01/10/2025] [Revised: 03/20/2025] [Accepted: 03/31/2025] [Indexed: 04/16/2025]
Abstract
The cytoskeleton, composed of microfilaments, intermediate filaments, and microtubules, provides the structural basis for cellular functions such as motility and adhesion. Equally crucial, phosphoinositide (PIPn) signaling is a critical regulator of these processes and other biological activities, though its precise impact on cytoskeletal dynamics has yet to be systematically investigated. This review explores the complex interplay between PIPn signaling and the cytoskeleton, detailing how PIPn modulates the dynamics of actin, intermediate filaments, and microtubules to shape cellular behavior. Dysregulation of PIPn signaling is implicated in various diseases, including cancer, highlighting promising therapeutic opportunities through targeted modulation of these pathways. Future research should aim to elucidate the intricate molecular interactions and broader cellular responses to PIPn signaling perturbations, particularly in disease contexts, to devise effective strategies for restoring cytoskeletal integrity.
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Affiliation(s)
- Xiaoting Hou
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yu Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Noah D Carrillo
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Vincent L Cryns
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Richard A Anderson
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Jichao Sun
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, Shenzhen, China
| | - Songlin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
| | - Mo Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
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Smelser W, Kim N, Jahanfard S, Sarno M, Chang SS, Giannico GA. Validation of Keratin 17 as a tissue biomarker in the diagnosis of upper tract urothelial carcinoma. Hum Pathol 2024; 154:105682. [PMID: 39549749 DOI: 10.1016/j.humpath.2024.105682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/04/2024] [Accepted: 11/11/2024] [Indexed: 11/18/2024]
Abstract
Upper tract urothelial carcinoma (UTUC) has a relatively low incidence but presents significant surveillance and treatment challenges. Therefore, novel biomarkers for the accurate detection of upper tract urothelial tumors are urgently needed. We evaluated the expression of Keratin 17 (KRT17), an oncoprotein implicated in the cell cycle progression of multiple human cancers and previously studied in bladder urothelial carcinoma, by immunohistochemistry in 139 UTUC cases, including noninvasive, invasive papillary urothelial carcinoma and urothelial carcinoma in situ. KRT17 expression pattern (basal/negative vs. nonbasal) and H-score were evaluated. The expression pattern was significantly different in normal (NL) compared to malignant urothelium. Nonbasal KRT17 expression was significantly higher in pTa (p < 0.001) and invasive (pTinv) (p = 0.0023) urothelial carcinoma compared to NL, and in pTinv compared to pTa (p = 0.0391). Sensitivity and specificity for distinguishing benign from malignant tumors were 85% and 82, respectively, with an area under the curve of 0.83 (p < 0.001). The KRT17 H-score was significantly higher in pTa and pTinv compared to NL (p < 0.001 and p = 0.0035, respectively). Sensitivity and specificity for distinguishing benign from malignant carcinoma were 91% and 69%, respectively, with an AUC of 0.81 (p = 0.0010). KRT17 was not associated with tumor site, grade, or stage. In summary, K17 is a sensitive and specific marker of neoplastic upper tract urothelium, and its potential use in routine diagnostics should be explored in larger studies.
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Affiliation(s)
- Woodson Smelser
- Division of Urology, Washington University in St. Louis, MO, USA
| | - Nam Kim
- KDx Diagnostics Inc, Campbell, CA, USA
| | | | - Mark Sarno
- Vision Clinical Research, LLC, San Marcos, CA, USA
| | - Sam S Chang
- Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Giovanna A Giannico
- Department of Pathology, University of California Irvine Medical Center, 101 The City Dr. South, Orange, 92868, CA, USA.
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3
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Tang J, Huang X. Transcriptome analysis of human dental pulp cells cultured on a novel cell-adhesive fragment by RNA sequencing. Gene 2024; 927:148709. [PMID: 38901533 DOI: 10.1016/j.gene.2024.148709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/09/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
AIM The aim of the present work was to find an efficient method for safe and reliable expansion of human dental pulp cells (hDPCs) in vitro. Here, we examined the effect of a novel recombinant E8 fragment of Laminin-511 (iMatrix-511) in hDPCs regarding viability and cell spreading. Further, we investigated the underlying mechanisms governing its effects in hDPCs using RNA sequencing (RNA-seq). METHODOLOGY hDPCs were obtained from caries-free maxilla third molars (n = 3). CCK-8 assay was conducted to measure the viability of cells cultured on iMatrix-511 and two other ECM proteins. Cell morphology was observed by phase contrast microscope. RNA-seq of hDPCs cultured on iMatrix-511 or noncoated control was performed on Illumina NovaseqTM 6000 platform. RESULTS iMatrix-511 (0.5 μg/cm2) enhanced the viability of hDPCs to an extent better than COL-1 and gelatin. Short term culture of hDPCs on iMatrix-511 resulted in 233 differentially expressed genes (DEGs). The top 12 most upregulated genes were XIAP, AL354740, MRFAP1, AC012321, KCND3, TMEM120B, AC009812, GET1-SH3BGR, CNTN3, AC090409, GEN1 and PIK3IP1, whereas the top 12 most downregulated genes were SFN, KRT17, RAB4B-EGLN2, CSTA, KCTD11, ATP6V1G2-DDX39B, AC010323, SBSN, LYPD3, FOSB, AC022400 and CHI3L1. qPCR validation confirmed the significant upregulation of GEN1, KCND3, PIK3IP1 and MRFAP1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, with genes enriched in various extracellular matrix interaction, estrogen and fat metabolism-related functions and pathways. CONCLUSIONS iMatrix-511 facilitated spreading and proliferation of hDPCs. It enhances expression of anti-apoptotic genes, while inhibits expression of epidermis development-related genes.
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Affiliation(s)
- Jia Tang
- School and Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, PR China
| | - Xiaofeng Huang
- Department of Stomatology, Huashan Hospital, Fudan University, Shanghai 200040, PR China.
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Khaleel AQ, Alshahrani MY, Rizaev JA, Malathi H, Devi S, Pramanik A, Mustafa YF, Hjazi A, Muazzamxon I, Husseen B. siRNA-based strategies to combat drug resistance in gastric cancer. Med Oncol 2024; 41:293. [PMID: 39428440 DOI: 10.1007/s12032-024-02528-w] [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: 08/17/2024] [Accepted: 09/27/2024] [Indexed: 10/22/2024]
Abstract
Chemotherapy is a key treatment option for gastric cancer, but over 50% of patients develop either inherent or acquired resistance to these drugs, resulting in a 5-year survival rate of only about 20%. The primary treatment for advanced gastric cancer typically involves chemotherapy based on platinum or fluorouracil. Several factors can contribute to platinum resistance, including decreased drug uptake, increased drug efflux or metabolism, enhanced DNA repair, activation of pro-survival pathways, and inhibition of pro-apoptotic pathways. In recent years, there has been significant progress in biology aimed at finding innovative and more effective methods to overcome chemotherapy resistance. Small interfering RNAs (siRNAs) have emerged as a significant advancement in gene expression regulation, showing promise in enhancing the sensitivity of gastric cancer cells to chemotherapy drugs. However, siRNA therapies still face major challenges, particularly in terms of stability and efficient delivery in vivo. This article discusses the advances in siRNA therapy and its potential role in overcoming resistance to chemotherapeutic drugs such as cisplatin, 5-FU, doxorubicin, and paclitaxel in the treatment of gastric cancer.
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Affiliation(s)
- Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, College of Engineering, University of Al Maarif, Ramadi, Al Anbar, 31001, Iraq.
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan.
| | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences Jain (Deemed to be University), Bangalore, Karnataka, India
| | - Seema Devi
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali, 140307, Punjab, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Ismoilova Muazzamxon
- Department of Propaedeutics of Internal Diseases, Fergana Medical Institute of Public Health, Fergana, Uzbekistan
- Western Caspian University, Scientific Researcher, Baku, Azerbaijan
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Liu J, Yuan Q, Chen X, Yang Y, Xie T, Zhang Y, Qi B, Li S, Shang D. Prognostic and therapeutic value of the Eph/Ephrin signaling pathway in pancreatic cancer explored based on bioinformatics. Sci Rep 2024; 14:17650. [PMID: 39085301 PMCID: PMC11291735 DOI: 10.1038/s41598-024-68385-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024] Open
Abstract
Pancreatic cancer (PC) is one of the most common malignant tumors of the digestive tract and has a very high mortality rate worldwide. Different PC patients may respond differently to therapy and develop therapeutic resistance due to the complexity and variety of the tumor microenvironment. The Eph/ephrin signaling pathway is extensively involved in tumor-related biological functions. However, the key function of the Eph/ephrin signaling pathway in PC has not been fully elucidated. We first explored a pan-cancer overview of Eph/ephrin signaling pathway genes (EPGs). Then we grouped the PC patients into 3 subgroups based on EPG expression levels. Significantly different prognoses and tumor immune microenvironments between different subtypes further validate Eph/ephrin's important role in the pathophysiology of PC. Additionally, we estimated the IC50 values for several commonly used molecularly targeted drugs used to treat PC in the three clusters, which could help patients receive a more personalized treatment plan. Following a progressive screening of optimal genes, we established a prognostic signature and validated it in internal and external test sets. The receiver operating characteristic (ROC) curves of our model exhibited great predictive performance. Meanwhile, we further validated the results through qRT-PCR and immunohistochemistry. Overall, this research provides fresh clues on the prognosis and therapy of PC as well as the theoretical groundwork for future Eph/ephrin signaling pathway research.
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Affiliation(s)
- Jifeng Liu
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qihang Yuan
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xu Chen
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yao Yang
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Tong Xie
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Yunshu Zhang
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Bing Qi
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Shuang Li
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Dong Shang
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
- Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China.
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Chen X, Sun H, Yang C, Wang W, Lyu W, Zou K, Zhang F, Dai Z, He X, Dong H. Bioinformatic analysis and experimental validation of six cuproptosis-associated genes as a prognostic signature of breast cancer. PeerJ 2024; 12:e17419. [PMID: 38912044 PMCID: PMC11192027 DOI: 10.7717/peerj.17419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 04/28/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Breast carcinoma (BRCA) is a life-threatening malignancy in women and shows a poor prognosis. Cuproptosis is a novel mode of cell death but its relationship with BRCA is unclear. This study attempted to develop a cuproptosis-relevant prognostic gene signature for BRCA. METHODS Cuproptosis-relevant subtypes of BRCA were obtained by consensus clustering. Differential expression analysis was implemented using the 'limma' package. Univariate Cox and multivariate Cox analyses were performed to determine a cuproptosis-relevant prognostic gene signature. The signature was constructed and validated in distinct datasets. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were also conducted using the prognostic signature to uncover the underlying molecular mechanisms. ESTIMATE and CIBERSORT algorithms were applied to probe the linkage between the gene signature and tumor microenvironment (TME). Immunotherapy responsiveness was assessed using the Tumor Immune Dysfunction and Exclusion (TIDE) web tool. Real-time quantitative PCR (RT-qPCR) was performed to detect the expressions of cuproptosis-relevant prognostic genes in breast cancer cell lines. RESULTS Thirty-eight cuproptosis-associated differentially expressed genes (DEGs) in BRCA were mined by consensus clustering and differential expression analysis. Based on univariate Cox and multivariate Cox analyses, six cuproptosis-relevant prognostic genes, namely SAA1, KRT17, VAV3, IGHG1, TFF1, and CLEC3A, were mined to establish a corresponding signature. The signature was validated using external validation sets. GSVA and GSEA showed that multiple cell cycle-linked and immune-related pathways along with biological processes were associated with the signature. The results ESTIMATE and CIBERSORT analyses revealed significantly different TMEs between the two Cusig score subgroups. Finally, RT-qPCR analysis of cell lines further confirmed the expressional trends of SAA1, KRT17, IGHG1, and CLEC3A. CONCLUSION Taken together, we constructed a signature for projecting the overall survival of BRCA patients and our findings authenticated the cuproptosis-relevant prognostic genes, which are expected to provide a basis for developing prognostic molecular biomarkers and an in-depth understanding of the relationship between cuproptosis and BRCA.
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Affiliation(s)
- Xiang Chen
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Hening Sun
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Changcheng Yang
- Department of The First Affiliated Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Wei Wang
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Wenzhi Lyu
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Kejian Zou
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Fan Zhang
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Zhijun Dai
- Department of The First Affiliated Hospital, Zhejiang University, Hangzhou City, Zhejiang Province, China
| | - Xionghui He
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
| | - Huaying Dong
- Department of Hainan General Hospital, Hainan Medical College, Haikou City, Hainan Province, China
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Salman DM, Mohammad TAM. siRNA-based therapy for gastric adenocarcinoma: what's next step? Pathol Res Pract 2024; 258:155328. [PMID: 38744002 DOI: 10.1016/j.prp.2024.155328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/16/2024]
Abstract
Gastric cancer continues to have a high death rate despite advancements in their diagnosis and treatment. Novel treatment techniques are thus desperately needed. This is where double-stranded RNA molecules known as small interfering RNA (siRNA), which may selectively target the mRNA of disease-causing genes, may find use in medicine. For siRNAs to function properly in the human body, they must be shielded from deterioration. Furthermore, in order to maintain organ function, they must only target the tumor and spare normal tissue. siRNAs have been designed using clever delivery mechanisms including polymers and lipids to achieve these objectives. Although siRNA protection is not hard to acquire, it is still challenging to target cancer cells with them. Here, we first discuss the basic characteristics of gastric cancer before describing the properties of siRNA and typical delivery methods created specifically for gastric tumors. Lastly, we provide a succinct overview of research using siRNAs to treat gastric tumors.
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Affiliation(s)
- Dyar Mudhafar Salman
- Department of Clinical Pharmacy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq; Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Talar Ahmad Merza Mohammad
- Department of Clinical Pharmacy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq; Pharmacy department, School of Medicine, University of Kurdistan Hewlêr (UKH), Erbil, Kurdistan Region, Iraq.
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Hashemi M, Aparviz R, Beickzade M, Paskeh MDA, Kheirabad SK, Koohpar ZK, Moravej A, Dehghani H, Saebfar H, Zandieh MA, Salimimoghadam S, Rashidi M, Taheriazam A, Entezari M, Samarghandian S. Advances in RNAi therapies for gastric cancer: Targeting drug resistance and nanoscale delivery. Biomed Pharmacother 2023; 169:115927. [PMID: 38006616 DOI: 10.1016/j.biopha.2023.115927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023] Open
Abstract
Gastric cancer poses a significant health challenge, and exploring innovative therapeutic strategies is imperative. RNA interference (RNAi) has employed as an important therapeutic strategy for diseases by selectively targeting key pathways involved in diseases pathogenesis. Small interfering RNA (siRNA), a potent RNAi tool, possesses the capability to silence genes and downregulate their expression. This review provides a comprehensive examination of the potential applications of small interfering RNA (siRNA) and short hairpin RNA (shRNA), supplemented by an in-depth analysis of nanoscale delivery systems, in the context of gastric cancer treatment. The potential of siRNA to markedly diminish the proliferation and invasion of gastric cancer cells through the modulation of critical molecular pathways, including PI3K, Akt, and EMT, is highlighted. Besides, siRNA demonstrates its efficacy in inducing chemosensitivity in gastric tumor cells, thus impeding tumor progression. However, the translational potential of unmodified siRNA faces challenges, particularly in vivo and during clinical trials. To address this, we underscore the pivotal role of nanostructures in facilitating the delivery of siRNA to gastric cancer cells, effectively suppressing their progression and enhancing gene silencing efficiency. These siRNA-loaded nanoparticles exhibit robust internalization into gastric cancer cells, showcasing their potential to significantly reduce tumor progression. The translation of these findings into clinical trials holds promise for advancing the treatment of gastric cancer patients.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Rezvaneh Aparviz
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marzie Beickzade
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Simin Khorsand Kheirabad
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Cell and Molecular Biology, Faculty of Biological Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Amir Moravej
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hossein Dehghani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Medical Laboratory Sciences, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran
| | - Hamidreza Saebfar
- European University Association, League of European Research Universities, University of Milan, Italy
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Saeed Samarghandian
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Chen X, Yuan Q, Guan H, Shi X, Sun J, Wu Z, Ren J, Xia S, Shang D. Identification and characterization of interferon-γ signaling-based personalized heterogeneity and therapeutic strategies in patients with pancreatic cancer. Front Oncol 2023; 13:1227606. [PMID: 37941546 PMCID: PMC10628740 DOI: 10.3389/fonc.2023.1227606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/03/2023] [Indexed: 11/10/2023] Open
Abstract
Background Interferon-γ (IFN-γ) is a key cytokine with diverse biological functions, including antiviral defense, antitumor activity, immune regulation, and modulation of cellular processes. Nonetheless, its role in pancreatic cancer (PC) therapy remains debated. Therefore, it is worthwhile to explore the role of Interferon-γ related genes (IFN-γGs) in the progression of PC development. Methodology Transcriptomic data from 930 PC were sourced from TCGA, GEO, ICGC, and ArrayExpress, and 93 IFN-γGs were obtained from the MSigDB. We researched the characteristics of IFN-γGs in pan-cancer. Subsequently, the cohort of 930 PC was stratified into two distinct subgroups using the NMF algorithm. We then examined disparities in the activation of cancer-associated pathways within these subpopulations through GSVA analysis. We scrutinized immune infiltration in both subsets and probed classical molecular target drug sensitivity variations. Finally, we devised and validated a novel IFN-γ related prediction model using LASSO and Cox regression analyses. Furthermore, we conducted RT-qPCR and immunohistochemistry assays to validate the expression of seven target genes included in the prediction model. Results We demonstrated the CNV, SNV, methylation, expression levels, and prognostic characteristics of IFN-γGs in pan-cancers. Notably, Cluster 2 demonstrated superior prognostic outcomes and heightened immune cell infiltration compared to Clusters 1. We also assessed the IC50 values of classical molecular targeted drugs to establish links between IFN-γGs expression levels and drug responsiveness. Additionally, by applying our prediction model, we segregated PC patients into high-risk and low-risk groups, identifying potential benefits of cisplatin, docetaxel, pazopanib, midostaurin, epothilone.B, thapsigargin, bryostatin.1, and AICAR for high-risk PC patients, and metformin, roscovitine, salubrinal, and cyclopamine for those in the low-risk group. The expression levels of these model genes were further verified through HPA website data and qRT-PCR assays in PC cell lines and tissues. Conclusion This study unveils IFN-γGs related molecular subsets in pancreatic cancer for the first time, shedding light on the pivotal role of IFN-γGs in the progression of PC. Furthermore, we establish an IFN-γGs related prognostic model for predicting the survival of PC, offering a theoretical foundation for exploring the precise mechanisms of IFN-γGs in PC.
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Affiliation(s)
- Xu Chen
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qihang Yuan
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hewen Guan
- Department of Dermatology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xueying Shi
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jiaao Sun
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zhiqiang Wu
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jie Ren
- Department of Oncology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Shilin Xia
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Dong Shang
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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10
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Wu L, Ding W, Wang X, Li X, Yang J. Interference KRT17 reverses doxorubicin resistance in triple-negative breast cancer cells by Wnt/β-catenin signaling pathway. Genes Genomics 2023; 45:1329-1338. [PMID: 37634232 PMCID: PMC10504156 DOI: 10.1007/s13258-023-01437-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/02/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the highest degree of malignancy and is easily resistant to drugs due to the lack of hormone receptors. Research on the resistance mechanisms in TNBC is particularly important. Keratin 17 (KRT17) is highly expressed in TNBC. Anthracycline doxorubicin (Dox) is a commonly used chemotherapeutic drug for early stage triple-negative breast cancer. OBJECTIVE This study investigated the role of KRT17 in TNBC-Dox resistance. METHODS Immuno-histochemical staining, qPCR, western blotting (WB), and immunofluorescence were used to detect the expression of KRT17 in TNBC-Dox-resistant patients and in TNBC-Dox-resistant MDA-MB-468 and MDA-MB-231. the effect of KRT17 on the proliferation and migration in KRT17 knockdown of TNBC-Dox-resistant cells was determined by the CCK8, clone formation, transwell invasion and wound healing assays were used to determine. RESULTS KRT17 was highly expressed in the TNBC-Dox-resistant cells. Knockdown of KRT17 significantly reduced the IC50s of TNBC-Dox-resistant and parental strains and also reduced the proliferation and invasion abilities of TNBC-Dox-resistant cell lines. KRT17 regulated the Wnt/β-catenin signaling pathway. The inhibitory effect of KRT17 knockdown on the proliferation and migration of TNBC-Dox-resistant cells was reversed by an activator of the Wnt signaling pathway. CONCLUSION KRT17 can inhibit the Wnt/β-catenin signaling pathway, thereby reducing the proliferation and invasion ability of TNBC-Dox-resistant cells.
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Affiliation(s)
- Liqiong Wu
- Department of Pathology, Guangzhou First People's Hospital, 51080, Guangzhou, R.P. China
- The Second Affiliated Hospital of South, China University of Technology, 51080, Guangzhou, R.P. China
| | - Wenshuang Ding
- Department of Pathology, Guangzhou First People's Hospital, 51080, Guangzhou, R.P. China
- The Second Affiliated Hospital of South, China University of Technology, 51080, Guangzhou, R.P. China
| | - Xiaopai Wang
- Department of Pathology, Guangzhou First People's Hospital, 51080, Guangzhou, R.P. China
- The Second Affiliated Hospital of South, China University of Technology, 51080, Guangzhou, R.P. China
| | - Xiubo Li
- Department of Pathology, Guangzhou First People's Hospital, 51080, Guangzhou, R.P. China
- The Second Affiliated Hospital of South, China University of Technology, 51080, Guangzhou, R.P. China
| | - Jing Yang
- Department of Pathology, Guangzhou First People's Hospital, 51080, Guangzhou, R.P. China.
- The Second Affiliated Hospital of South, China University of Technology, 51080, Guangzhou, R.P. China.
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11
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Meng F, Dai L. Transcription factors TP63 facilitates malignant progression of thyroid cancer by upregulating KRT17 expression and inducing epithelial-mesenchymal transition. Growth Factors 2023; 41:71-81. [PMID: 36919456 DOI: 10.1080/08977194.2023.2184656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 02/10/2023] [Indexed: 03/16/2023]
Abstract
Thyroid cancer (TC) is a relatively prevalent endocrine tumor among women, the incidence of which is rapidly rising. In this present study, we aimed to provide new therapeutic targets from the aspect of transcription factor-target gene interaction. TP63 and KRT17 were both highly expressed in TC tissues and cells. The results of ChIP and dual-luciferase assays confirmed TP63 to bind the KRT17 promoter. Cell function assays revealed that knockdown of TP63 could repress TC cell progression. Furthermore, the rescue assay verified that TP63 could facilitate KRT17 expression to activate the AKT signaling pathway, which in turn stimulated TC cell invasion and migration, and induced EMT. All these results verified that TP63 facilitates TC malignant progression by promoting KRT17 expression and inducing EMT.
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Affiliation(s)
- Fanbo Meng
- Department of Breast and Thyroid Surgery, the Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Liting Dai
- Medical Examination Center, the Affiliated Hospital of Shaoxing University, Shaoxing, China
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12
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Wu X, Ma Y, Wang L, Qin X. A Route for Investigating Psoriasis: From the Perspective of the Pathological Mechanisms and Therapeutic Strategies of Cancer. Int J Mol Sci 2023; 24:14390. [PMID: 37762693 PMCID: PMC10532365 DOI: 10.3390/ijms241814390] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
Psoriasis is an incurable skin disease that develops in about two-thirds of patients before the age of 40 and requires lifelong treatment; its pathological mechanisms have not been fully elucidated. The core pathological process of psoriasis is epidermal thickening caused by the excessive proliferation of epidermal keratinocytes, which is similar to the key feature of cancer; the malignant proliferation of cancer cells causes tumor enlargement, suggesting that there is a certain degree of commonality between psoriasis and cancer. This article reviews the pathological mechanisms that are common to psoriasis and cancer, including the interaction between cell proliferation and an abnormal immune microenvironment, metabolic reprogramming, and epigenetic reprogramming. In addition, there are common therapeutic agents and drug targets between psoriasis and cancer. Thus, psoriasis and cancer share a common pathological mechanisms-drug targets-therapeutic agents framework. On this basis, it is proposed that investigating psoriasis from a cancer perspective is beneficial to enriching the research strategies related to psoriasis.
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Affiliation(s)
- Xingkang Wu
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, China; (Y.M.); (L.W.)
| | | | | | - Xuemei Qin
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, China; (Y.M.); (L.W.)
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13
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Wang JL, Zhang L, Xu CZ, Qin XQ, Liu SJ, Wen BJ, Ren HZ. KRT17 serves as an oncogene biomarker of poor survival in patients with hepatocellular carcinoma. BIOMEDICAL TECHNOLOGY 2023; 3:18-25. [DOI: 10.1016/j.bmt.2022.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
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14
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Nian F, Zhu C, Jin N, Xia Q, Wu L, Lu X. Gut microbiota metabolite TMAO promoted lipid deposition and fibrosis process via KRT17 in fatty liver cells in vitro. Biochem Biophys Res Commun 2023; 669:134-142. [PMID: 37271025 DOI: 10.1016/j.bbrc.2023.05.041] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 06/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide but still lacks specific treatment modalities. The gut microbiota and its metabolites have been shown to be intimately involved in NAFLD development, participating in and regulating disease progression. Trimethylamine N-oxide (TMAO), a metabolite highly dependent on the gut microbiota, has been shown to play deleterious regulatory roles in cardiovascular disease, but the relationship between it and NAFLD lacks validation from basic experiments. This research applied TMAO intervention by constructing fatty liver cell models in vitro to observe its effect on fatty liver cells and potential key genes and performed siRNA interference on the gene to verify the action. The results showed that TMAO intervention promoted the appearance of more red-stained lipid droplets in Oil-red O staining results, increased triglyceride (TG) levels and increased mRNA levels of liver fibrosis-related genes, and also identified one of the key genes, keratin17 (KRT17) via transcriptomics. Following the reduction in its expression level, under the same treatment, there were decreased red-stained lipid droplets, decreased TG levels, decreased indicators of impaired liver function as well as decreased mRNA levels of liver fibrosis-related genes. In conclusion, the gut microbiota metabolite TMAO could promote lipid deposition and fibrosis process via the KRT17 gene in fatty liver cells in vitro.
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Affiliation(s)
- Fulin Nian
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Chen Zhu
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Nuyun Jin
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Qiaoyun Xia
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Longyun Wu
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China
| | - Xiaolan Lu
- Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
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KRT17 Accelerates Cell Proliferative and Invasive Potential of Laryngeal Squamous Cell Carcinoma (LSCC) through Regulating AKT/mTOR and Wnt/ β-Catenin Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6176043. [PMID: 36248412 PMCID: PMC9556256 DOI: 10.1155/2022/6176043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/11/2022] [Accepted: 08/24/2022] [Indexed: 11/19/2022]
Abstract
Background Laryngeal squamous cell carcinoma (LSCC) is a prevalent malignant tumor of the head and neck with a dismal prognosis. Keratin17 (KRT17) has been proven to serve as an oncogene in various cancers, but it has never been explored in LSCC. We proposed to assess the impact and possible mechanisms of KRT17 in the development of LSCC. Methods Quantitative reverse transcription-PCR (qRT-PCR) was utilized to examine the mRNA levels. The Kaplan-Meier method was used to calculate the relationship between KRT17 expression and survival curves in LSCC patients. Cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays were utilized to estimate LSCC cell proliferation. The migration and invasion abilities of LSCC cells were ascertained by wound-healing and transwell assays. Immunohistochemical and western blot assays were utilized to appraise protein levels. The xenograft tumor model was used to determine the effect of KRT17 on tumor growth. Results In the present study, KRT17 was extremely high in LSCC tissues and cells and correlated with a poor prognosis. Inhibition of KRT17 weakens cell proliferative, migratory, and invasive abilities in LSCC and contributes to cell cycle arrest. Besides, we approved that knockdown of KRT17 extraordinarily restrained the xenograft tumor growth in vivo. We preliminarily investigated the role of KRT17 on the AKT/mTOR and Wnt/β-catenin signaling axes and found that these signaling pathways were largely blocked by KRT17 deletion. Conclusion Collectively, we uncovered that exhaustion of KRT17 suppresses LSCC progression through coordinating AKT/mTOR and Wnt/β-catenin signaling axes, illustrating KRT17 as a promising biomarker for making strides in LSCC treatment.
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Tang S, Liu W, Yong L, Liu D, Lin X, Huang Y, Wang H, Cai F. Reduced Expression of KRT17 Predicts Poor Prognosis in HER2high Breast Cancer. Biomolecules 2022; 12:biom12091183. [PMID: 36139022 PMCID: PMC9496156 DOI: 10.3390/biom12091183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer (BC) is one of the most common types of malignancies in women and greatly threatens female health. KRT17 is a member of the keratin (KRT) protein family that is abundant in the outer layer of the skin, where it protects epithelial cells from damage. Although KRT17 has been studied in many types of cancer, the expression of KRT17 in specific subtypes of BC remains to be determined. In our study, we explored the expression and prognostic implications of KRT17 in BC patients using mRNA transcriptome data and clinical BC data from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curves and the chi-square test were used to assess the diagnostic value of KRT17 expression. Quantitative real-time PCR (qRT−PCR) analysis of BC cells and tissues and immunohistochemistry (IHC) analysis of clinical tissues were used for external validation. Furthermore, the relationship between KRT17 and immune function was studied by using the CIBERSORT algorithm to predict the proportions of tumor-infiltrating immune cells (TIICs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the potential mechanisms by which KRT17 expression influences patient survival. We found that KRT17 expression was significantly lower in BC tissues than in normal tissues, especially in the luminal-A, luminal-B and human epidermal growth factor receptor-2 (HER2)+ subtypes of BC. ROC analysis revealed that KRT17 expression had moderate diagnostic value. Interestingly, decreased expression of KRT17 was significantly correlated with poor prognosis in BC patients, especially in HER2high and ERhigh patients. This trend was also verified by tissue microarray (TMA) analysis. KRT17 was found to be involved in some antitumor immune pathways, especially the IL-17 signaling pathway, and associated with multiple immune cells, such as natural killer (NK) and CD4+ T cells. In conclusion, high expression of KRT17 predicted favorable prognosis in BC patients with higher HER2 expression. This result may indicate that KRT17 plays a different role depending on the level of HER2 expression and could serve as a promising and sensitive biomarker for the diagnosis and prognostication of HER2high BC.
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Affiliation(s)
- Shasha Tang
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, No.450 Tengyue Road, Shanghai 200090, China
| | - Wenjing Liu
- Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 201100, China
| | - Liyun Yong
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, No.450 Tengyue Road, Shanghai 200090, China
| | - Dongyang Liu
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, No.450 Tengyue Road, Shanghai 200090, China
| | - Xiaoyan Lin
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, No.450 Tengyue Road, Shanghai 200090, China
| | - Yuan Huang
- Cellomics International Limited, Hong Kong, China
| | - Hui Wang
- Laboratory of Tumor Molecular Biology, School of Basic Medical Sciences, Shanghai University of Medicine and Health Sciences, No.279 Zhouzhu Highway, Shanghai 201318, China
- Correspondence: (H.W.); (F.C.)
| | - Fengfeng Cai
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, No.450 Tengyue Road, Shanghai 200090, China
- Correspondence: (H.W.); (F.C.)
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Duan C, Townley H. Exploitation of High Tumour GSH Levels for Targeted siRNA Delivery in Rhabdomyosarcoma Cells. Biomolecules 2022; 12:biom12081129. [PMID: 36009022 PMCID: PMC9405954 DOI: 10.3390/biom12081129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/09/2022] [Accepted: 08/15/2022] [Indexed: 11/16/2022] Open
Abstract
Metastatic alveolar rhabdomyosarcoma (aRMS) is an aggressive paediatric cancer with a poor prognosis. Downregulation of critical tumour genes using targeted siRNA remains an obstacle, but association with nanoparticles could help to deliver, protect, target, and enhance penetration. siRNA towards two genes was investigated: (i) Human αB-crystallin (CRYAB) and Heat Shock Protein Family B (Small) Member 2 (HSPB2), and (ii) Keratin 17 (KRT17). A mesoporous silica based nanosystem was linked to siRNA via disulfide bonds and loaded with IR820 dye. Transfection efficiency and signalling was evaluated, and the metabolic effects and cell proliferation were monitored in 2D culture and 3D spheroid models. The bound siRNA was protected from degradation with RNase I for at least 24 h. The delivered siRNA showed significant suppression of viability; 53.21 ± 23.40% for CRYAB and HSPB2 siRNA, and 88.06 ± 17.28% for KRT17 siRNA. After 72 h this increased to >50% cell apoptosis and necrosis. Intracellular total glutathione (GSH) levels were also compared with fibroblasts, and the RMS cell lines showed a several-fold increase. IR820 cellular uptake rate and penetration depth was significantly improved by nanoparticle delivery. Targetted siRNA delivery may pave the way for less invasive and more effective treatments of aRMS.
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Affiliation(s)
- Chengchen Duan
- Nuffield Department of Women’s and Reproductive Health, Oxford University John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
| | - Helen Townley
- Nuffield Department of Women’s and Reproductive Health, Oxford University John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
- Department of Engineering Science, Oxford University, Parks Road, Oxford OX1 3PJ, UK
- Correspondence: ; Tel.: +44-1865-283792
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Zhang H, Zhang Y, Feng Z, Lu L, Li Y, Liu Y, Chen Y. Analysis of the Expression and Role of Keratin 17 in Human Tumors. Front Genet 2022; 13:801698. [PMID: 35646078 PMCID: PMC9133940 DOI: 10.3389/fgene.2022.801698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 03/25/2022] [Indexed: 11/25/2022] Open
Abstract
Objective: We aimed to explore the expression and carcinogenic effect of KRT17 in human tumors and provide useful information for the study of KRT17. Methods: We used databases including the Cancer Genome Atlas, Gene Expression Omnibus, GTEx, and GEPIA2 to analyze the expression, mutation, and prognosis of KRT17 in human tumors. Through webservers, including UALCAN, TIMER2.0, and STRING, we learned about the genetic variation, immune cell penetration, and enrichment analysis of KRT17-related genes. Results: KRT17 was highly expressed in most tumors (such as esophageal cancer, lung cancer, cervical cancer, etc.), and the high expression level correlated with tumor stage and prognosis. In addition, amplification was the main type of KRT17 tumor variation, with an amplification rate of about 9%, followed by mutation, with a mutation rate of 4%. Moreover, KRT17 was strongly associated with tumor-infiltrating immune cells (such as macrophages, CD8+T, Tregs, and cancer-associated fibroblasts). KEGG analysis suggested that KRT17 may play a role in tumor pathogenesis following human papillomavirus infection, and the gene ontology enrichment analysis indicated that the carcinogenicity of KRT17 can be attributed to cadherin binding, intermediate fibrocytoskeleton and epidermal development. Conclusion: KRT17 may play an important role in the occurrence, development, and prognosis of malignant tumors. We provided a relatively comprehensive description of the carcinogenic role of KRT17 in different tumors for the first time.
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Affiliation(s)
- Hanqun Zhang
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yun Zhang
- Department of Pathology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Zhiyu Feng
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Liang Lu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yong Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yanping Chen
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
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Chen J, Ge SJ, Feng HJ, Wu SZ, Ji R, Huang WR, Huang W, Lu CH. KRT17 Promotes the Activation of HSCs via EMT in Liver Fibrosis. J Clin Transl Hepatol 2022; 10:207-218. [PMID: 35528988 PMCID: PMC9039702 DOI: 10.14218/jcth.2021.00101] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/19/2021] [Accepted: 06/06/2021] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Although activation of hepatic stellate cells (HSCs) plays a central role in the development of liver fibrosis, the mechanism underlying the activation of HSCs remains unclear. Keratin 17 (KRT17), a member of the intermediate filament family, can regulate tumor cell proliferation and migration. The current study aimed to elucidate the role of KRT17 in the activation of HSCs and the mechanisms underlying liver fibrosis. METHODS The expression of KRT17 was determined using immunohistochemistry in tissue microarray. Western blotting and qRT-PCR assays were used to determine the KRT17 expression in fibrotic liver tissues obtained from human subjects and mice. LX-2 cells were treated with TGF-β1 recombinant protein and adipocyte differentiation mixture (MDI) mix to induce and reverse LX-2 cell activation, respectively, in order to explore the correlation between KRT17 and HSC activation. Additionally, cell proliferation and migration abilities of LX-2 cells transfected with KRT17-overexpressing plasmid or small interfering RNA were determined using CCK-8, flow cytometry, Transwell, and wound healing assays. Finally, rescue assay was used to explore the role of KRT17 in HSC activation and epithelial-mesenchymal transition (EMT). RESULTS The expression of KRT17 was higher in the human and mouse fibrotic liver tissues than in healthy liver tissues, and it was positively correlated with HSC activation. Upregulated KRT17 enhanced proliferation, migration, HSC activation and EMT in LX-2 cells, while knockdown of KRT17 reversed these effects. TGF-β1 recombinant protein accelerated KRT17-mediated EMT, HSC activation and proliferation, while TGF-β1 inhibitor counteracted the effect of KRT17 in vitro. CONCLUSIONS KRT17 promoted HSC activation, proliferation and EMT in hepatic fibrosis probably via TGF-β1 signaling, and KRT17 might serve as a therapeutic target for the treatment of liver fibrosis.
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Affiliation(s)
- Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Si-Jia Ge
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Hai-Juan Feng
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Shu-Zhen Wu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Ran Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei-Rong Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Correspondence to: Wei Huang and Cui-Hua Lu, Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China. ORCID: https://orcid.org/0000-0001-8471-530X (WH), https://orcid.org/0000-0002-1377-5820 (CHL). Tel: +86-13962991839 (WH), +86-13962801685 (CHL), Fax: +86-513-8116-1826, E-mail: (WH), (CHL)
| | - Cui-Hua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Correspondence to: Wei Huang and Cui-Hua Lu, Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China. ORCID: https://orcid.org/0000-0001-8471-530X (WH), https://orcid.org/0000-0002-1377-5820 (CHL). Tel: +86-13962991839 (WH), +86-13962801685 (CHL), Fax: +86-513-8116-1826, E-mail: (WH), (CHL)
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El-Masry OS, Alshwareb AA, Alnasser FH, al mishaal SG, Alsamman KM. Whole-transcriptome bioinformatics revealed HTRA3, KRT8, KRT17, and RHEX as novel targets in acute myeloid leukaemia. J Taibah Univ Med Sci 2022; 17:897-903. [PMID: 36050959 PMCID: PMC9396045 DOI: 10.1016/j.jtumed.2021.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/15/2021] [Accepted: 12/13/2021] [Indexed: 12/08/2022] Open
Abstract
Acute myeloid leukaemia (AML) is characterised by heterogeneous genomic signatures that vary among different patient groups. Hence, the current study aims to conduct a whole transcriptome analysis of a female patient with AML and a family history of the disease at the time of diagnosis. Genetic profiling has a useful impact on clinical management and treatment success of the disease as the complex genetic landscape of AML and differential responses to treatment might indicate inadequate therapeutic targeting. A 37 year old female patient with AML was admitted to the hospital complaining of general fatigue arthralgia and chest pain. AML diagnosis was confirmed by complete blood count and blood smears before being confirmed by cytogenetic analysis. Herein, we conducted whole-transcriptome sequencing analysis to assess differential gene expression profiles in patients and healthy control subjects. In addition, single nucleotide polymorphism/insertion-deletion analyses (SNP/INDEL) were performed to investigate gene variants in the present case. The results revealed a remarkable differential gene expression profile in AML compared to the corresponding control at the time of diagnosis, indicating that HTRA3, KRT8, KRT17, and RHEX are potential novel therapeutic targets. Additionally, a number of novel gene variants were also reported in the current study, as concluded from the SNP/INDEL analysis, which might be associated with disease risk assessment and probably affect prognosis. These genes and their new variants might be worth reporting to the scientific community for further exploration of AML.
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Zhang H, Zhang Y, Xia T, Lu L, Luo M, Chen Y, Liu Y, Li Y. The Role of Keratin17 in Human Tumours. Front Cell Dev Biol 2022; 10:818416. [PMID: 35281081 PMCID: PMC8912659 DOI: 10.3389/fcell.2022.818416] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/03/2022] [Indexed: 12/24/2022] Open
Abstract
Keratins are a group of proteins that can constitute intermediate fibers. It is a component of the cytoskeleton and plays an important role in cell protection and structural support. Keratin 17, a Type I keratin, is a multifunctional protein that regulates a variety of biological processes, including cell growth, proliferation, migration, apoptosis and signal transduction. Abnormal expression of KRT17 is associated with a variety of diseases, such as skin diseases. In recent years, studies have shown that KRT17 is abnormally expressed in a variety of malignant tumours, such as lung cancer, cervical cancer, oral squamous cell carcinoma and sarcoma. These abnormal expressions are related to the occurrence, development and prognosis of malignant tumors. In this review, we summarized the expression patterns of KRT17 in a variety of malignant tumours, the role of KRT17 in the development and prognosis of different malignant tumors and its molecular mechanisms. We also discuss the potential clinical application of KRT17 as a valuable therapeutic target.
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Affiliation(s)
- Hanqun Zhang
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yun Zhang
- Department of Pathology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Tingting Xia
- Department of Nephrology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Liang Lu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Min Luo
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yanping Chen
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
- *Correspondence: Yuncong Liu, ; Yong Li,
| | - Yong Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guizhou, China
- *Correspondence: Yuncong Liu, ; Yong Li,
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22
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Li C, Teng Y, Wu J, Yan F, Deng R, Zhu Y, Li X. A pan-cancer analysis of the oncogenic role of Keratin 17 ( KRT17) in human tumors. Transl Cancer Res 2022; 10:4489-4501. [PMID: 35116305 PMCID: PMC8797707 DOI: 10.21037/tcr-21-2118] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022]
Abstract
Background Although new evidence from cells or animals suggests a relationship between Keratin 17 (KRT17) and cancer, no pan-cancer analysis is currently available. Methods The expression level of KRT17 in generalized carcinoma was detected by the Tumor Immune Estimation Resource, version 2 (TIMER2) database, and then verified the protein expression of KRT17 in different cancer species in UALCAN database, and analyzed the relationship between the expression level of KRT17 and the clinical stage and survival of different cancers. We further explored the genetic variation of KRT17 in different tumor types included in The Cancer Genome Atlas (TCGA) and the specific mutations in each domain. The changes of KRT17 protein phosphorylation levels and protein expression levels at different phosphorylation sites in different tumors were explored. TIMER2 database was used to explore the potential relationship between the infiltration level of different immune cells and KRT17 gene expression in different TCGA cancer types. Finally, the protein binding to KRT17 and genes related to KRT17 expression were explored by STRING database and TCGA database. Results KRT17 is overexpressed in most malignancies, and we observed a distinct relationship between KRT17 expression and tumor patient prognosis. Enhanced phosphorylation levels of S13, S24, S32, and S39 were observed in several tumors, such as lung adenocarcinoma (LUAD), colon and ovarian cancers, and uterine corpus endometrial carcinoma (UCEC). Intermediate filament cytoskeleton and keratinization may be simultaneously acting with KRT17 on tumor pathogenesis. Conclusions Our pan-cancer analysis provides relatively complete information on the oncogenic functions of KRT17 in various cancers.
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Affiliation(s)
- Chenchen Li
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Teng
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jiacheng Wu
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Fei Yan
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Rong Deng
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Ying Zhu
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyou Li
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Li M, Rao X, Cui Y, Zhang L, Li X, Wang B, Zheng Y, Teng L, Zhou T, Zhuo W. The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer. Oncogene 2022; 41:770-781. [PMID: 34845376 DOI: 10.1038/s41388-021-02119-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 11/07/2021] [Accepted: 11/12/2021] [Indexed: 12/24/2022]
Abstract
DGC is a particular aggressive malignancy with poor prognosis. Recent omics studies characterized DGC with CDH1/E-cadherin loss and EMT-signatures. However, the underlying mechanisms for maintaining the aggressive behavior and molecular features of DGC remain unclear. Here, we find that intermediate filaments KRT17 is significantly lower in DGC tissues than that in intestinal gastric cancer tissues and associated with poor prognosis of DGC. We demonstrate that downregulation of KRT17 induces E-cadherin loss, EMT changes, and metastasis behaviors of GC cells. Mechanistically, the loss of intermediate filaments KRT17 induces reorganization of cytoskeleton, further activates YAP signaling, and increases IL6 expression, which contributes to the enhanced metastasis ability of GC cells. Together, these results indicate that KRT17/YAP/IL6 axis contributes to maintaining E-cadherin loss, EMT feature, and metastasis of DGC, providing a new insight into the role of aberrant intermediate filaments in DGC malignancy.
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Affiliation(s)
- Mengjie Li
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Xianping Rao
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Yun Cui
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Lu Zhang
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Xiang Li
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Boya Wang
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
- Department of Pharmacy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yijun Zheng
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China
| | - Lisong Teng
- Cancer Center, Zhejiang University, Hangzhou, China
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China
| | - Tianhua Zhou
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| | - Wei Zhuo
- Department of Cell Biology and Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Center, Zhejiang University, Hangzhou, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China.
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Zhou L, Lu H, Zeng F, Zhou Q, Li S, Wu Y, Yuan Y, Xin L. Constructing a new prognostic signature of gastric cancer based on multiple data sets. Bioengineered 2021; 12:2820-2835. [PMID: 34157940 PMCID: PMC8806649 DOI: 10.1080/21655979.2021.1940030] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 02/07/2023] Open
Abstract
In order to explore new prediction methods and key genes for gastric cancer. Firstly, we downloaded the 6 original sequencing data of gastric cancer on the Illumina HumanHT-12 platform from Array Expression and Gene Expression Omnibus, and used bioinformatics methods to identify 109 up-regulated genes and 271 down-regulated genes. Further, we performed univariate Cox regression analysis of prognostic-related genes, then used Lasso regression to remove collinearity, and finally used multivariate Cox regression to analyze independent prognostic genes (MT1M, AKR1C2, HEYL, KLK11, EEF1A2, MMP7, THBS1, KRT17, RPESP, CMTM4, UGT2B17, CGNL1, TNFRSF17, REG1A). Based on these, we constructed a prognostic risk proportion signature, and found that patients with high-risk gastric cancer have a high degree of malignancy. Subsequently, we used the GSE15459 data set to verify the signature. By calculating the area under the recipient operator characteristic curve of 5-year survival rate, the test set and verification set are 0.739 and 0.681, respectively, suggesting that the prognostic signature has a moderate prognostic ability. The nomogram is used to visualize the prognostic sig-nature, and the calibration curve verification showed that the prediction accuracy is higher. Finally, we verified the expression and prognosis of the hub gene, and suggested that HEYL, MMP7, THBS1, and KRT17 may be potential prognostic biomarkers.
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Affiliation(s)
- Liqiang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Hao Lu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Fei Zeng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Qi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Shihao Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - You Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Yiwu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
| | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R China
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Cassimeris L, Armstrong C, Burger QC, Stokes S, van Eps A, Galantino-Homer H. Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia. Vet Immunol Immunopathol 2021; 241:110326. [PMID: 34562796 DOI: 10.1016/j.vetimm.2021.110326] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 11/25/2022]
Abstract
The euglycemic hyperinsulinemic clamp model (EHC) of equine endocrinopathic laminitis induces rapid loss of lamellar tissue integrity, disrupts keratinocyte functions, and induces inflammation similar to natural disease. Continuous digital hypothermia (CDH) blocks tissue damage in this experimental model, allowing identification of specific genes or molecular pathways contributing to disease initiation or early progression. Archived lamellar tissues (8 horses, 48 h EHC treatment, including CDH-treated front limbs) were used to measure relative expression levels of genes encoding keratin 17 (KRT17), a stress-induced intermediate filament protein, and genes upregulated downstream of keratin 17 and/or interleukin 17A (IL-17A), as mediators of inflammation. Compared to front or hind limbs at ambient temperature, CDH resulted in significantly lower expression of KRT17, CCL2, CxCL8, PTGS2 (encoding COX2), IL6, TNFα, S100A8 and MMP1. By immunofluorescence, COX2 was robustly expressed in lamellar keratinocytes from ambient limbs, but not in CDH-treated limbs. Genes not significantly reduced by CDH were IL17A, DEFB4B, S100A9 and MMP9. Overall, 8 of 12 genes were expressed at lower levels in the CDH-treated limb. These 8 genes are expressed by wounded or stress-activated keratinocytes in human disease or mouse models, highlighting the role of keratinocytes in equine laminitis.
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Affiliation(s)
- Lynne Cassimeris
- 111 Research Dr., Department of Biological Sciences, Lehigh University, Bethlehem, PA, 18015, USA.
| | - Caitlin Armstrong
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA
| | - Quinnlyn C Burger
- 111 Research Dr., Department of Biological Sciences, Lehigh University, Bethlehem, PA, 18015, USA
| | - Simon Stokes
- Australian Equine Laminitis Research Unit, School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia
| | - Andrew van Eps
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA
| | - Hannah Galantino-Homer
- 382 West Street Rd., Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, 19348, USA
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Keratin 8/18 Regulate the Akt Signaling Pathway. Int J Mol Sci 2021; 22:ijms22179227. [PMID: 34502133 PMCID: PMC8430995 DOI: 10.3390/ijms22179227] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Keratin 8 and keratin 18 (K8/K18) are intermediate filament proteins that form the obligate heteropolymers in hepatocytes and protect the liver against toxins. The mechanisms of protection include the regulation of signaling pathway associated with cell survival. Previous studies show K8/K18 binding with Akt, which is a well-known protein kinase involved in the cell survival signaling pathway. However, the role of K8/K18 in the Akt signaling pathway is unclear. In this study, we found that K8/K18-Akt binding is downregulated by K8/K18 phosphorylation, specifically phosphorylation of K18 ser7/34/53 residues, whereas the binding is upregulated by K8 gly-62-cys mutation. K8/K18 expression in cultured cell system tends to enhance the stability of the Akt protein. A comparison of the Akt signaling pathway in a mouse system with liver damage shows that the pathway is downregulated in K18-null mice compared with nontransgenic mice. K18-null mice with Fas-induced liver damage show enhanced apoptosis combined with the downregulation of the Akt signaling pathway, i.e., lower phosphorylation levels of GSK3β and NFκB, which are the downstream signaling factors in the Akt signaling pathway, in K18-null mice compared with the control mice. Our study indicates that K8/K18 expression protects mice from liver damage by participating in enhancing the Akt signaling pathway.
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27
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Wu J, Xu H, Ji H, Zhai B, Zhu J, Gao M, Zhu H, Wang X. Low Expression of Keratin17 is Related to Poor Prognosis in Bladder Cancer. Onco Targets Ther 2021; 14:577-587. [PMID: 33500631 PMCID: PMC7826064 DOI: 10.2147/ott.s287891] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
Objective To investigate the association between KRT17 and the prognosis in bladder cancer patients. Methods The clinical data of 101 patients with bladder cancer from May 2013 to May 2015 were retrospectively analyzed. At the same time, the expression of KRT17 and its correlation with clinicopathological factors were examined by immunohistochemistry. We search the prognostic value of KRT17 in bladder cancer from the cancer genome map (TCGA) online database. To explore the possible cellular mechanism, gene set enrichment analysis (GSEA) was used. The patients were divided into two groups: high expression of KRT17 and low expression of KRT17. The patients were followed up for 5 years to observe the survival. Kaplan–Meier method and Log rank test were used for univariate survival analysis, and Cox regression analysis was used for multivariate analysis. Finally, a nomogram was constructed on this basis for internal verification. Results Among the 101 patients, 46 (45.5%) were in the KRT17 low expression group and 55 (54.5%) in the high KRT17 expression group. After 5 years of follow-up, 79 patients survived with a survival rate of 78.2% and 22 patients died with a mortality rate of 21.8%. Kaplan–Meier survival analysis showed that OS and PFS of patients with high expression of KRT17 were significantly higher than those of patients with low expression of KRT17 (p<0.001, p=0.005). Cox multivariate analysis showed that KRT17 expression was an independent risk factor for tumor progression (p=0.019). And tumor size, vascular tumor thrombus, and T stage also affected tumor progression (p<0.05). In the internal validation, the c-index of nomogram was 0.898 (95% CI: 0.854–0.941). Conclusion The decreased expression of KRT17 is associated with poor prognosis in patients with bladder cancer. KRT17 can be used as a novel predictive biomarker to provide a new therapeutic target for bladder cancer patients.
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Affiliation(s)
- Jiacheng Wu
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China.,Cancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Haifei Xu
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Hao Ji
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Baoqian Zhai
- Cancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Jinfeng Zhu
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Mingde Gao
- Department of Urology, Medical College of Nantong University, Nantong 226019, People's Republic of China
| | - Haixia Zhu
- Cancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
| | - Xiaolin Wang
- Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People's Republic of China
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Transcript levels of keratin 1/5/6/14/15/16/17 as potential prognostic indicators in melanoma patients. Sci Rep 2021; 11:1023. [PMID: 33441834 PMCID: PMC7806772 DOI: 10.1038/s41598-020-80336-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
Keratins (KRTs), the intermediate filament-forming proteins of epithelial cells, are extensively used as diagnostic biomarkers in cancers and associated with tumorigenesis and metastasis in multiple cancers. However, the diverse expression patterns and prognostic values of KRTs in melanoma have yet to be elucidated. In the current study, we examined the transcriptional and clinical data of KRTs in patients with melanoma from GEO, TCGA, ONCOMINE, GEPIA, cBioPortal, TIMER and TISIDB databases. We found that the mRNA levels of KRT1/2/5/6/8/10/14/15/16/17 were significantly differential expressed between primary melanoma and metastatic melanoma. The expression levels of KRT1/2/5/6/10/14/15/16/17 were correlated with advanced tumor stage. Survival analysis revealed that the high transcription levels of KRT1/5/6/14/15/16/17 were associated with low overall survival in melanoma patients. GSEA analysis indicated that the most involved hallmarks pathways were P53 pathway, KRAS signaling, estrogen response early and estrogen response late. Furthermore, we found some correlations among the expression of KRTs and the infiltration of immune cells. Our study may provide novel insights for the selection of prognostic biomarkers for melanoma.
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Enaka M, Nakanishi M, Muragaki Y. The Gain-of-Function Mutation p53R248W Suppresses Cell Proliferation and Invasion of Oral Squamous Cell Carcinoma through the Down-Regulation of Keratin 17. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:555-566. [PMID: 33307039 DOI: 10.1016/j.ajpath.2020.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/20/2020] [Accepted: 11/30/2020] [Indexed: 11/28/2022]
Abstract
Keratin 17 (KRT17) expression promotes the proliferation and invasion of oral squamous cell carcinoma (OSCC), and mutations in TP53 have been reported in 65% to 85% of OSCC cases. We studied the correlation between KRT17 expression and TP53 mutants. Ca9-22 cells, which exhibit low KRT17 expression, carried mutant p53 (p53R248W) and p53R248W knockdown promoted KRT17 expression. p53R248W knockdown in Ca9-22 cells promoted migration and invasion activity. In contrast, in HSC3 cells, which have p53 nonsense mutations and exhibit high KRT17 expression, the overexpression of p53R248W decreased KRT17 expression, cell size, proliferation, and migration and invasion activities. In addition, p53R248W significantly suppressed MMP2 mRNA expression and enzyme activity. Moreover, s.c. and orthotopic xenografts were generated from p53R248W- or p53R248Q-expressing HSC3 cells. Tumors formed from p53R248W-expressing HSC3 cells grew more slowly and had a lower Ki-67 index than those derived from the control or p53R248Q-expressing HSC3 cells. Finally, the survival rate of the mice inoculated with p53R248W-expressing HSC3 cells was significantly higher than that of the control mice. These results indicate that the p53R248W mutant suppresses proliferation and invasion activity through the suppression of KRT17 expression. We propose that OSCC with p53R248W-expressing cells may be classified as a new OSCC type that has a good prognosis.
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Affiliation(s)
- Mayu Enaka
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Masako Nakanishi
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Yasuteru Muragaki
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan.
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30
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Zeng Y, Zou M, Liu Y, Que K, Wang Y, Liu C, Gong J, You Y. Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer. Front Med (Lausanne) 2020; 7:572494. [PMID: 33324659 PMCID: PMC7726264 DOI: 10.3389/fmed.2020.572494] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 10/28/2020] [Indexed: 02/05/2023] Open
Abstract
Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.
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Affiliation(s)
- Yong Zeng
- Department of Emergency, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Zou
- Department of Gastroenterology, West China Hospital of Sichuan University, Sichuan, China
| | - Yan Liu
- Department of Gastroenterology, The Fifth People's Hospital of Chengdu, Chengdu, China
| | - Keting Que
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunbing Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Changan Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianpin Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu You
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Yi L, Cui J, Hu N, Li L, Chen Y, Mu H, Yin J, Wei S, Gong Y, Wei Y, Liu B, Ding D. iTRAQ-Based Proteomic Profiling of Potential Biomarkers in Rat Serum for Uranium Tailing Suspension Intratracheal Instillation. J Proteome Res 2020; 20:995-1004. [PMID: 33151695 DOI: 10.1021/acs.jproteome.0c00766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Protection against low-dose ionizing radiation is of great significance. Uranium tailings are formed as a byproduct of uranium mining and a potential risk to organisms. In this study, we identified potential biomarkers associated with exposure to low-dose radiation from uranium tailings. We established a Wistar rat model of low dose rate irradiation by intratracheal instillation of a uranium tailing suspension. We observed pathological changes in the liver, lung, and kidney tissues of the rats. Using isobaric tags for relative and absolute quantification, we screened 17 common differentially expressed proteins in three dose groups. We chose alpha-1 antiproteinase (Serpina1), keratin 17 (Krt17), and aldehyde dehydrogenase (Aldh3a1) for further investigation. Our data showed that expression of Serpina1, Krt17, and Aldh3a1 had changed after the intratracheal instillation in rats, which may be potential biomarkers for uranium tailing low-dose irradiation. However, the underlying mechanisms require further investigation.
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Affiliation(s)
- Lan Yi
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Jian Cui
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Nan Hu
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China
| | - Linwei Li
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Yonglin Chen
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Hongxiang Mu
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Jie Yin
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Shuang Wei
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Yaqi Gong
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Yuanyun Wei
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Bang Liu
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P. R. China.,Hengyang Medical College, Institute of Cytology and Genetics, University of South China, Hengyang 421001, Hunan Province, P. R. China
| | - Dexin Ding
- The Hengyang Key Laboratory of Cellular Stress Biology, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Hengyang, Hunan 421001, P. R. China
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Ujiie D, Okayama H, Saito K, Ashizawa M, Thar Min AK, Endo E, Kase K, Yamada L, Kikuchi T, Hanayama H, Fujita S, Sakamoto W, Endo H, Saito M, Mimura K, Saze Z, Momma T, Ohki S, Kono K. KRT17 as a prognostic biomarker for stage II colorectal cancer. Carcinogenesis 2020; 41:591-599. [PMID: 31754689 DOI: 10.1093/carcin/bgz192] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/15/2019] [Accepted: 11/20/2019] [Indexed: 01/08/2023] Open
Abstract
Adjuvant chemotherapy is considered for patients with stage II colorectal cancer (CRC) characterized by poor prognostic clinicopathological features; however, current stratification algorithms remain inadequate for identifying high-risk patients. To develop prognostic assays, we conducted a step-wise screening and validation strategy using nine cohorts of stage II patients based on multiple platforms, including microarray, RNA-sequencing (RNA-seq) and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tissues. Four microarray datasets (total n = 458) were used as the discovery set to screen for single genes associated with postoperative recurrence. Prognostic values of candidate genes were evaluated in three independent microarray/RNA-seq validation cohorts (n = 89, n = 93 and n = 183, respectively), and then IHC for KRT17 was conducted in two independent FFPE series (n = 110 and n = 44, respectively). We found that high levels of KRT17 transcript expression were significantly associated with poor relapse-free survival (RFS) not only in the discovery set, but also in three validation cohorts, and its prognostic impact was independent of conventional factors by multivariate analyses. Positive staining of KRT17 protein was significantly associated with poor RFS in two independent FFPE cohorts. KRT17 protein expression had independent prognostic impact on RFS in a multivariate model adjusted for conventional variables, including high-risk clinicopathological features. In conclusion, using nine independent cohorts consisting of 997 stage II patients, we identified and validated the expression of KRT17 transcript and KRT17 protein as a robust prognostic biomarker that can discriminate postoperative stage II patients who are at high probability of disease recurrence, providing additional prognostic stratification beyond the currently available high-risk factors.
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Affiliation(s)
- Daisuke Ujiie
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mai Ashizawa
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Aung Kyi Thar Min
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Eisei Endo
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Koji Kase
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Leo Yamada
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomohiro Kikuchi
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroyuki Hanayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shotaro Fujita
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hisahito Endo
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Advanced Cancer Immunotherapy, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Progressive DOHaD Research, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shinji Ohki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
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Massaro C, Sgueglia G, Frattolillo V, Baglio SR, Altucci L, Dell’Aversana C. Extracellular Vesicle-Based Nucleic Acid Delivery: Current Advances and Future Perspectives in Cancer Therapeutic Strategies. Pharmaceutics 2020; 12:pharmaceutics12100980. [PMID: 33081417 PMCID: PMC7589909 DOI: 10.3390/pharmaceutics12100980] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 12/17/2022] Open
Abstract
Extracellular vesicles (EVs) are sophisticated and sensitive messengers released by cells to communicate with and influence distant and neighboring cells via selective transfer of bioactive content, including protein lipids and nucleic acids. EVs have therefore attracted broad interest as new and refined potential therapeutic systems in many diseases, including cancer, due to their low immunogenicity, non-toxicity, and elevated bioavailability. They might serve as safe and effective vehicles for the transport of therapeutic molecules to specific tissues and cells. In this review, we focus on EVs as a vehicle for gene therapy in cancer. We describe recent developments in EV engineering to achieve efficient intracellular delivery of cancer therapeutics and avoid off-target effects, to provide an overview of the potential applications of EV-mediated gene therapy and the most promising biomedical advances.
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Affiliation(s)
- Crescenzo Massaro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy; (C.M.); (G.S.); (V.F.)
| | - Giulia Sgueglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy; (C.M.); (G.S.); (V.F.)
| | - Victoria Frattolillo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy; (C.M.); (G.S.); (V.F.)
| | - S. Rubina Baglio
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan 1117, 1081HV Amsterdam, The Netherlands;
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy; (C.M.); (G.S.); (V.F.)
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-5667569 (L.A.); +39-081-5667564 (C.D.)
| | - Carmela Dell’Aversana
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio 7, 80138 Naples, Italy; (C.M.); (G.S.); (V.F.)
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR), Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-5667569 (L.A.); +39-081-5667564 (C.D.)
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Demirkol Canlı S, Dedeoğlu E, Akbar MW, Küçükkaraduman B, İşbilen M, Erdoğan ÖŞ, Erciyas SK, Yazıcı H, Vural B, Güre AO. A novel 20-gene prognostic score in pancreatic adenocarcinoma. PLoS One 2020; 15:e0231835. [PMID: 32310997 PMCID: PMC7170253 DOI: 10.1371/journal.pone.0231835] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. In order to better prognosticate patients with PDAC, we identified 20 genes by utilizing publically available high-throughput transcriptomic data from GEO, TCGA and ICGC which are associated with overall survival and event-free survival. A score generated based on the expression matrix of these genes was validated in two independent cohorts. We find that this “Pancreatic cancer prognostic score 20 –PPS20” is independent of the confounding factors in multivariate analyses, is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.
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Affiliation(s)
- Seçil Demirkol Canlı
- Molecular Pathology Application and Research Center, Hacettepe University, Ankara, Turkey
- * E-mail:
| | - Ege Dedeoğlu
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Muhammad Waqas Akbar
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Barış Küçükkaraduman
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Murat İşbilen
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Özge Şükrüoğlu Erdoğan
- Cancer Genetics Division, Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Seda Kılıç Erciyas
- Cancer Genetics Division, Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Hülya Yazıcı
- Cancer Genetics Division, Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Burçak Vural
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Ali Osmay Güre
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
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Li D, Ni XF, Tang H, Zhang J, Zheng C, Lin J, Wang C, Sun L, Chen B. KRT17 Functions as a Tumor Promoter and Regulates Proliferation, Migration and Invasion in Pancreatic Cancer via mTOR/S6k1 Pathway. Cancer Manag Res 2020; 12:2087-2095. [PMID: 32256116 PMCID: PMC7090205 DOI: 10.2147/cmar.s243129] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/14/2020] [Indexed: 12/19/2022] Open
Abstract
Background Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC. Methods The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels. Results KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated. Conclusion KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.
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Affiliation(s)
- Ding Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Xiao-Feng Ni
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Hengjie Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Jiecheng Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Chenlei Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Jianhu Lin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China.,Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China
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Liu Z, Yu S, Ye S, Shen Z, Gao L, Han Z, Zhang P, Luo F, Chen S, Kang M. Keratin 17 activates AKT signalling and induces epithelial-mesenchymal transition in oesophageal squamous cell carcinoma. J Proteomics 2019; 211:103557. [PMID: 31669361 DOI: 10.1016/j.jprot.2019.103557] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/18/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022]
Abstract
Oesophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and a leading cause of cancer-related death worldwide. Lack of effective early diagnosis strategies and ensuing complications from tumour metastasis account for the majority of ESCC death. Thus, identification of key molecular targets involved in ESCC carcinogenesis and progression is crucial for ESCC prognosis. In this study, four pairs of ESCC tissues were used for mRNA sequencing to determine differentially expressed genes (DEGs). 347 genes were found to be upregulated whereas 255 genes downregulated. By screening DEGs plus bioinformatics analyses such as KEGG, PPI and IPA, we found that there were independent interactions between KRT family members. KRT17 upregulation was confirmed in ESCC and its relationship with clinicopathological features were analysed. KRT17 was significantly associated with ESCC histological grade, lymph node and distant metastasis, TNM stage and five-year survival rate. Upregulation of KRT17 promoted ESCC cell growth, migration, and lung metastasis. Mechanistically, we found that KRT17-promoted ESCC cell growth and migration was accompanied by activation of AKT signalling and induction of EMT. These findings suggested that KRT17 is significantly related to malignant progression and poor prognosis of ESCC patients, and it may serve as a new biological target for ESCC therapy. SIGNIFICANCE: Oesophageal cancer is one of the leading causes of cancer mortality worldwide and oesophageal squamous cell carcinoma (ESCC) is the major histological type of oesophageal cancer in Eastern Asia. However, the molecular basis for the development and progression of ESCC remains largely unknown. In this study, RNA sequencing was used to establish the whole-transcriptome profile in ESCC tissues versus the adjacent non-cancer tissues and the results were bioinformatically analysed to predict the roles of the identified differentially expressed genes. We found that upregulation of KRT17 was significantly associated with advanced clinical stage, lymph node and distant metastasis, TNM stage and poor clinical outcome. Keratin 17 (KRT17) upregulation in ESCC cells not only promoted cell proliferation but also increased invasion and metastasis accompanied with AKT activation and epithelial-mesenchymal transition (EMT). These data suggested that KRT17 played an important role in ESCC development and progression and may serve as a prognostic biomarker and therapeutic target in ESCC.
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Affiliation(s)
- Zhun Liu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Shaobin Yu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Shuting Ye
- Key Laboratory of Gastrointestinal Cancer, Fujian Medical University, Ministry of Education, Fuzhou 350122, China
| | - Zhimin Shen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Lei Gao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Ziyang Han
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Peipei Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Fei Luo
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Sui Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China.
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China; Key Laboratory of Gastrointestinal Cancer, Fujian Medical University, Ministry of Education, Fuzhou 350122, China; Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350122, China.
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Dong M, Dong Z, Zhu X, Zhang Y, Song L. Long non-coding RNA MIR205HG regulates KRT17 and tumor processes in cervical cancer via interaction with SRSF1. Exp Mol Pathol 2019; 111:104322. [PMID: 31655037 DOI: 10.1016/j.yexmp.2019.104322] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/09/2019] [Accepted: 10/17/2019] [Indexed: 12/17/2022]
Abstract
Abnormal expression of long non-coding RNAs (lncRNAs) has been demonstrated to be a vital regulatory factor in a large number of malignancies. The investigation in cervical cancer and the associated modulation mechanisms are yet to be probed. The aim of this study is to specifically investigate the expression pattern and modulatory mechanism of MIR205HG in cervical cancer. Our paper firstly revealed the up-regulation of KRT17 in cervical cancer. Function assays further displayed that KRT17 silencing impaired the proliferation and migration, and activated the apoptosis of cervical cancer cells. Based on the finding that MIR205HG could regulate KRT17 expression, we further probed the detailed mechanism between MIR205HG and KRT17. It was observed from mechanism experiments that MIR205HG depleted SRSF1 to increase KRT17 expression. The whole mechanism of MIR205HG/SRSF1/KRT17 axis affecting cell proliferation, apoptosis and migration in cervical cancer was validated using rescue assays. In conclusion, MIR205HG modulated the biological activities of cervical cancer cells via targeting SRSF1 and regulating KRT17, which better understood the pathogenesis of cervical carcinoma and excavated a novel therapeutic target.
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Affiliation(s)
- Mingli Dong
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhennan Dong
- Department of Medical Laboratory, Chinese PLA General Hospital, Beijing 100853, China
| | - Xinyu Zhu
- Department of Obstetrics and Gynecology, Beijing Corps Hospital of Chinese People's Armed Police Force, Beijing 100027, China
| | - Yunhe Zhang
- Department of Obstetrics and Gynecology, China Mei-tan General Hospital, Beijing 100028, China
| | - Lei Song
- Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing 100853, China..
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Wang Z, Yang MQ, Lei L, Fei LR, Zheng YW, Huang WJ, Li ZH, Liu CC, Xu HT. Overexpression of KRT17 promotes proliferation and invasion of non-small cell lung cancer and indicates poor prognosis. Cancer Manag Res 2019; 11:7485-7497. [PMID: 31496806 PMCID: PMC6689799 DOI: 10.2147/cmar.s218926] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 07/22/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Keratin 17 (KRT17) is a 48 KDa type I intermediate filament, which is mainly expressed in epithelial basal cells. KRT17 has been shown to be overexpressed in many malignant tumors and play an important role in the occurrence and development of tumors. Therefore, this study explored the role and underlying mechanism of KRT17 in non-small cell lung cancers (NSCLC). METHODS KRT17 expression and its correlations with clinicopathological factors were examined in lung cancer tissues by immunohistochemistry. The prognosis value of KRT17 in NSCLCs was retrieved from The Cancer Genome Atlas (TCGA) online databases. The expression level of KRT17 was increased or decreased by KRT17 gene transfection or small RNA interference in lung cancer cells, respectively. Further, proliferation and invasiveness of lung cancer cells were determined by cell proliferation and invasion assays, respectively. Finally, expression levels of proteins related to Wnt signaling pathways and epithelial mesenchymal transition (EMT) were detected by Western blot. RESULTS The expression level of KRT17 in NSCLCs was significantly higher than normal lung tissues. High expression of KRT17 predicted poor prognosis of patients with NSCLCs, especially lung adenocarcinomas, and was correlated with poor differentiation and lymphatic metastasis. Overexpression of KRT17 enhanced, while KRT17 knockdown inhibited, the proliferation and invasiveness of lung cancer cells. Overexpression of KRT17 up-regulated β-catenin activity and levels of Wnt target genes, such as cyclin D1, c-Myc, and MMP7. Moreover, KRT17 promoted EMT by up-regulating Vimentin, MMP-9, and Snail expression and down-regulating E-cadherin expression. CONCLUSION Overexpression of KRT17 is common in NSCLCs and indicates poor prognosis. Overexpression of KRT17 enhances the proliferation and invasiveness of NSCLC cells by activating the Wnt signaling pathway and EMT process. KRT17 is a potential indicator of NSCLC progression and poor survival.
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Affiliation(s)
- Zhao Wang
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
- Department of Pathology, General Hospital of Heilongjiang Land Reclamation Bureau, Harbin150088, People’s Republic of China
| | - Mai-Qing Yang
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
- Department of Pathology, Changyi People’s Hospital, Changyi, People’s Republic of China
| | - Lei Lei
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Liang-Ru Fei
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Yi-Wen Zheng
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Wen-Jing Huang
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Zhi-Han Li
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Chen-Chen Liu
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
| | - Hong-Tao Xu
- Department of Pathology, The First Hospital and College of Basic Medical Sciences of China Medical University, Shenyang110001, People’s Republic of China
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Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, Bleotu C, Diaconu CC, Chivu-Economescu M. Recent advances in gastric cancer early diagnosis. World J Gastroenterol 2019; 25:2029-2044. [PMID: 31114131 PMCID: PMC6506585 DOI: 10.3748/wjg.v25.i17.2029] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/03/2019] [Accepted: 04/19/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.
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Affiliation(s)
- Laura Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Faculty of Medicine, Titu Maiorescu University, Bucharest 040441, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Denisa Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Ana I Neagu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Cristina Mambet
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Saviana Nedeianu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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40
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Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia. Mod Pathol 2019; 32:717-724. [PMID: 30443013 DOI: 10.1038/s41379-018-0177-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/18/2018] [Accepted: 10/26/2018] [Indexed: 12/25/2022]
Abstract
There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann-Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20-90%) in PUNLMP, 30% (range 5-100%) in PUC-LG, 20% (range 1-100%), in PUC-HG, 35% (range 5-100%) in UC but staining was rarely detected (range 0-10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80-96%) and the specificity was 88% (95% CI: 70-95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.
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Yang L, Zhang S, Wang G. Keratin 17 in disease pathogenesis: from cancer to dermatoses. J Pathol 2018; 247:158-165. [PMID: 30306595 DOI: 10.1002/path.5178] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/17/2018] [Accepted: 10/02/2018] [Indexed: 12/16/2022]
Abstract
Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue-specific diseases, represented by steatocystoma multiplex and pachyonychia congenita. In this review, we summarize our findings concerning the regulatory mechanisms of K17 overexpression in psoriasis and compare them to the literature relating to other diseases. We discuss data that proinflammatory cytokines, including interleukin-17 (IL-17), IL-22, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β) and transcription factors glioma-associated oncogene homolog 1/2 (Gli1/2), Nrf2 and p53 can regulate K17 by transcriptional and translational control. Moreover, post-translational modification, including phosphorylation and ubiquitination, is involved in the regulation of K17 stability and biological functions. We therefore review the current understanding of the K17 regulatory mechanism and its pathogenic role in diseases from dermatoses to cancer. Prospects for anti-K17 therapy in diagnosis, prognosis and disease treatment are also discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Luting Yang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR, China
| | - Shaolong Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR, China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR, China
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Abstract
BACKGROUND The identification of high-risk colorectal cancer (CRC) patient is key to individualized treatment after surgery and reliable prognostic biomarkers are needed identifying high-risk CRC patients. METHODS We developed a gene pair based prognostic signature that could can the prognosis risk in patients with CRC. This study retrospectively analyzed 4 public CRC datasets, and 1123 patients with CRC were divided into a training cohort (n = 300) and 3 independent validation cohorts (n = 507, 226, and 90 patients). RESULTS A signature of 9 prognosis-related gene pairs (PRGPs) consisting of 17 unique genes was constructed. Then, a PRGP index (PRGPI) was constructed and divided patients into high- and low-risk groups according to the signature score. Patients in the high-risk group showed a poorer relapse-free survival than the low-risk group in both the training cohort [hazard ratio (HR) range, 4.6, 95% confidence interval (95% CI), 2.55-8.32; P < .0001] and meta-validation set (hazard ratio range, 4.09, 95% CI, 1.99-8.39; P < .0001). The PRGPI signature achieved a higher accuracy [mean concordance index (C-index): 0.6∼0.74] than a commercialized molecular signature (mean C-index, 0.48∼0.56) for estimation of relapse-free survival in comparable validation sets. CONCLUSION The gene pair based prognostic signature is a promising biomarker for estimating relapse-free survival of CRC.
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Affiliation(s)
- Peng Shu
- Beilun People's Hospital, Ningbo
| | - Jianping Wu
- Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yao Tong
- College of Agriculture and Life Sciences, Cornell University, Ithaca, NY
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Andolino C, Hess C, Prince T, Williams H, Chernin M. Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells. Cell Stress Chaperones 2018; 23:1137-1142. [PMID: 29802537 PMCID: PMC6111075 DOI: 10.1007/s12192-018-0913-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 04/05/2018] [Accepted: 05/08/2018] [Indexed: 12/18/2022] Open
Abstract
A pull-down experiment (co-immunoprecipitation) was performed on a T24 human bladder cancer cell lysate treated with the Hsp inhibitor VER155008 using an Hsp70 antibody attached to Dynabeads. Keratin 9, a cytoskeleton intermediate filament protein, was identified by LC MS/MS analysis. This novel finding was confirmed by Western blotting, RT-PCR, and immunocytochemistry. Other members of the keratin family of proteins have been shown to be involved in cancer progression, most recently identified to be associated with cell invasion and metastasis. The specific role of keratin 9 expression in these cells is yet to be determined.
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Affiliation(s)
- C Andolino
- Biology Department, Bucknell University, 1 Dent Drive, Lewisburg, PA, 17837, USA
| | - C Hess
- Biology Department, Bucknell University, 1 Dent Drive, Lewisburg, PA, 17837, USA
| | - T Prince
- Department of Urology, Geisinger Clinic, Danville, PA, USA
| | - H Williams
- Department of Urology, Geisinger Clinic, Danville, PA, USA
| | - M Chernin
- Biology Department, Bucknell University, 1 Dent Drive, Lewisburg, PA, 17837, USA.
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Liu J, Liu L, Cao L, Wen Q. Keratin 17 Promotes Lung Adenocarcinoma Progression by Enhancing Cell Proliferation and Invasion. Med Sci Monit 2018; 24:4782-4790. [PMID: 29991674 PMCID: PMC6069497 DOI: 10.12659/msm.909350] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Backgrounds Lung adenocarcinoma (LAC) accounts for the majority of lung cancer, which is the leading cause of cancer-related mortality worldwide. Keratin 17 (KRT17) was reported to promote the tumor development of skin tumor and oral cancer. The aim of this study was to investigate the expression and function of KRT17 in LAC. Material/Methods Immunohistochemical staining and quantitative PCR were performed to explore the expression of KRT17 in both LAC tissues and adjacent normal liver tissues. Chi-square test, univariate analysis, and multivariate analysis were conducted to statistically evaluate the clinical significance of KRT17 in LAC. Proliferation, migration, and invasion capacities of LAC cells were assessed after overexpression or silencing KRT17. Results Both the RNA and protein levels of KRT17 were up-regulated in LAC tissues compared to normal lung tissues. High expression of KRT17 was correlated with advanced TNM stage and poor overall survival. Moreover, KRT17 was identified as a novel independent prognostic factor for LAC patients. Cellular studies showed that KRT17 can enhance the proliferation, migration, and invasion capacities of LAC cells, thereby promoting tumor progression. Conclusions High expression of KRT17 is frequent in LAC tissues, which promotes tumor proliferation and invasion, and is correlated with a poor overall survival. Targeting KRT17 may be a novel direction for LAC drug development.
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Affiliation(s)
- Jianbo Liu
- Department of Public Health, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Lei Liu
- General Department of Health and Geriatrics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Lina Cao
- General Department of Health and Geriatrics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Qiang Wen
- Third Department of Internal Medicine, Linyi People's Hospital, Linyi, Shandong, China (mainland).,Third Department of Internal Medicine, East District of Linyi People's Hospital, Linyi, Shandong, China (mainland)
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Chivu-Economescu M, Matei L, Necula LG, Dragu DL, Bleotu C, Diaconu CC. New therapeutic options opened by the molecular classification of gastric cancer. World J Gastroenterol 2018; 24:1942-1961. [PMID: 29760539 PMCID: PMC5949709 DOI: 10.3748/wjg.v24.i18.1942] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/12/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Denisa L Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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