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Zheng Y, Chen X, Huang Y, Lin X, Lin J, Mo Y, Gan L, Wei S, Wang Z, Song X, Tu Z. DDX27: An RNA helicase regulating cancer progression and therapeutic prospects. Int J Biol Macromol 2025; 313:144388. [PMID: 40394785 DOI: 10.1016/j.ijbiomac.2025.144388] [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: 04/13/2025] [Revised: 05/07/2025] [Accepted: 05/18/2025] [Indexed: 05/22/2025]
Abstract
DDX27, a member of the DEAD-box RNA helicase family, plays a crucial role in RNA metabolism, inflammation, and cancer progression. Elevated expression of DDX27 has been observed in multiple cancers, including oral squamous cell carcinoma (OSCC), breast cancer (BC), colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC), where it is associated with poor prognosis, tumor growth, metastasis, and chemoresistance. DDX27 regulates the NF-κB signaling pathway, which is central to inflammation and tumor progression, and influences key cellular processes such as cell cycle regulation, apoptosis, migration, and stemness. Additionally, DDX27 promotes epithelial-mesenchymal transition (EMT), further contributing to metastasis. Its interactions with non-coding RNAs and various signaling pathways complicate treatment responses, making DDX27 a promising therapeutic target. This review explores the role of DDX27 as both a biomarker and therapeutic target, with potential strategies including small molecule inhibitors, RNA interference, and combination therapies with existing treatments such as NF-κB inhibitors or chemotherapy. Targeting DDX27 may help overcome resistance, reduce metastasis, and improve cancer treatment outcomes. Further research into its molecular mechanisms and interactions will be crucial for developing effective therapies, particularly for cancers with high metastatic potential.
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Affiliation(s)
- Yuantong Zheng
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xinyi Chen
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Yunfei Huang
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xuanli Lin
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Jiaxin Lin
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Yuting Mo
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Lu Gan
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Shuhua Wei
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Zhen Wang
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Xiaojuan Song
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China
| | - Zhengchao Tu
- College of Pharmacy, Jinan University, Guangzhou 510006, Guangdong, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development (MOE), School of Pharmacy, Jinan University, Guangzhou 510632, PR China.
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Ma H, Ge Y, Li Y, Wang T, Chen W. Construction of a prognostic model based on cuproptosis-related genes and exploration of the value of DLAT and DLST in the metastasis for non-small cell lung cancer. Medicine (Baltimore) 2024; 103:e40727. [PMID: 39654205 PMCID: PMC11631004 DOI: 10.1097/md.0000000000040727] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/20/2024] [Accepted: 11/08/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND To reveal the clinical value of cuproptosis-related genes on prognosis and metastasis in non-small cell lung cancer. METHODS Gene expression profiles and clinical information of non-small cell lung cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. The data were grouped into training set, internal testing set, and external testing set. A risk prognostic model was constructed by Lasso-Cox regression analysis. Hub genes were identified and evaluated using immunohistochemistry and the transwell migration assay in 50 clinical patients. RESULTS A total of 17/19 cuproptosis-related genes were differentially expressed in tumors, 8 were significantly associated with prognosis, and 4 were markedly associated with metastasis. A risk model based on 2 cuproptosis-related genes was constructed and validated for predicting overall survival. The risk score was proven to be an independent risk factor for the prognosis of non-small cell lung cancer. Dihydrolipoamide S-acetyltransferase and dihydrolipoamide S-succinyltransferase, key genes in cuproptosis, were proven to be associated with non-small cell lung cancer prognosis and metastasis. Immunohistochemistry showed that their expression significantly predicted metastasis but failed to predict prognosis in non-small cell lung cancer patients. The transwell migration assay further increased the cellular reliability of our findings. CONCLUSION The cuproptosis-related genes prognostic model effectively predicted the prognosis of non-small cell lung cancer. Dihydrolipoamide S-acetyltransferase and dihydrolipoamide S-succinyltransferase may serve as predictive markers for metastasis in non-small cell lung cancer.
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Affiliation(s)
- Huiying Ma
- Department of Radiation Oncology, The First People’s Hospital of Jiande, Hangzhou, China
| | - Yizhi Ge
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Yuhong Li
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Tingting Wang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
| | - Wei Chen
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China
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Malekjafarian SM, Mohtasham N, Mirhashemi M, Sadeghi M, Arab F, Mohajertehran F. Metastasis and cell proliferation inhibition by microRNAs and its potential therapeutic applications in OSCC: A systematic review. Pathol Res Pract 2024; 262:155532. [PMID: 39142242 DOI: 10.1016/j.prp.2024.155532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND AND AIMS Oral squamous cell carcinoma (OSCC) is among the most malignant cancers in the world and has a high mortality rate. MicroRNAs (miRNAs) have progressively gained attention due to their roles in the pathogenesis and maintenance of various kinds of cancers, including OSCC. In this research, we carried out a scoping review to analyze the role of miRNA and therapeutic response in OSCC and focus on target axes associated with miRNA that inhibit metastasis and cell proliferation in OSCC. METHODS This review adhered to a six-stage methodology framework and PRISMA guidelines. Three databases were systematically searched to find eligible articles until July 2024. Two reviewers conducted publication screening and data extraction independently. 54 articles meeting the predefined inclusion criteria were successfully identified. Quality assessment was done using the QUIN checklist specified for dental in vitro studies. RESULTS Studies with different designs reported 53 miRNAs that were experimentally validated to act as therapeutic targets in OSCC in vivo and in vitro studies. The study found that 25 miRNAs were up-regulated in OSCC patients and cell lines, while another 25 were down-regulated. Mir-186 was also found to be up- and down-regulated in two different investigations. The study highlights the potential of six microRNAs (miR-32-5p, miR-195-5p, miR-3529-3p, miR-191, miR-146b-5p, and miR-377-3p) as anti-proliferation, migration, and invasion therapeutics for OSCC treatment. Two miRNAs (miR-302b and miR-18a) are identified as anti-metastatic therapeutics, while four miRNAs (miR-617, miR-23a-3p, miR-105, miR-101) are anti-proliferation therapeutics. CONCLUSION The study recommends that restoring the expression of tumor suppressor miRNAs may be a suitable cancer therapy. Utilizing this technology does present certain difficulties, and resolving them will improve the methods for miRNA transfer to target cells. With more research and the resolution of associated issues, miRNA can be employed as an efficient therapeutic method for OSCC.
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Affiliation(s)
| | - Nooshin Mohtasham
- Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Mirhashemi
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoumeh Sadeghi
- Department of Epidemiology, Faculty of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Arab
- Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Jamshidi S, Tavangar M, Shojaei S, Taherkhani A. Malignant Transformation of Normal Oral Tissue to Dysplasia and Early Oral Squamous Cell Carcinoma: An In Silico Transcriptomics Approach. Anal Cell Pathol (Amst) 2024; 2024:6260651. [PMID: 39376501 PMCID: PMC11458300 DOI: 10.1155/2024/6260651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 06/22/2024] [Accepted: 08/19/2024] [Indexed: 10/09/2024] Open
Abstract
Background: Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive form of head and neck cancer, often diagnosed at advanced stages. Elucidating the molecular mechanisms involved in the malignant transformation from normal oral tissue to oral preinvasive lesions (OPL) and primary OSCC could facilitate early diagnosis and improve therapeutic strategies. Methods: Differentially expressed genes (DEGs) were identified from the GSE30784 dataset by comparing normal oral tissue, oral dysplasia, and primary OSCC samples. Cross-validation was performed using an independent RNA-seq dataset, GSE186775. Protein-protein interaction (PPI) network analysis, gene ontology annotation, and pathway enrichment analysis were conducted on the common DEGs. Hub genes were identified, and their prognostic significance was evaluated using survival analysis. Transcription factor (TF) enrichment analysis, cross-validation, and immunohistochemistry analyses were also performed. Results: A total of 226 proteins and 677 interactions were identified in the PPI network, with 34 hub genes, including FN1, SERPINE1, PLAUR, THBS1, and ITGA6. Pathways such as "Formation of the cornified envelope," "Keratinization," and "Developmental biology" were enriched. Overexpression of SERPINE1, PLAUR, THBS1, and ITGA6 correlated with poor prognosis, while upregulation of CALML5 and SPINK5 was associated with favorable outcomes. NFIB emerged as the most significant TF-regulating hub genes. Immunohistochemistry validated ITGA6 overexpression in primary OSCC. Cross-validation using the RNA-seq dataset supported the involvement of critical genes in the malignant transformation process. Conclusion: This study identified vital genes, pathways, and prognostic markers involved in the malignant transformation from normal oral tissue to OPL and primary OSCC, providing insights for early diagnosis and targeted therapy development. Cross-validation with an independent RNA-seq dataset and immunohistochemistry reinforced the findings, supporting the robustness of the identified molecular signatures.
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Affiliation(s)
- Shokoofeh Jamshidi
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Matina Tavangar
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Setareh Shojaei
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Taherkhani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Bai HX, Qiu XM, Xu CH, Guo JQ. MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1- extracellular signal-regulated kinase-1/2 axis. World J Gastrointest Oncol 2024; 16:2123-2140. [PMID: 38764835 PMCID: PMC11099451 DOI: 10.4251/wjgo.v16.i5.2123] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/19/2024] [Accepted: 03/13/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) regulate gene expression and play a critical role in cancer physiology. However, there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer (GC). AIM To investigate the role and molecular mechanism of miRNA-145-5p (miR145-5p) in the progression of GC. METHODS Real-time polymerase chain reaction (RT-PCR) was used to detect miRNA expression in human GC tissues and cells. The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays, respectively. Cell proliferation was measured using cell counting kit-8 and colony formation assays, and apoptosis was evaluated using flow cytometry. Expression of the epithelial-mesenchymal transition (EMT)-associated protein was determined by Western blot. Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system. Serpin family E member 1 (SERPINE1) expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining. The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis. The association between SERPINE1 and GC progression was also tested. A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p. The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice. RESULTS GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA. Overexpression of miR-145-5p was associated with decreased GC cell proliferation, invasion, migration, and EMT, and these effects were reversed by forcing SERPINE1 expression. Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression. Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2 (ERK1/2). CONCLUSION This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC. MiR-145-5p was found to affect GC cell proliferation, migration, and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.
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Affiliation(s)
- Hong-Xia Bai
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan 250000, Shandong Province, China
- Department of Gastroenterology, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
| | - Xue-Mei Qiu
- Department of Reproductive Center, Zaozhuang Maternal and Child Health Care Hospital, Zaozhuang 277000, Shandong Province, China
| | - Chun-Hong Xu
- Department of Gastroenterology, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
| | - Jian-Qiang Guo
- Department of Gastroenterology, The Second Hospital of Shandong University, Jinan 250000, Shandong Province, China
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Mu X, Ono M, Nguyen HTT, Wang Z, Zhao K, Komori T, Yonezawa T, Kuboki T, Oohashi T. Exploring the Regulators of Keratinization: Role of BMP-2 in Oral Mucosa. Cells 2024; 13:807. [PMID: 38786031 PMCID: PMC11119837 DOI: 10.3390/cells13100807] [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: 03/29/2024] [Revised: 05/02/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024] Open
Abstract
The oral mucosa functions as a physico-chemical and immune barrier to external stimuli, and an adequate width of the keratinized mucosa around the teeth or implants is crucial to maintaining them in a healthy and stable condition. In this study, for the first time, bulk RNA-seq analysis was performed to explore the gene expression of laser microdissected epithelium and lamina propria from mice, aiming to investigate the differences between keratinized and non-keratinized oral mucosa. Based on the differentially expressed genes (DEGs) and Gene Ontology (GO) Enrichment Analysis, bone morphogenetic protein 2 (BMP-2) was identified to be a potential regulator of oral mucosal keratinization. Monoculture and epithelial-mesenchymal cell co-culture models in the air-liquid interface (ALI) indicated that BMP-2 has direct and positive effects on epithelial keratinization and proliferation. We further performed bulk RNA-seq of the ALI monoculture stimulated with BMP-2 in an attempt to identify the downstream factors promoting epithelial keratinization and proliferation. Analysis of the DEGs identified, among others, IGF2, ID1, LTBP1, LOX, SERPINE1, IL24, and MMP1 as key factors. In summary, these results revealed the involvement of a well-known growth factor responsible for bone development, BMP-2, in the mechanism of oral mucosal keratinization and proliferation, and pointed out the possible downstream genes involved in this mechanism.
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Affiliation(s)
- Xindi Mu
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
| | - Mitsuaki Ono
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
- Department of Oral Rehabilitation and Implantology, Okayama University Hospital, Okayama 700-8558, Japan;
| | - Ha Thi Thu Nguyen
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Ziyi Wang
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
| | - Kun Zhao
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
| | - Taishi Komori
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, Department of Health and Human Services, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tomoko Yonezawa
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
| | - Takuo Kuboki
- Department of Oral Rehabilitation and Implantology, Okayama University Hospital, Okayama 700-8558, Japan;
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
| | - Toshitaka Oohashi
- Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; (X.M.); (H.T.T.N.); (Z.W.); (K.Z.); (T.Y.); (T.O.)
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Wang G, Li P, Su SW, Xu R, Huang ZY, Yang TX, Li JM. Identification of key pathways and mRNAs in interstitial cystitis/bladder pain syndrome treatment with quercetin through bioinformatics analysis of mRNA-sequence data. Aging (Albany NY) 2024; 16:5949-5966. [PMID: 38526326 PMCID: PMC11042929 DOI: 10.18632/aging.205682] [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: 02/06/2023] [Accepted: 03/03/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition with painful bladder. At present, the pathogenesis of IC/BPS is still unknown. Quercetin (QCT) is a kind of natural flavonoid with wide sources and multiple biological activities. The purpose of this study was to explore the effects of QCT on mRNA expression and related regulatory signal pathways in IC model rats. METHODS LL-37 was used to induce the IC/BPS model rats. 20 mg/kg QCT was injected intraperitoneally into IC/BPS rats. ELISA, HE, Masson and TB staining were used to evaluate the level of inflammation and pathology. The concentration of QCT in rats was detected by HPLC. The mRNA sequencing was used to detect the differentially expressed (DE) mRNA in each group. The over-expression experiment of Lpl was carried out in IC/BPS model rats. RESULTS QCT treatment significantly decreased the level of MPO, IL-1β, IL-6 and TNF-α induced by LL-37 in rats, and alleviated bladder injury and mast cell degranulation. There were significant differences in mRNA sequencing data between groups, and the hub gene Lpl were screened by Cytohubba. The expression of Lpl was downregulated in IC/BPS rats. QCT intervention promoted Lpl expression. Overexpression of Lpl reduced the bladder injury induced by LL-37, increased GAG level and decreased the expression of MPO, IL-1β, IL-6 and TNF-α. CONCLUSION In this study, we provided the DE mRNA in IC/BPS rats treated with QCT, the signaling pathways for DE enrichment, screened out the hub genes, and revealed that Lpl overexpression alleviated IC/BPS model rats.
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Affiliation(s)
- Guang Wang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Pei Li
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Si-Wei Su
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Rui Xu
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Zi-Ye Huang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Tong-Xin Yang
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
| | - Jiong-Ming Li
- Department of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China
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Bayat Z, Mazaheri T, Farhadifard H, Taherkhani A. Mechanisms Involved in Therapeutic Effects of Scutellaria baicalensis Georgi in Oral Squamous Cell Carcinoma Based on Systems Biology and Structural Bioinformatics Approaches. BIOMED RESEARCH INTERNATIONAL 2024; 2024:1236910. [PMID: 38322303 PMCID: PMC10846925 DOI: 10.1155/2024/1236910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 11/30/2023] [Accepted: 01/10/2024] [Indexed: 02/08/2024]
Abstract
Objective Oral squamous cell carcinoma (OSCC) is the most frequent oral cancer, constituting more than 90% of all oral carcinomas. The 5-year survival rate of OSCC patients is not satisfactory, and therefore, there is an urgent need for new practical therapeutic approaches besides the current therapies to overcome OSCC. Scutellaria baicalensis Georgi (SBG) is a plant of the family Lamiaceae with several pharmaceutical properties such as antioxidant, anti-inflammatory, and anticancer effects. Previous studies have demonstrated the curative effects of SBG in OSCC. Methods A systems biology approach was conducted to identify differentially expressed miRNAs (DEMs) in OSCC patients with a dismal prognosis compared to OSCC patients with a favorable prognosis. A protein interaction map (PIM) was built based on DEMs targets, and the hub genes within the PIM were indicated. Subsequently, the prognostic role of the hubs was studied using Kaplan-Meier curves. Next, the binding affinity of SBG's main components, including baicalein, wogonin, oroxylin-A, salvigenin, and norwogonin, to the prognostic markers in OSCC was evaluated using molecular docking analysis. Results Survival analysis showed that overexpression of CAV1, SERPINE1, ACTB, SMAD3, HMGA2, MYC, EIF2S1, HSPA4, HSPA5, and IL6 was significantly related to a poor prognosis in OSCC. Besides, molecular docking analysis demonstrated the ΔGbinding and inhibition constant values between SBG's main components and SERPINE1, ACTB, HMGA2, EIF2S1, HSPA4, and HSPA5 were as <-8.00 kcal/mol and nanomolar concentration, respectively. The most salient binding affinity was observed between wogonin and SERPINE1 with a criterion of ΔGbinding < -10.02 kcal/mol. Conclusion The present results unraveled potential mechanisms involved in therapeutic effects of SBG in OSCC based on systems biology and structural bioinformatics analyses.
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Affiliation(s)
- Zeynab Bayat
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Tina Mazaheri
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Homa Farhadifard
- Department of Orthodontics, School of Dentistry, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Taherkhani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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He W, Gu L, Yang J, Zhang R, Long J, Peng W, Liang B, Zhu L, Lv M, Nan A, Su L. Exosomal circCNOT6L Regulates Astrocyte Apoptotic Signals Induced by Hypoxia Exposure Through miR99a-5p/SERPINE1 and Alleviates Ischemic Stroke Injury. Mol Neurobiol 2023; 60:7118-7135. [PMID: 37531026 DOI: 10.1007/s12035-023-03518-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 07/12/2023] [Indexed: 08/03/2023]
Abstract
Circular RNAs are involved in intervention strategies for treating ischemic stroke (IS). However, circCNOT6L (hsa_circ_0006168) has not yet been reported in IS. Thus, we aimed to explore the potential role of circCNOT6L and its molecular mechanism in IS. In this study, we first found that the expression of both exosomal circCNOT6L (P = 0.0006) and plasma circCNOT6L (P = 0.0054) was down-regulated in IS patients compared with controls. Clinically, a negative correlation was observed between the relative expression level of circCNOT6L and the National Institutes of Health Stroke Scale (NIHSS) score and infarct volume of the brain. Simultaneously, the relative expression level of circCNOT6L was negatively associated with multiple risk factors for IS, such as mean platelet volume (MPV), red cell distribution width (RDW), very low-density lipoprotein (VLDL), and serum potassium, whereas it was positively correlated with high-density lipoprotein (HDL). In vitro, circCNOT6L silencing blocked cell viability and proliferation, while it promoted cell apoptosis of astrocytes undergoing oxygen-glucose deprivation/reperfusion (OGD/R) treatment. Mechanistically, the RNA antisense purification (RAP) assay and luciferase reporter assay revealed that circCNOT6L acts as a miRNA sponge to absorb miR-99a-5p and then regulates the expression of serine proteinase inhibitor (SERPINE1). In the further rescue experiment, overexpressing SERPINE1 could rescue the cell apoptotic signals due to circCNOT6L depletion. In conclusion, CircCNOT6L attenuated the cell apoptotic signal of astrocytes via the miR99a-5p/SERPINE1 axis and then alleviated injury after hypoxia induced by ischemic stroke.
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Affiliation(s)
- Wanting He
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lian Gu
- First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jialei Yang
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Ruirui Zhang
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Jianxiong Long
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Wenyi Peng
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Baoyun Liang
- First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Lulu Zhu
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Miao Lv
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Aruo Nan
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China.
| | - Li Su
- School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, Guangxi, China.
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Kozłowska-Masłoń J, Guglas K, Kolenda T, Lamperska K, Makałowska I. miRNA in head and neck squamous cell carcinomas: promising but still distant future of personalized oncology. Rep Pract Oncol Radiother 2023; 28:681-697. [PMID: 38179293 PMCID: PMC10764040 DOI: 10.5603/rpor.96666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/24/2023] [Indexed: 01/06/2024] Open
Abstract
Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Lack of appropriate preventive screening tests, late detection, and high heterogeneity of these tumors are the main reasons for the unsatisfactory effects of therapy and, consequently, unfavorable outcomes for patients. An opportunity to improve the quality of diagnostics and treatment of this group of cancers are microRNAs (miRNAs) - molecules with a great potential both as biomarkers and therapeutic targets. This review aims to present the characteristics of these short non-coding RNAs (ncRNAs) and summarize the current reports on their use in oncology focused on medical strategies tailored to patients' needs.
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Affiliation(s)
- Joanna Kozłowska-Masłoń
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Katarzyna Lamperska
- Laboratory of Cancer Genetics, Greater oland Cancer Centre, Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Poznan, Poland
| | - Izabela Makałowska
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Poznan, Poland
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11
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Li L, Li F, Xu Z, Li L, Hu H, Li Y, Yu S, Wang M, Gao L. Identification and validation of SERPINE1 as a prognostic and immunological biomarker in pan-cancer and in ccRCC. Front Pharmacol 2023; 14:1213891. [PMID: 37680718 PMCID: PMC10482042 DOI: 10.3389/fphar.2023.1213891] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023] Open
Abstract
Background: SERPINE1, a serine protease inhibitor involved in the regulation of the plasminogen activation system, was recently identified as a cancer-related gene. However, its clinical significance and potential mechanisms in pan-cancer remain obscure. Methods: In pan-cancer multi-omics data from public datasets, including The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), and online web tools were used to analyze the expression of SERPINE1 in different cancers and its correlation with prognosis, genetic alteration, DNA promoter methylation, biological processes, immunoregulator expression levels, immune cell infiltration into tumor, tumor mutation burden (TMB), microsatellite instability (MSI), immunotherapy response and drug sensitivity. Further, two single-cell databases, Tumor Immune Single-cell Hub 2 (TISCH2) and CancerSEA, were used to explore the expression and potential roles of SERPINE1 at a single-cell level. The aberrant expression of SERPINE1 was further verified in clear cell renal cell carcinoma (ccRCC) through qRT-PCR of clinical patient samples, validation in independent cohorts using The Gene Expression Omnibus (GEO) database, and proteomic validation using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Results: The expression of SERPINE1 was dysregulated in cancers and enriched in endothelial cells and fibroblasts. Copy number amplification and low DNA promoter methylation could be partly responsible for high SERPINE1 expression. High SERPINE1 expression was associated with poor prognosis in 21 cancers. The results of gene set enrichment analysis (GSEA) indicated SERPINE1 involvement in the immune response and tumor malignancy. SERPINE1 expression was also associated with the expression of several immunoregulators and immune cell infiltration and could play an immunosuppression role. Besides, SERPINE1 was found to be related with TMB, MSI, immunotherapy response and sensitivity to several drugs in cancers. Finally, the high expression of SERPINE1 in ccRCC was verified using qRT-PCR performed on patient samples, six independent GEO cohorts, and proteomic data from the CPTAC database. Conclusion: The findings of the present study revealed that SERPINE1 exhibits aberrant expression in various types of cancers and is associated with cancer immunity and tumor malignancy, providing novel insights for individualized cancer treatment.
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Affiliation(s)
- Lingqin Li
- Department of Operating Room, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, HangZhou, China
| | - Fan Li
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhehao Xu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liyang Li
- University of New South Wales, School of Medicine, Sydney, NSW, Australia
| | - Haiyi Hu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yang Li
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shicheng Yu
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingchao Wang
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lei Gao
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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12
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Collins KE, Wang X, Klymenko Y, Davis NB, Martinez MC, Zhang C, So K, Buechlein A, Rusch DB, Creighton CJ, Hawkins SM. Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis. Front Endocrinol (Lausanne) 2023; 14:1162786. [PMID: 37621654 PMCID: PMC10445169 DOI: 10.3389/fendo.2023.1162786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
Introduction Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.
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Affiliation(s)
- Kaitlyn E. Collins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Xiyin Wang
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Yuliya Klymenko
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Noah B. Davis
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Maria C. Martinez
- Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kaman So
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Aaron Buechlein
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Douglas B. Rusch
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN, United States
| | - Chad J. Creighton
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Shannon M. Hawkins
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, United States
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Wang B, Gu B, Zhang T, Li X, Wang N, Ma C, Xiang L, Wang Y, Gao L, Yu Y, Song K, He P, Wang Y, Zhu J, Chen H. Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors. Cancer Lett 2023; 559:216117. [PMID: 36889376 DOI: 10.1016/j.canlet.2023.216117] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.
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Affiliation(s)
- Bofang Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Baohong Gu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Tao Zhang
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xuemei Li
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Na Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Chenhui Ma
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lin Xiang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yunpeng Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yang Yu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Kewei Song
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Puyi He
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yueyan Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Jingyu Zhu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, Gansu, China; Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu, China; Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
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Kumari P, Kumar S, Sethy M, Bhue S, Mohanta BK, Dixit A. Identification of therapeutically potential targets and their ligands for the treatment of OSCC. Front Oncol 2022; 12:910494. [PMID: 36203433 PMCID: PMC9530560 DOI: 10.3389/fonc.2022.910494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Recent advancements in cancer biology have revealed molecular changes associated with carcinogenesis and chemotherapeutic exposure. The available information is being gainfully utilized to develop therapies targeting specific molecules involved in cancer cell growth, survival, and chemoresistance. Targeted therapies have dramatically increased overall survival (OS) in many cancers. Therefore, developing such targeted therapies against oral squamous cell carcinoma (OSCC) is anticipated to have significant clinical implications. In the current work, we have identified drug-specific sensitivity-related prognostic biomarkers (BOP1, CCNA2, CKS2, PLAU, and SERPINE1) using gene expression, Cox proportional hazards regression, and machine learning in OSCC. Dysregulation of these markers is significantly associated with OS in many cancers. Their elevated expression is related to cellular proliferation and aggressive malignancy in various cancers. Mechanistically, inhibition of these biomarkers should significantly reduce cellular proliferation and metastasis in OSCC and should result in better OS. It is pertinent to note that no effective small-molecule candidate has been identified against these biomarkers to date. Therefore, a comprehensive in silico drug design strategy assimilating homology modeling, extensive molecular dynamics (MD) simulation, and ensemble molecular docking has been applied to identify potential compounds against identified targets, and potential molecules have been identified. We hope that this study will help in deciphering potential genes having roles in chemoresistance and a significant impact on OS. It will also result in the identification of new targeted therapeutics against OSCC.
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Affiliation(s)
- Pratima Kumari
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology (RCB), Faridabad, India
| | - Sugandh Kumar
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
| | - Madhusmita Sethy
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
| | - Shyamlal Bhue
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology (RCB), Faridabad, India
| | - Bineet Kumar Mohanta
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
- Regional Centre for Biotechnology (RCB), Faridabad, India
| | - Anshuman Dixit
- Computational Biology and Bioinformatics Laboratory, Institute of Life Sciences, Bhubaneswar, India
- *Correspondence: Anshuman Dixit,
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Mortazavi-Jahromi SS, Aslani M. Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation. Int Immunopharmacol 2022; 110:109040. [PMID: 35839566 PMCID: PMC9271492 DOI: 10.1016/j.intimp.2022.109040] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/02/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022]
Abstract
Known as a pivotal immunohemostatic response, immunothrombosis is activated to restrict the diffusion of pathogens. This beneficial intravascular defensive mechanism represents the close interaction between the immune and coagulation systems. However, its uncontrolled form can be life-threatening to patients with the critical coronavirus disease 2019 (COVID-19). Hyperinflammation and ensuing cytokine storm underlie the activation of the coagulation system, something which results in the provocation of more immune-inflammatory responses by the thrombotic mediators. This vicious cycle causes grave clinical complications and higher risks of mortality. Classified as an evolutionarily conserved family of the small non-coding RNAs, microRNAs (miRNAs) serve as the fine-tuners of genes expression and play a key role in balancing the pro/anticoagulant and pro-/anti-inflammatory factors maintaining homeostasis. Therefore, any deviation from their optimal expression levels or efficient functions can lead to severe complications. Despite their extensive effects on the molecules and processes involved in uncontrolled immunothrombosis, some genetic agents and uncontrolled immunothrombosis-induced interfering factors (e.g., miRNA-single nucleotide polymorphysms (miR-SNPs), the complement system components, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and reactive oxygen species (ROS)) have apparently disrupted their expressions/functions. This review study aims to give an overview of the role of miRNAs in the context of uncontrolled immunothrombosis/thromboinflammation accompanied by some presumptive interfering factors affecting their expressions/functions in the critical COVID-19. Detecting, monitoring, and resolving these interfering agents mafy facilitate the design and development of the novel miRNAs-based therapeutic approaches to the reduction of complications incidence and mortality in patients with the critical COVID-19.
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Affiliation(s)
- Seyed Shahabeddin Mortazavi-Jahromi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Department of Cellular and Molecular Biology, Kish International Campus, University of Tehran, Kish, Iran.
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Identification of Potential miRNA-mRNA Regulatory Network in the Development of Oral Cancer. DISEASE MARKERS 2022; 2022:9376608. [PMID: 36033831 PMCID: PMC9410825 DOI: 10.1155/2022/9376608] [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: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 11/18/2022]
Abstract
Background Oral cancer is a difficult question in modern medical system, and there are few effective strategies to completely heal these diseases. This research investigated the miRNA-mRNA network in oral cancer development via bioinformatics excavation. Methods GSE28100 and GSE23558 in the GEO database were selected for bioinformatics analysis. The datasets were analyzed with GEO2R to obtain the related matrix files. The hot plot and heatmap of the matrix files were drawn with R language. The MiRDIP database was applied to predict and screen the targets of miRNAs. The DEGs in the matrix files were analyzed with the DAVID database and visualized with R language for enrichment analysis. The PPI-network of the DEGs was established with the STRING database and Cytoscape. Besides, the miRNA-mRNA was visualized by Cytoscape. Results 35 genes were identified as the DEGs in GES28100. 1651 genes were identified as the DEGs in GSE23558. 143 common genes in the targets of miRNAs in GSE28100 and the DEGs in GSE the targets of DEGs in GES28100 and common genes were enriched in the PI3K/AKT pathway, MAPK pathway, etc. The DEGs in GSE28100 and GSE23558 were involved in the regulations of transcription from RNA polymerase II promoter and DNA transcription. The DEGs in GSE28100 and GSE23558 were established with the miRNA-mRNA network. Conclusion This research identified miR-15b-5p, miR-199a-3p, miR-21-5p, miR-424-5p, and miR-454-3p as the biomarker of oral cancer and established the miRNA-mRNA network in oral progression.
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Minemura C, Asai S, Koma A, Kase-Kato I, Tanaka N, Kikkawa N, Kasamatsu A, Yokoe H, Hanazawa T, Uzawa K, Seki N. Identification of Tumor-Suppressive miR-30e-3p Targets: Involvement of SERPINE1 in the Molecular Pathogenesis of Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2022; 23:ijms23073808. [PMID: 35409173 PMCID: PMC8998321 DOI: 10.3390/ijms23073808] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 02/04/2023] Open
Abstract
Recently, our studies revealed that some passenger strands of microRNAs (miRNAs) were closely involved in cancer pathogenesis. Analysis of miRNA expression signatures showed that the expression of miR-30e-3p (the passenger strand of pre-miR-30e) was significantly downregulated in cancer tissues. In this study, we focused on miR-30e-3p (the passenger strand of pre-miR-30e). We addressed target genes controlled by miR-30e-3p that were closely associated with the molecular pathogenesis of head and neck squamous cell carcinoma (HNSCC). Ectopic expression assays demonstrated that the expression of miR-30e-3p attenuated cancer cell malignant phenotypes (e.g., cell proliferation, migration, and invasive abilities). Our analysis of miR-30e-3p targets revealed that 11 genes (ADA, CPNE8, C14orf126, ERGIC2, HMGA2, PLS3, PSMD10, RALB, SERPINE1, SFXN1, and TMEM87B) were expressed at high levels in HNSCC patients. Moreover, they significantly predicted the short survival of HNSCC patients based on 5-year overall survival rates (p < 0.05) in The Cancer Genome Atlas (TCGA). Among these targets, SERPINE1 was found to be an independent prognostic factor for patient survival (multivariate Cox regression; hazard ratio = 1.6078, p < 0.05). Aberrant expression of SERPINE1 was observed in HNSCC clinical samples by immunohistochemical analysis. Functional assays by targeting SERPINE1 expression revealed that the malignant phenotypes (e.g., proliferation, migration, and invasion abilities) of HNSCC cells were suppressed by the silencing of SERPINE1 expression. Our miRNA-based approach will accelerate our understanding of the molecular pathogenesis of HNSCC.
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Affiliation(s)
- Chikashi Minemura
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
- Department of Oral and Maxillofacial Surgery, National Defense Medical College Hospital, Tokorozawa 359-8513, Japan;
| | - Shunichi Asai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (S.A.); (N.K.)
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan;
| | - Ayaka Koma
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
| | - Ikuko Kase-Kato
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
| | - Nozomi Tanaka
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
| | - Naoko Kikkawa
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (S.A.); (N.K.)
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan;
| | - Atsushi Kasamatsu
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
| | - Hidetaka Yokoe
- Department of Oral and Maxillofacial Surgery, National Defense Medical College Hospital, Tokorozawa 359-8513, Japan;
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan;
| | - Katsuhiro Uzawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (C.M.); (A.K.); (I.K.-K.); (N.T.); (A.K.); (K.U.)
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (S.A.); (N.K.)
- Correspondence: ; Tel.: +81-43-226-2971; Fax: +81-43-227-3442
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Zhang S, Zhang W, Zhang J. Comprehensive analysis of immune cell infiltration and significant genes in head and neck squamous cell carcinoma. Oral Oncol 2022; 126:105755. [PMID: 35144208 DOI: 10.1016/j.oraloncology.2022.105755] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/13/2022] [Accepted: 01/26/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Immunotherapy directed at the tumor microenvironment is effective in the treatment of head and neck squamous cell carcinoma (HNSCC). In contrast, there has been a paucity of research on the relationship between the HNSCC microenvironment and prognostic outcome. Meanwhile, tumor immune cell infiltration (ICI) has emerged as a critical step in immunotherapy. METHODS Two algorithms, CIBERSORT and ESTIMATE, were performed to evaluate the ICI view of 885 HNSCC patients using three databases: the Cancer Genome Atlas (TCGA), Arrayexpress, and Gene Expression Omnibus (GEO). RESULTS Different ICI subtypes were identified. Following that, 57 different expression genes (DEGs) were discovered. The ICI scores of all patients were calculated using the Principal Component Analysis (PCA) algorithm. Additionally, an immune-related prognostic signature was developed and validated using 17 of 57 DEGs. Patients with a low-ICI or low-risk score had a higher infiltration immune-activated related cells and higher expression of most immune checkpoint-related molecules, indicating a better prognosis. Furthermore, using the pRRophetic algorithm, the sensitivities of many chemotherapeutic drugs were significantly different between two ICI subtypes or two risk groups. Moreover, a nomogram incorporating the ICI score, risk score, and clinical characteristics was developed and was capable of accurately predicting outcomes. CONCLUSION The ICI score and 17-gene signature could improve HNSCC survival prediction, promote individual treatment strategies, and provide promising novel immunotherapy biomarkers.
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Affiliation(s)
- Shoujing Zhang
- Department of Oral and Maxillofacial Surgery, Tianjin Medical University School and Hospital of Stomatology, Tianjin 300070, China
| | - Wenyi Zhang
- Department of Prosthodontics, Tianjin Medical University School and Hospital of Stomatology, Tianjin 300070, China
| | - Jian Zhang
- Department of Oral and Maxillofacial Surgery, Tianjin Medical University School and Hospital of Stomatology, Tianjin 300070, China.
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Mehterov N, Vladimirov B, Sacconi A, Pulito C, Rucinski M, Blandino G, Sarafian V. Salivary miR-30c-5p as Potential Biomarker for Detection of Oral Squamous Cell Carcinoma. Biomedicines 2021; 9:biomedicines9091079. [PMID: 34572265 PMCID: PMC8465705 DOI: 10.3390/biomedicines9091079] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/16/2021] [Accepted: 08/20/2021] [Indexed: 01/22/2023] Open
Abstract
The levels of different classes of extracellular RNAs (exRNAs) remain stable in bodily fluids. The detection of either enriched or depleted specific subsets of salivary microRNAs (miRNAs) has the potential to serve as a non-invasive approach for biomarker development. Thus, salivary miRNAs have emerged as a promising molecular tool for early diagnosis and screening of oral squamous cell carcinoma (OSCC). Total RNA was extracted from saliva supernatant of 33 OSCC patients and 12 controls (discovery set), and the differential expression of 8 cancer-related miRNAs was detected by TaqMan assay. Among the screened miRNAs, miR-30c-5p (p < 0.04) was significantly decreased in OSCC saliva. The same transcriptional behavior of miR30c-5p was observed in an additional validation set. miR-30c-5p showed a significant statistical difference between cases and controls with areas under the curve (AUC) of 0.82 (95% CI: 0.71–0.89). The sensitivity and the specificity of miR-30c-5p were 86% and 74%, respectively. The target identification analysis revealed enrichment of miR-30c-5p targets in p53 and Wnt signaling pathways in OSCC. Additionally, the miR-30c-5p targets had clinical significance related to overall survival. In conclusion, these findings show that downregulated miR-30c-5p has the potential to serve as a novel, non-invasive biomarker for early OSCC detection.
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Affiliation(s)
- Nikolay Mehterov
- Department of Medical Biology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
- Correspondence: ; Tel.: +359-897-837-998
| | - Boyan Vladimirov
- Department of Maxillofacial Surgery, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Andrea Sacconi
- UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Claudio Pulito
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Marcin Rucinski
- Department of Histology and Embryology, Poznan University of Medical Sciences, 61-781 Poznan, Poland;
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.P.); (G.B.)
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria
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