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Liu Y, Yang L, Wang J, Song L. Physicochemical and colon cancer HT-29 cell inhibitory property of homogeneous polysaccharide from Stropharia rugosoannulata. Int J Biol Macromol 2025; 307:141975. [PMID: 40081691 DOI: 10.1016/j.ijbiomac.2025.141975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 01/23/2025] [Accepted: 03/10/2025] [Indexed: 03/16/2025]
Abstract
The development of active polysaccharides from edible mushrooms for antitumor drugs or functional foods has become a research hotspot. In this study, the physicochemical properties and monosaccharide composition of four homogeneous polysaccharides (CASP-0, CASP-1, CASP-2 and CASP-3) purified from alkali-extracted Stropharia rugosoannulata polysaccharides by DEAE-52 column were investigated, and the inhibitory effect against colon cancer HT-29 cell in vitro were explored. Results showed that four polysaccharides were homogeneous with molecular weights of 84.8 KDa (CASP-0), 11.1 KDa (CASP-1), 58.6 KDa (CASP-2) and 97.8 KDa (CASP-3). CASP-0 and CASP-3 contained glucose, mannose and galactose in molar ratios of 83.76:13.96:2.27 and 89.72:4.68:5.59, while CASP-1 and CASP-2 contained glucan. The four polysaccharides significantly reduced the cell viability of HT-29 cell in dose-dependent and time-dependent manner. With the increase of polysaccharide concentration, CASPs significantly inhibited the migration and invasion of HT-29 cell. The four polysaccharides induced HT-29 cell apoptosis by up-regulating the expression of Caspase-3 and Bax protein, and down-regulating the expression of Bcl-2 protein, suggesting that HT-29 cell apoptosis may be a mitochondria-mediated pathway. This study provides a theoretical basis for the potential application in medicine and functional food.
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Affiliation(s)
- Yong Liu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China.
| | - Linyuan Yang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
| | - Junhui Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, People's Republic of China
| | - Liyuan Song
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, People's Republic of China
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Yang H, Liu J, Yang N, Fu Q, Wang Y, Ye M, Tao S, Liu X, Li Q. Enhancing metastatic colorectal cancer prediction through advanced feature selection and machine learning techniques. Int Immunopharmacol 2024; 142:113033. [PMID: 39226823 DOI: 10.1016/j.intimp.2024.113033] [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: 06/28/2024] [Revised: 08/15/2024] [Accepted: 08/25/2024] [Indexed: 09/05/2024]
Abstract
BACKGROUND AND AIMS Colorectal cancer (CRC) is the third most prevalent cancer globally, posing a significant challenge due to its high rate of metastasis. Approximately 20% of patients with CRC present with distant metastases at diagnosis, and over 50% develop metastases within five years. Accurate prediction of metastasis is crucial for improving survival outcomes in patients with CRC. METHODS This study introduces an innovative cost-sensitive fast correlation-based filter (CS-FCBF) algorithm for feature selection, integrated with machine learning techniques to predict metastatic CRC. The CS-FCBF algorithm effectively reduced the number of genomic features from 184 to 9 critical genes: CXCL9, C2CD4B, RGCC, GFI1, BEX2, CXCL3, FOXQ1, PBK, and PLAG1. The methodology combined in vitro, in vivo, and analysis of publicly available single-cell RNA-seq datasets to validate the findings. RESULTS The application of the CS-FCBF algorithm led to a significant improvement in prediction model performance, with an average 21.16% increase in the area under the precision-recall curve. The nine identified genes hold potential as diagnostic biomarkers and therapeutic targets for metastatic CRC. CONCLUSIONS This study highlights the critical role of advanced feature selection methods, combined with machine learning, in addressing the challenge of class imbalance in medical diagnosis, particularly for CRC. Early detection of metastasis is vital, and the identified genes underscore their importance in the metastatic process of CRC. The methodology applied here offers valuable insights and paves the way for future research in other cancers or diseases that face similar diagnostic challenges.
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Affiliation(s)
- Hui Yang
- Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China; Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Jun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Na Yang
- Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China; Clinical Research Center for Critical Respiratory Medicine of Anhui Province, Wuhu, Anhui, China
| | - Qingsheng Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Yingying Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, China
| | - Mingquan Ye
- Research Center of Health Big Data Mining and Applications, School of Medical Information, Wannan Medical College, Wuhu, Anhui, China
| | - Shaoneng Tao
- Department of Nuclear Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, China.
| | - Xiaocen Liu
- Department of Nuclear Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, China.
| | - Qingqing Li
- Research Center of Health Big Data Mining and Applications, School of Medical Information, Wannan Medical College, Wuhu, Anhui, China.
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Wang J, Cheng H, Zhao X, Zhang X, Ding X, Huang T. Imperatorin Suppresses Aberrant Hedgehog Pathway and Overcomes Smoothened Antagonist Resistance via STAT3 Inhibition. Drug Des Devel Ther 2024; 18:5307-5322. [PMID: 39588392 PMCID: PMC11586484 DOI: 10.2147/dddt.s482894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 11/09/2024] [Indexed: 11/27/2024] Open
Abstract
Background Hyperactive Hedgehog (Hh) signaling initiates and drives the progression of various tumors. Despite the clinical success of Hh inhibitors targeting Smoothened (SMO), drug resistance, often stemming from SMO mutations, remains a formidable obstacle in cancer therapy. Here, we investigated the potential of imperatorin (IMP), a Chinese herbal medicine, to overcome drug resistance and revealed the potential mechanisms. Methods The effect of IMP on Hh signaling pathway was evaluated via Quantitative reverse transcription-polymerase chain reaction, Dual-luciferase reporter assay and Western blot. Meanwhile, we tested its ani-proliferative potential on Hh-driven tumor cells. Loss/gain-of-function, network pharmacology analysis, RNA-sequence analysis and molecular docking were performed to investigate the potential mechanisms of IMP-mediated functions. Furthermore, we established a subcutaneous Hh-driven medulloblastoma xenograft model using the DAOY cell line and examined the in vivo therapeutic efficacy of IMP. Results We identified IMP as a novel Hh inhibitor capable of overcoming drug-resistance caused by SMO mutants by inhibiting downstream transcription factor GLI1. IMP suppressed the proliferation of Hh-dependent cancer cells along with Hh activity inhibition. Mechanistically, IMP attenuated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and its interaction with GLI1 promoter, consequently blocking GLI1 transcription and the target gene expressions. Molecular docking analysis revealed the favorable binding affinity between IMP and STAT3. Importantly, IMP application effectively inhibited the growth of medulloblastoma in vivo, accompanied by the downregulation of GLI1 and phosphorylated STAT3. Conclusion Our findings revealed IMP as an innovative approach to combat the drug resistance of SMO inhibitors in Hh-driven tumors, highlighting the crucial role of STAT3 as a transcriptional regulator in Hh signaling.
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Affiliation(s)
- Juan Wang
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China
| | - Hua Cheng
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA
| | - Xinyue Zhao
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China
| | - Xiuwen Zhang
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China
| | - Xiaolei Ding
- Department of Pharmacy, School of Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China
| | - Taomin Huang
- Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China
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Zhao H, Zhao H, Ji S. A Mesenchymal stem cell Aging Framework, from Mechanisms to Strategies. Stem Cell Rev Rep 2024; 20:1420-1440. [PMID: 38727878 DOI: 10.1007/s12015-024-10732-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2024] [Indexed: 08/13/2024]
Abstract
Mesenchymal stem cells (MSCs) are extensively researched for therapeutic applications in tissue engineering and show significant potential for clinical use. Intrinsic or extrinsic factors causing senescence may lead to reduced proliferation, aberrant differentiation, weakened immunoregulation, and increased inflammation, ultimately limiting the potential of MSCs. It is crucial to comprehend the molecular pathways and internal processes responsible for the decline in MSC function due to senescence in order to devise innovative approaches for rejuvenating senescent MSCs and enhancing MSC treatment. We investigate the main molecular processes involved in senescence, aiming to provide a thorough understanding of senescence-related issues in MSCs. Additionally, we analyze the most recent advancements in cutting-edge approaches to combat MSC senescence based on current research. We are curious whether the aging process of stem cells results in a permanent "memory" and if cellular reprogramming may potentially revert the aging epigenome to a more youthful state.
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Affiliation(s)
- Hongqing Zhao
- Nanbu County People's Hospital, Nanchong City, 637300, Sichuan Province, China
- Jinzhou Medical University, No.82 Songpo Road, Guta District, Jinzhou, 121001, Liaoning Province, China
| | - Houming Zhao
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China
| | - Shuaifei Ji
- Graduate School of PLA Medical College, Chinese PLA General Hospital, Beijing, 100083, China.
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Khorshid Sokhangouy S, Alizadeh F, Lotfi M, Sharif S, Ashouri A, Yoosefi Y, Bozorg Qomi S, Abbaszadegan MR. Recent advances in CRISPR-Cas systems for colorectal cancer research and therapeutics. Expert Rev Mol Diagn 2024; 24:677-702. [PMID: 39132997 DOI: 10.1080/14737159.2024.2388777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/28/2024] [Indexed: 08/13/2024]
Abstract
INTRODUCTION Colon cancer, ranked as the fourth leading global cause of cancer death, exhibits a complex progression marked by genetic variations. Over the past decade, the utilization of diverse CRISPR systems has propelled accelerated research into colorectal cancer (CRC) treatment. AREAS COVERED CRISPR/Cas9, a key player in this research, identifies new oncogenes, tumor suppressor genes (TSGs), and drug-resistance genes. Additionally, it facilitates the construction of experimental models, conducts genome-wide library screening, and develops new therapeutic targets, especially for targeted knockout in vivo or molecular targeted drug delivery, contributing to personalized treatments and significantly enhancing the care of colon cancer patients. In this review, we provide insights into the mechanism of the CRISPR/Cas9 system, offering a comprehensive exploration of its applications in CRC, spanning screening, modeling, gene functions, diagnosis, and gene therapy. While acknowledging its transformative potential, the article highlights the challenges and limitations of CRISPR systems. EXPERT OPINION The application of CRISPR/Cas9 in CRC research provides a promising avenue for personalized treatments. Its potential for identifying key genes and enabling experimental models and genome-wide screening enhances patient care. This review underscores the significance of CRISPR-Cas9 gene editing technology across basic research, diagnosis, and the treatment landscape of colon cancer.
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Affiliation(s)
| | - Farzaneh Alizadeh
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Lotfi
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Sharif
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Atefeh Ashouri
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yasamin Yoosefi
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeed Bozorg Qomi
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Ren S, Zhou R, Tang Z, Song Z, Li N, Shi X, Liu Y, Chu Y. Wuling capsule modulates macrophage polarization by inhibiting the TLR4-NF-κB signaling pathway to relieve liver fibrosis. Int Immunopharmacol 2024; 129:111598. [PMID: 38309092 DOI: 10.1016/j.intimp.2024.111598] [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: 11/20/2023] [Revised: 01/15/2024] [Accepted: 01/24/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND AND PURPOSE Wuling capsule (WL) has good efficacy in the clinical treatment of chronic hepatitis B and liver injury. Liver fibrosis is a common pathological feature of chronic liver disease and may progress to irreversible cirrhosis and liver cancer. Accumulating evidence reveals that modulating macrophage polarization contribute to the therapy of liver fibrosis. However, the effects of WL on modulating macrophage polarization to relive liver fibrosis remain unclear. This study investigated the anti-liver fibrosis effects of WL in carbon tetrachloride (CCl4)-induced liver fibrosis in rats, and the modulation effects and underlying molecular mechanism on macrophage polarization. METHODS A rat liver fibrosis model was constructed by intraperitoneal injection of 40 % CCl4 olive oil mixture. At 2, 4, 6, and 8 weeks, the histopathological status of the liver was assessed by hematoxylin-eosin (HE) and Masson staining; the liver biochemical indexes were measured in rat liver tissue. The expression levels of inflammatory cytokines in liver tissue were detected by ELISA. The mRNA levels and proteins expression of macrophage markers of different phenotypes, TLR4-NF-κB signaling pathway indicators were detected independently by ELISA, immunofluorescence, RT-PCR and western blotting. RESULTS In vivo, WL treatment attenuated abnormal changes in weight, organ indices and biochemical indices, alleviated pathological changes, and reduced collagen fiber deposition as well as the expression of α-SMA in liver tissues. Further studies revealed that WL decreased the expression of the macrophage M1 polarization markers inducible nitric oxide synthase (iNOS), TNF-α, IL-6, and CD86, promoted the expression of the M2 macrophage polarization markers IL-10, CD206, and arginase-1 (Arg-1), and inhibited the activation of the TLR4-NF-κB signaling pathway via several key signaling proteins. In vitro, WL significantly suppressed macrophage M1 polarization, and promoted M2 polarization while boosted M1 polarization transform to M2 polarization in LPS-activated RAW264.7 cells. CONCLUSIONS This study demonstrated that WL modulated macrophage polarization against liver fibrosis mainly by inhibiting the activation of the TLR4-NF-κB signaling pathway.
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Affiliation(s)
- Sujuan Ren
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China
| | - Rui Zhou
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China.
| | - Zhishu Tang
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China; China Academy of Chinese Medical Sciences, Beijing 100029, China.
| | - Zhongxing Song
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China
| | - Nan Li
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China
| | - Xinbo Shi
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China
| | - Yanru Liu
- Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi Innovative Drug Research Center, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712000, China
| | - Yajun Chu
- Tsing Hua De Ren Xi'an Happiness Pharmaceutical Co., Ltd., Xi'an 710000, China
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An SX, Yu ZJ, Fu C, Wei MJ, Shen LH. Biological factors driving colorectal cancer metastasis. World J Gastrointest Oncol 2024; 16:259-272. [PMID: 38425391 PMCID: PMC10900157 DOI: 10.4251/wjgo.v16.i2.259] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/23/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
Approximately 20% of colorectal cancer (CRC) patients present with metastasis at diagnosis. Among Stage I-III CRC patients who undergo surgical resection, 18% typically suffer from distal metastasis within the first three years following initial treatment. The median survival duration after the diagnosis of metastatic CRC (mCRC) is only 9 mo. mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue, allowing cancer cells to spread from primary to distant organs; however, increasing evidence suggests that the mCRC process can begin early in tumor development. CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations. Different genomic and nongenomic events can induce subclone diversity, which leads to cancer and metastasis. Throughout the course of mCRC, metastatic cascades are associated with invasive cancer cell migration through the circulatory system, extravasation, distal seeding, dormancy, and reactivation, with each step requiring specific molecular functions. However, cancer cells presenting neoantigens can be recognized and eliminated by the immune system. In this review, we explain the biological factors that drive CRC metastasis, namely, genomic instability, epigenetic instability, the metastatic cascade, the cancer-immunity cycle, and external lifestyle factors. Despite remarkable progress in CRC research, the role of molecular classification in therapeutic intervention remains unclear. This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.
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Affiliation(s)
- Shuai-Xing An
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
- BD Department, Greenpine Pharma Group Co., Ltd, Tianjin 300020, China
| | - Zhao-Jin Yu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Chen Fu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Min-Jie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, Liaoning Province, China
- Liaoning Key Laboratory of Molecular Targeted Antitumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang 110122, Liaoning Province, China
| | - Long-Hai Shen
- Center of Oncology, Genertec Liaoyou Gem Flower Hospital, PanJin 124010, Liaoning Province, China
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Sun Q, Tao Q, Ming T, Tang S, Zhao H, Liu M, Yang H, Ren S, Lei J, Liang Y, Peng Y, Wang M, Xu H. Berberine is a suppressor of Hedgehog signaling cascade in colorectal cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 114:154792. [PMID: 37028248 DOI: 10.1016/j.phymed.2023.154792] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/01/2023] [Accepted: 03/28/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a malignant affliction that burdens people globally. Overactivated Hedgehog signal is highly implicated in CRC pathogenesis. Phytochemical berberine exerts strong potency on CRC, with molecular mechanism elusive. PURPOSE We sought to study berberine's anti-CRC action and explore its underlying mechanism based on Hedgehog signaling cascade. METHODS In CRC HCT116 cells and SW480 cells treated with berberine, the proliferation, migration, invasion, clonogenesis, apoptosis and cell cycle were measured, with determination of Hedgehog signaling pathway activity. Following establishment of mouse model of HCT116 xenograft tumor, the efficacies of berberine on carcinogenesis, pathological manifestation and malignant phenotypes of CRC were examined, with analysis of Hedgehog signaling axis in HCT116 xenograft tumor tissues. Additionally, toxicological study of berberine was conducted on zebrafish. RESULTS Berberine was discovered to suppress the proliferation, migration, invasion and clonogenesis of HCT116 cells and SW480 cells. Furthermore, berberine caused cell apoptosis and blockaded cell cycle at phase G0/G1 in CRC cells, with dampened Hedgehog signaling cascade. In HCT116 xenograft tumor of nude mice, berberine inhibited tumor growth, alleviated pathological score, and promoted apoptosis and cell cycle arrest in tumor tissues, through constraining Hedgehog signaling. The toxicological study of berberine on zebrafish indicated that berberine incurred damage to the liver and heart of zebrafish at high dosage and prolonged administration. CONCLUSIONS Taken together, berberine may inhibit the malignant phenotypes of CRC through diminishing Hedgehog signaling cascade. However, the potential adverse reactions should be taken into account upon abuse of berberine.
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Affiliation(s)
- Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Qiu Tao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tianqi Ming
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shun Tang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jiarong Lei
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuanjing Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuhui Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Minmin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Department of Pharmacology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Wu X, Wang Q, Liu P, Sun L, Wang Y. Potential value of the homologous recombination deficiency signature we developed in the prognosis and drug sensitivity of gastric cancer. Front Genet 2022; 13:1026871. [PMID: 36468004 PMCID: PMC9709314 DOI: 10.3389/fgene.2022.1026871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/28/2022] [Indexed: 10/29/2023] Open
Abstract
Background: Homologous recombination is an important DNA repair mechanism, which deficiency is a common feature of many cancers. Defining homologous recombination deficiency (HRD) status can provide information for treatment decisions of cancer patients. HRD score is a widely accepted method to evaluate HRD status. This study aimed to explored HRD in gastric cancer (GC) patients' clinical outcomes with genes related to HRD score and HRD components score [HRD-loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (NtAI)]. Methods: Based on LOH, NtAI scores, LST, and integrated HRD scores-related genes, a risk model for stratifying 346 TCGA GC cases were developed by Cox regression analysis and LASSO Cox regression. The risk scores of 33 cancers in TCGA were calculated to analyze the relationship between risk scores of each cancer and HRD scores and 3 HRD component scores. Relationship between the risk model and patient survival, BRCA1, BRCA2 mutation, response to Cisplatin and Talazoparib treatment was analyzed by generating Kaplan-Meier curve, mutations waterfall map and conducting Pearson correlation analysis. Results: An gene signature was constructed based on 11 HRD scores-related gene (BEX2, C1QL2, DKK1, DRC1, GLUD2, HCAR1, IGFBP1, NXPH1, PROC, SERPINA5, and SLCA1A2). Risk groups were stratified by risk score. Prognosis of the high-risk score group was worse than the low-risk ones. Risk score was associated with BRCA2 mutation, and patients grouped according to BRCA2 mutation status had distinguishable risk score, NtAI score, HRD-LOH, LST, and HRD scores. The low-score group showed higher sensitivity to Cisplatin and Talazoparib. The risk score of adrenocortical carcinoma (ACC), stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC), kidney renal clear cell carcinoma (KIRC), sarcoma (SARC), prostate adenocarcinoma (PRAD), breast invasive carcinoma (BRCA) was significantly positively correlated with HRD score. Conclusion: We developed an 11 HRD scores-related genes risk model and revealed the potential association between HRD status and GC prognosis, gene mutations, patients' sensitivity to therapeutic drugs.
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Affiliation(s)
- Xin Wu
- Department of General Surgical Medicine, The First Medical Center of PLA General Hospital, Beijing, China
| | - Qiong Wang
- Pathology Department, The First Medical Center of PLA General Hospital, Beijing, China
| | - Peifa Liu
- Department of General Surgical Medicine, The First Medical Center of PLA General Hospital, Beijing, China
| | - Linde Sun
- Department of General Surgical Medicine, The First Medical Center of PLA General Hospital, Beijing, China
| | - Yu Wang
- Department of General Surgical Medicine, The First Medical Center of PLA General Hospital, Beijing, China
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10
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Gonzalez-Salinas F, Martinez-Amador C, Trevino V. Characterizing genes associated with cancer using the CRISPR/Cas9 system: A systematic review of genes and methodological approaches. Gene 2022; 833:146595. [PMID: 35598687 DOI: 10.1016/j.gene.2022.146595] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/22/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022]
Abstract
The CRISPR/Cas9 system enables a versatile set of genomes editing and genetic-based disease modeling tools due to its high specificity, efficiency, and accessible design and implementation. In cancer, the CRISPR/Cas9 system has been used to characterize genes and explore different mechanisms implicated in tumorigenesis. Different experimental strategies have been proposed in recent years, showing dependency on various intrinsic factors such as cancer type, gene function, mutation type, and technical approaches such as cell line, Cas9 expression, and transfection options. However, the successful methodological approaches, genes, and other experimental factors have not been analyzed. We, therefore, initially considered more than 1,300 research articles related to CRISPR/Cas9 in cancer to finally examine more than 400 full-text research publications. We summarize findings regarding target genes, RNA guide designs, cloning, Cas9 delivery systems, cell enrichment, and experimental validations. This analysis provides valuable information and guidance for future cancer gene validation experiments.
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Affiliation(s)
- Fernando Gonzalez-Salinas
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Morones Prieto avenue 3000, Monterrey, Nuevo Leon 64710, Mexico
| | - Claudia Martinez-Amador
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Morones Prieto avenue 3000, Monterrey, Nuevo Leon 64710, Mexico
| | - Victor Trevino
- Tecnologico de Monterrey, School of Medicine and Health Sciences, Morones Prieto avenue 3000, Monterrey, Nuevo Leon 64710, Mexico; Tecnologico de Monterrey, The Institute for Obesity Research, Eugenio Garza Sada avenue 2501, Monterrey, Nuevo Leon 64849, México.
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11
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Aisa A, Tan Y, Li X, Zhang D, Shi Y, Yuan Y. Comprehensive Analysis of the Brain-Expressed X-Link Protein Family in Glioblastoma Multiforme. Front Oncol 2022; 12:911942. [PMID: 35860560 PMCID: PMC9289282 DOI: 10.3389/fonc.2022.911942] [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: 04/03/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common, malignant, and deadly primary brain tumor in adults. Brain-expressed X-link (BEX) protein family is involved in tumorigenesis. Here, we have explored the biological function and the prognostic value of the BEX family in GBM. Differentially expressed BEX genes between GBM and normal tissue were screened by using The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses identified the prognosis‐related genes BEX1, BEX2, and BEX4, which were involved in the regulation of immune response. The results of correlation analysis and protein–protein interaction network (PPI network) showed that there was a significant correlation between the BEX family and TCEAL family in GBM. Furthermore, the expression of transcription elongation factor A (SII)-like (TCEAL) family is generally decreased in GBM and related to poor prognosis. With the use of the least absolute shrinkage and selection operator (LASSO) Cox regression, a prognostic model including the BEX family and TCEAL family was built to accurately predict the likelihood of overall survival (OS) in GBM patients. Therefore, we demonstrated that the BEX family and TCEAL family possessed great potential as therapeutic targets and prognostic biomarkers in GBM. Further investigations in large‐scale, multicenter, and prospective clinical cohorts are needed to confirm the prognostic model developed in our study.
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Affiliation(s)
- Adilai Aisa
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yinuo Tan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xinyu Li
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Ding Zhang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yun Shi
- Nursing Department, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- *Correspondence: Ying Yuan,
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12
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Da W, Yinhang W, Jing Z, Jiamin X, Xinyi G, Yongmao S, Yuefen P. Immune-Related Biomarkers Associated with Lung Metastasis from the Colorectal Cancer Microenvironment. J Interferon Cytokine Res 2022; 42:220-234. [PMID: 35576491 PMCID: PMC9142768 DOI: 10.1089/jir.2021.0214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Immune-associated biomarkers can predict lung metastases from colorectal cancer. Differentially expressed genes (DEGs) were screened from sample data extracted from gene expression omnibus (GEO) database. The DEGs were screened from the lung metastasis (LM) and primary cancer (PC) groups of the Moffitt Cancer Center cohort dataset. Then, the tumor immune microenvironment and abundance of immune cell infiltration analyses were performed, and the immune-related DEGs were retrieved. In addition, the transcription factor (TF)-miRNA-mRNA network was constructed and enrichment analyses of the immune-related DEGs and upregulated and downregulated DEGs were carried out. Then, the protein-protein interaction (PPI) network was conducted and the drug-gene interaction was predicted. A total of 268 DEGs were screened. The Immune_Score of samples in the LM group was significantly higher compared with the PC group. The infiltration ratio of M0 macrophages and M2 macrophages of samples was higher than others. A total of 54 immune-related DEGs in M0 macrophages were screened. Moreover, the TF-miRNA-mRNA network was constructed among 8 miRNA-mRNA and 50 TF-mRNA, and the secreted phosphoprotein 1 was regulated by 12 TFs, and the oxidized low-density lipoprotein receptor 1 was regulated by 3 miRNAs and 3 TFs. The TF SAM pointed domain containing ETS TF was also a downregulated DEG. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the DEGs in the TF-miRNA-mRNA network were mainly involved in the interleukin-7 signaling pathway and cell adhesion molecules. In total, 23 protein interactions in this PPI network of M0 macrophage cells were involved in 27 mRNAs. There were 38 drug-gene interactions of immune-related DEGs of M0 macrophage cells predicted to contain 34 small molecule drugs and 8 mRNAs. Finally, the CON cohort dataset verified that the infiltration ratio of M0 and M2 macrophages of the samples was higher.
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Affiliation(s)
- Wang Da
- Department of Colorectal Surgery, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education (Key Laboratory of Molecular Biology in Medical Sciences); The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education (Key Laboratory of Molecular Biology in Medical Sciences); The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wu Yinhang
- Graduate School of Second Clinical Medicine Faculty, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhuang Jing
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, China
| | - Xu Jiamin
- Department of Nursing, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Gao Xinyi
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Hangzhou, China
| | - Song Yongmao
- Department of Colorectal Surgery, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education (Key Laboratory of Molecular Biology in Medical Sciences); The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education (Key Laboratory of Molecular Biology in Medical Sciences); The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pan Yuefen
- Department of Oncology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou, China
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13
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Sun Y, Zhao J. Transcription Elongation Factor A (SII)-Like (TCEAL) Gene Family Member-TCEAL2: A Novel Prognostic Marker in Pan-Cancer. Cancer Inform 2022; 21:11769351221126285. [PMID: 36199541 PMCID: PMC9527986 DOI: 10.1177/11769351221126285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Cancer is the leading cause of death in the world. The mechanism is not fully elucidated and the therapeutic effect is also unsatisfactory. In our study, we aim to find new target gene in pan-cancer. Methods: Differently expressed genes (DEGs) was screened out in various types of cancers from GEO database. The expression of DEG (TCEAL2) in tumor cell lines, normal tissues and tumor tissues was calculated. Then the clinical characteristics, DNA methylation, tumor infiltration and gene enrichment of TCEAL2 was studied. Results: TCEAL2 expressions were down-regulated in most cancers. Its expression and methylation were positively or negatively associated with prognosis in different cancers. The tumor infiltration results revealed that TCEAL2 was significantly related with many immune cells especially NK cells and immune-related genes in majority cancers. Furthermore, tau protein and tubulin binding were involved in the molecular function mechanisms of TCEAL2. Conclusion: TCEAL2 may be a novel prognostic marker in different cancers and may affect tumor through immune infiltration.
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Affiliation(s)
- Yu Sun
- Department of Nuclear Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jun Zhao
- Department of Nuclear Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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14
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Bahadar N, Ullah H, Adlat S, Kumar Sah R, Zun Zaw Myint M, Mar Oo Z, Binta Bah F, Hayel Nagi F, Htoo H, Ud Din A, Feng X, Zheng Y. Analyzing differentially expressed genes and pathways of Bex2-deficient mouse lung via RNA-Seq. Turk J Biol 2021; 45:588-598. [PMID: 34803456 PMCID: PMC8574191 DOI: 10.3906/biy-2104-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/28/2021] [Indexed: 11/17/2022] Open
Abstract
Bex2 is well known for its role in the nervous system, and is associated with neurological disorders, but its role in the lung’s physiology is still not reported. To elucidate the functional role of Bex2 in the lung, we generated a Bex2 knock-out (KO) mouse model using the CRISPR-Cas9 technology and performed transcriptomic analysis. A total of 652 genes were identified as differentially expressed between Bex2-/- and Bex2+/+ mice, out of which 500 were downregulated, while 152 were upregulated genes. Among these DEGs, Ucp1, Myh6, Coxa7a1, Myl3, Ryr2, RNaset2b, Npy, Enob1, Krt5, Myl2, Hba-a2, and Nrob2 are the most prominent genes. Myl2, was the most downregulated gene, followed by Npy, Hba-a2, Rnaset2b, nr0b2, Klra8, and Ucp1. Tcte3, Eno1b, Zfp990, and Pcdha9 were the most upregulated DEGs. According to gene enrichment analysis, PPAR pathway, cardiac muscle contraction, and cytokine-cytokine receptor interaction were the most enriched pathways. Besides, the nuclear factor-κB signaling pathway and hematopoietic cell linage pathways were also enriched. Chronic obstructive pulmonary disease (COPD) is enriched among KEGG disease pathways. RT-qPCR assays confirmed the RNA-Seq results. This study opens a new window toward the biological functions of Bex2 in different systems.
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Affiliation(s)
- Noor Bahadar
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Hanif Ullah
- School of medicine, Tsinghua University, Beijing China
| | - Salah Adlat
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Rajiv Kumar Sah
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - May Zun Zaw Myint
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Zin Mar Oo
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Fatoumata Binta Bah
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Farooq Hayel Nagi
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Hsu Htoo
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Ahmad Ud Din
- Drug Discovery Research Center, Southwest Medical University, Luzhou China
| | - Xuechao Feng
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
| | - Yaowu Zheng
- Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin China
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15
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Shi W, Li X, Su X, Wen H, Chen T, Wu H, Liu M. The role of multiple metabolic genes in predicting the overall survival of colorectal cancer: A study based on TCGA and GEO databases. PLoS One 2021; 16:e0251323. [PMID: 34398900 PMCID: PMC8367004 DOI: 10.1371/journal.pone.0251323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 04/25/2021] [Indexed: 12/22/2022] Open
Abstract
The recent advances in gene chip technology have led to the identification of multiple metabolism-related genes that are closely associated with colorectal cancer (CRC). Nevertheless, none of these genes could accurately diagnose or predict CRC. The prognosis of CRC has been made by previous prognostic models constructed by using multiple genes, however, the predictive function of multi-gene prognostic models using metabolic genes for the CRC prognosis remains unexplored. In this study, we used the TCGA-CRC cohort as the test dataset and the GSE39582 cohort as the experimental dataset. Firstly, we constructed a prognostic model using metabolic genes from the TCGA-CRC cohort, which were also associated with CRC prognosis. We analyzed the advantages of the prognostic model in the prognosis of CRC and its regulatory mechanism of the genes associated with the model. Secondly, the outcome of the TCGA-CRC cohort analysis was validated using the GSE39582 cohort. We found that the prognostic model can be employed as an independent prognostic risk factor for estimating the CRC survival rate. Besides, compared with traditional clinical pathology, it can precisely predict CRC prognosis as well. The high-risk group of the prognostic model showed a substantially lower survival rate as compared to the low-risk group. In addition, gene enrichment analysis of metabolic genes showed that genes in the prognostic model are enriched in metabolism and cancer-related pathways, which may explain its underlying mechanism. Our study identified a novel metabolic profile containing 11 genes for prognostic prediction of CRC. The prognostic model may unravel the imbalanced metabolic microenvironment, and it might promote the development of biomarkers for predicting treatment response and streamlining metabolic therapy in CRC.
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Affiliation(s)
- Weijun Shi
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xincan Li
- Department of General Medicine, Second Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xu Su
- School of Life Sciences, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
| | - Hexin Wen
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Tianwen Chen
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Huazhang Wu
- School of Life Sciences, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
- * E-mail: (HW); (ML)
| | - Mulin Liu
- Department of Gastroenterology, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- * E-mail: (HW); (ML)
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16
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Yamamoto-Shimojima K, Osawa M, Saito MK, Yamamoto T. Induced pluripotent stem cells established from a female patient with Xq22 deletion confirm that BEX2 escapes from X-chromosome inactivation. Congenit Anom (Kyoto) 2021; 61:63-67. [PMID: 33244819 DOI: 10.1111/cga.12403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/30/2020] [Accepted: 11/23/2020] [Indexed: 11/27/2022]
Abstract
Large deletions in Xq22 are responsible for neurodevelopmental disorders, including severe intellectual disability and behavioral abnormalities. Although the deletion regions contain PLP1, the gene related to Pelizaeus-Merzbacher disease (PMD), patients with Xq22 deletions show no clinical features of PMD such as paraplegia and white matter abnormalities. This could be due to skewed X-chromosome inactivation (XCI) occurring predominantly in the affected allele. Isogenic pairs of wild type and mutant induced pluripotent stem cells (iPSCs) were established from the patient. In the iPSC line in which the wild type allele was inactivated, PLP1 was not expressed, but biallelic expression of BEX2 was identified. This suggests that BEX2 escaped from XCI and haploinsufficiency of BEX2 may be related to the phenotype of Xq22 deletions.
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Affiliation(s)
| | - Mitsujiro Osawa
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Megumu K Saito
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Toshiyuki Yamamoto
- Institute of Medical Genetics, Tokyo Women's Medical genetics, Tokyo, Japan
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17
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Xu M, Wang J, Li H, Zhang Z, Cheng Z. AIM2 inhibits colorectal cancer cell proliferation and migration through suppression of Gli1. Aging (Albany NY) 2020; 13:1017-1031. [PMID: 33291082 PMCID: PMC7835022 DOI: 10.18632/aging.202226] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is a common malignant tumor and is one of the leading causes of cancer-related deaths worldwide. Absent in melanoma 2 (AIM2), as a member of the pyrin-HIN family proteins, plays contentious roles in different types of cancers. In the present work, we provide evidence that AIM2 was commonly downregulated in human CRC and loss of AIM2 significantly correlated with tumor size, depth of invasion, lymph node metastasis (LNM) and TNM (Tumor, Node, Metastases) stage in patients suffering from CRC. AIM2 knockdown promoted CRC cell proliferation, migration and epithelial-mesenchymal transition (EMT) progress, whereas AIM2 overexpression did the opposite. AIM2 inhibited glioma-associated oncogene-1 (Gli1) expression through Smoothened homolog (SMO)-independent pathway and regulated CRC cell proliferation and migration in a Gli1-dependent manner. Moreover, AIM2 could modulate Protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway and the increased Gli1 expression and EMT progress induced by AIM2 depletion was reversed after incubation with AKT inhibitor Ly294002 in CRC cells. In conclusion, our results define AIM2 as a novel regulator of Gli1 in CRC cell growth and metastasis, and suggest that the AIM2/AKT/mTOR/Gli1 signaling axis may serve as a potential target for treatment of CRC.
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Affiliation(s)
- Menglin Xu
- Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Junfeng Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Haoran Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Zhengrong Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
| | - Zhengwu Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China
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18
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Chen W, Liu X. Proteoform Identification by Combining RNA-Seq and Top-Down Mass Spectrometry. J Proteome Res 2020; 20:261-269. [PMID: 33183009 DOI: 10.1021/acs.jproteome.0c00369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In proteogenomic studies, genomic and transcriptomic variants are incorporated into customized protein databases for the identification of proteoforms, especially proteoforms with sample-specific variants. Most proteogenomic research has been focused on combining genomic or transcriptomic data with bottom-up mass spectrometry data. In the last decade, top-down mass spectrometry has attracted increasing attention because of its capacity to identify various proteoforms with alterations. However, top-down proteogenomics, in which genomic or transcriptomic data are combined with top-down mass spectrometry data, has not been widely adopted, and there is still a lack of software tools for top-down proteogenomic data analysis. In this paper, we introduce TopPG, a proteogenomic tool for generating proteoform sequence databases with genetic alterations and alternative splicing events. Experiments on top-down proteogenomic data of DLD-1 colorectal cancer cells showed that TopPG coupled with database search confidently identified proteoforms with sample-specific alterations.
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Affiliation(s)
- Wenrong Chen
- Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202, United States
| | - Xiaowen Liu
- Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202, United States.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
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