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Zhang Y, Zhao Y, Zhang BA. Machine Learning-Based Identification of Survival-Associated CpG Biomarkers in Pancreatic Ductal Adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.29.646090. [PMID: 40236182 PMCID: PMC11996429 DOI: 10.1101/2025.03.29.646090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally aggressive cancer with a 5-year survival rate of less than 10%, driven by late-stage diagnosis, limited treatment options, and a lack of reliable biomarkers for early detection and prognosis. In this study, we integrated DNA methylation data from TCGA and ICGC cohorts, categorizing samples based on survival time, and identified 684 differentially methylated CpG sites, along with 224 CpG biomarkers significantly associated with patient survival through statistical and machine learning-based analyses. We developed a random forest model to predict patient survival, achieving 85.2% accuracy for short-survival patients and 70.0% for long-survival patients in the validation set. External dataset validation further confirmed the model's robustness and accuracy. De novo motif analysis of genomic regions surrounding the 224 CpG biomarkers identified TWIST1 and FOXA2 as key transcriptional regulators enriched in survival-associated CpG sites, linking their activity to patient survival outcomes. Collectively, our findings highlight valuable epigenetic biomarkers and provide a predictive model to assess PDAC risk levels post-surgery, offering the potential for improved patient stratification and personalized therapeutic strategies.
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Wang R, Liao Z, Liu C, Yu S, Xiang K, Wu T, Feng J, Ding S, Yu T, Cheng G, Li S. CRABP2 promotes cell migration and invasion by activating PI3K/AKT and MAPK signalling pathways via upregulating LAMB3 in prostate cancer. J Biochem 2024; 176:313-324. [PMID: 39038078 DOI: 10.1093/jb/mvae052] [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: 10/26/2023] [Revised: 07/02/2024] [Accepted: 07/12/2024] [Indexed: 07/24/2024] Open
Abstract
Prostate cancer (PCa) has become a worldwide health burden among men. Previous studies have suggested that cellular retinoic acid binding protein 2 (CRABP2) significantly affects the regulation of cell proliferation, motility and apoptosis in multiple cancers; however, the effect of CRABP2 on PCa is poorly reported. CRABP2 expression in different PCa cell lines and its effect on different cellular functions varied. While CRABP2 promotes cell migration and invasion, it appears to inhibit cell proliferation specifically in PC-3 cells. However, the proliferation of DU145 and 22RV1 cells did not appear to be significantly affected by CRABP2. Additionally, CRABP2 had no influence on the cell cycle distribution of PCa cells. The RNA-seq assay showed that overexpressing CRABP2 upregulated laminin subunit beta-3 (LAMB3) mRNA expression, and the enrichment analyses revealed that the differentially expressed genes were enriched in the phosphoinositide 3-kinase (PI3K)/activated protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signalling pathways. The following western blot experiments also confirmed the upregulated LAMB3 protein level and the activation of the PI3K/AKT and MAPK signalling pathways. Moreover, overexpressing CRABP2 significantly inhibited tumour growth in vivo. In conclusion, CRABP2 facilitates cell migration and invasion by activating PI3K/AKT and MAPK signalling pathways through upregulating LAMB3 in PCa.
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Affiliation(s)
- Rui Wang
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Zhaoping Liao
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Chunhua Liu
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Shifang Yu
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Kaihua Xiang
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Ting Wu
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Jie Feng
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Senjuan Ding
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Tingao Yu
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Gang Cheng
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
| | - Sanlian Li
- Department of Transfusion, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang 310009, China
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Yu F, Zeng G, Yang L, Zhou H, Wang Y. LAMB3: Central role and clinical significance in neoplastic and non-neoplastic diseases. Biomed Pharmacother 2024; 178:117233. [PMID: 39111076 DOI: 10.1016/j.biopha.2024.117233] [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: 05/25/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/25/2024] Open
Abstract
Recently, topics related to targeted gene therapy and diagnosis have become increasingly important in disease research. The progression of many diseases is associated with specific gene signaling pathways. Therefore, the identification of precise gene targets in various diseases is crucial for the development of effective treatments. Laminin subunit beta 3 (LAMB3), a component of laminin 5, functions as an adhesive protein in the extracellular matrix and plays a vital role in regulating cell proliferation, migration, and cell cycle in certain diseases. Previous studies have indicated that LAMB3 is highly expressed in numerous tumorous and non-tumorous conditions, including renal fibrosis; squamous cell carcinoma of the skin, thyroid, lung, pancreatic, ovarian, colorectalr, gastric, breast, cervical, nasopharyngeal, bladder, prostate cancers; and cholangiocarcinoma. Conversely, it is underexpressed in other conditions, such as hepatocellular carcinoma, epidermolysis bullosa, and amelogenesis imperfecta. Consequently, LAMB3 may serve as a molecular diagnostic and therapeutic target for various diseases through its involvement in critical gene signaling pathways. This paper reviews the research status of LAMB3 and its role in related diseases.
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Affiliation(s)
- Fangqiu Yu
- Urological Department, First Hospital of Jilin University, Changchun, Jilin Province 130021, China
| | - Guoqiang Zeng
- Urological Department, First Hospital of Jilin University, Changchun, Jilin Province 130021, China
| | - Lei Yang
- Urological Department, First Hospital of Jilin University, Changchun, Jilin Province 130021, China
| | - Honglan Zhou
- Urological Department, First Hospital of Jilin University, Changchun, Jilin Province 130021, China
| | - Yuantao Wang
- Urological Department, First Hospital of Jilin University, Changchun, Jilin Province 130021, China.
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Kong MW, Li XR, Gao Y, Yang TF. Tumor-related factor complement Clq/TNF-related protein 6 affects the development of digestive system tumors through the phosphatidylinositol 3-kinase pathway. World J Gastroenterol 2024; 30:3206-3209. [PMID: 39086639 PMCID: PMC11287406 DOI: 10.3748/wjg.v30.i26.3206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/03/2024] [Accepted: 06/19/2024] [Indexed: 07/09/2024] Open
Abstract
In this editorial, we review the work of Razali et al published in World J Gastroenterology, with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase (PI3K) pathway and buparlisib on colitis-associated cancer. The role of PI3K in promoting cancer progression has been widely recognized, as it is involved in regulating the survival, differentiation, and proliferation of cancer cells. The complement Clq/TNF-related protein 6 (CTRP6) is a newer tumor-associated factor. Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer, hepatocellular carcinoma, colorectal cancer, and other gastrointestinal tumors through the PI3K pathway. This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.
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Affiliation(s)
- Mo-Wei Kong
- Department of Cardiology, Guiqian International General Hospital, Guiyang 550018, Guizhou Province, China
| | - Xin-Rui Li
- Department of Cardiology, Guiqian International General Hospital, Guiyang 550018, Guizhou Province, China
| | - Yu Gao
- Department of Endocrinology, The Affiliated Hospital of Chengde Medical College, Chengde 067000, Hebei Province, China
| | - Ting-Fang Yang
- Department of Oncology, Guiqian International General Hospital, Guiyang 550018, Guizhou Province, China
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Zhang Y, Zhang Y, Song J, Cheng X, Zhou C, Huang S, Zhao W, Zong Z, Yang L. Targeting the "tumor microenvironment": RNA-binding proteins in the spotlight in colorectal cancer therapy. Int Immunopharmacol 2024; 131:111876. [PMID: 38493688 DOI: 10.1016/j.intimp.2024.111876] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/04/2024] [Accepted: 03/13/2024] [Indexed: 03/19/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate among cancers. The development of CRC involves both genetic and epigenetic abnormalities, and recent research has focused on exploring the ex-transcriptome, particularly post-transcriptional modifications. RNA-binding proteins (RBPs) are emerging epigenetic regulators that play crucial roles in post-transcriptional events. Dysregulation of RBPs can result in aberrant expression of downstream target genes, thereby affecting the progression of colorectal tumors and the prognosis of patients. Recent studies have shown that RBPs can influence CRC pathogenesis and progression by regulating various components of the tumor microenvironment (TME). Although previous research on RBPs has primarily focused on their direct regulation of colorectal tumor development, their involvement in the remodeling of the TME has not been systematically reported. This review aims to highlight the significant role of RBPs in the intricate interactions within the CRC tumor microenvironment, including tumor immune microenvironment, inflammatory microenvironment, extracellular matrix, tumor vasculature, and CRC cancer stem cells. We also highlight several compounds under investigation for RBP-TME-based treatment of CRC, including small molecule inhibitors such as antisense oligonucleotides (ASOs), siRNAs, agonists, gene manipulation, and tumor vaccines. The insights gained from this review may lead to the development of RBP-based targeted novel therapeutic strategies aimed at modulating the TME, potentially inhibiting the progression and metastasis of CRC.
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Affiliation(s)
- Yiwei Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; Queen Mary School, Nanchang University, 330006 Nanchang, China
| | - Yujun Zhang
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China
| | - Jingjing Song
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China; School of Ophthalmology and Optometry of Nanchang University, China
| | - Xifu Cheng
- School of Ophthalmology and Optometry of Nanchang University, China
| | - Chulin Zhou
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Shuo Huang
- The Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Wentao Zhao
- The 3rd Clinical Department of China Medical University, 10159 Shenyang, China
| | - Zhen Zong
- Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, 330006 Nanchang, China.
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rd., Nanchang 330006, Jiangxi, China.
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