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Zhang Y, Zhu WL, Wu M, Gao TY, Hu HX, Xu ZY. Using bioinformatics methods to elucidate fatty acid-binding protein 4 as a potential biomarker for colon adenocarcinoma. World J Gastrointest Oncol 2025; 17:103113. [DOI: 10.4251/wjgo.v17.i4.103113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/07/2025] [Accepted: 02/14/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon adenocarcinoma (COAD) ranks second in terms of cancer-related deaths. We found that fatty acid-binding protein 4 (FABP4), which is related to cell adhesion and immunity, affects the occurrence and development of COAD. This study focused on the possibility of using FABP4 as a biomarker for COAD and constructed a nomogram for predicting the survival of COAD patients.
AIM To verify the possibility of using FABP4 as a biomarker for COAD.
METHODS A total of 453 COAD tissue samples, along with 41 normal tissue samples, were obtained from The Cancer Genome Atlas database. The difference in FABP4 expression between COAD tissues and normal tissues was analyzed, and the results were verified by immunohistochemistry. The WGCNA algorithm links FABP4 expression with an enrichment analysis and with immune cell infiltration pathways. The biological functions of FABP4 and its coexpressed genes were explored through enrichment analyses. The ESTIMATE, CIBERSORT and ssGSEA methods were used for the immune infiltration analysis. Finally, risk scores were calculated by a Cox analysis. A nomogram was constructed by combining risk scores with routine clinicopathological factors. We assessed the accuracy of survival predictions based on the C-index. The C-index ranges from 0.5 to 1.0, and in general, a C-index value greater than 0.65 indicates a reasonable estimate. The results were validated using the Gene Expression Omnibus (GEO) database.
RESULTS FABP4 was significantly differentially expressed in COAD. It is a promising auxiliary biomarker for screening and diagnosis. Enrichment analyses suggested that FABP4 may influence the invasion and progression of COAD through cell adhesion. The immunological analysis revealed that FABP4 expression in COAD was significantly positively correlated with immune cell infiltration. Moreover, a nomogram to predict the survival of COAD patients was successfully constructed by integrating the calculated risk scores of 15 candidate genes and routine clinicopathological factors. This nomogram could effectively predict 1-year, 3-year, and 5-year survival (C-index = 0.786) and was verified (C-index = 0.73).
CONCLUSION This study established FABP4 as an effective biomarker for screening, assisting in the diagnosis and determining the prognosis.
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Affiliation(s)
- Yun Zhang
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
| | - Wen-Li Zhu
- Seven Inpatient Ward, The Fourth People's Hospital of Wuhu, Wuhu 241002, Anhui Province, China
| | - Min Wu
- Sixteen Inpatient Ward, The Fourth People's Hospital of Wuhu, Wuhu 241002, Anhui Province, China
| | - Tian-Yuan Gao
- Department of Pathology, The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, Anhui Province, China
| | - Hui-Xian Hu
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
| | - Zheng-Yuan Xu
- Department of Medical Engineering, Wannan Medical College, Wuhu 241002, Anhui Province, China
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Angarola BL, Sharma S, Katiyar N, Kang HG, Nehar-Belaid D, Park S, Gott R, Eryilmaz GN, LaBarge MA, Palucka K, Chuang JH, Korstanje R, Ucar D, Anczukόw O. Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer. NATURE AGING 2025; 5:122-143. [PMID: 39587369 PMCID: PMC11754115 DOI: 10.1038/s43587-024-00751-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 10/16/2024] [Indexed: 11/27/2024]
Abstract
Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk.
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Affiliation(s)
| | | | - Neerja Katiyar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Hyeon Gu Kang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - SungHee Park
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Giray N Eryilmaz
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Mark A LaBarge
- Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Karolina Palucka
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Jeffrey H Chuang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Duygu Ucar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
- Institute for Systems Genomics, UConn Health, Farmington, CT, USA.
| | - Olga Anczukόw
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.
- Institute for Systems Genomics, UConn Health, Farmington, CT, USA.
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Sadhukhan P, Feng M, Illingworth E, Sloma I, Ooki A, Matoso A, Sidransky D, Johnson BA, Marchionni L, Sillé FC, Choi W, McConkey D, Hoque M. YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/STAT3 pathway and CXCL deregulation. J Clin Invest 2024; 135:e171164. [PMID: 39630608 PMCID: PMC11735109 DOI: 10.1172/jci171164] [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: 04/05/2023] [Accepted: 11/15/2024] [Indexed: 12/07/2024] Open
Abstract
The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo effector YAP1 in the tumor immune microenvironment (TIME) of urothelial carcinoma of the bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mouse and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and myeloid-derived suppressor cells in the TIME compared with YAP1-expressing cells. In summary, this study provides insights into YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating patients with UCB.
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Affiliation(s)
| | - Mingxiao Feng
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Emily Illingworth
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Ido Sloma
- Champions Oncology, R&D, Baltimore, Maryland, USA
| | - Akira Ooki
- Department of Otolaryngology–Head and Neck Surgery and
| | | | - David Sidransky
- Department of Otolaryngology–Head and Neck Surgery and
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Burles A. Johnson
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Luigi Marchionni
- Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Fenna C.M. Sillé
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Woonyoung Choi
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David McConkey
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mohammad Hoque
- Department of Otolaryngology–Head and Neck Surgery and
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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4
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Shen M, García-Marqués F, Muruganantham A, Liu S, White JR, Bermudez A, Rice MA, Thompson K, Chen CL, Hung CN, Zhang Z, Huang TH, Liss MA, Pienta KJ, Pitteri SJ, Stoyanova T. Identification of a 5-gene signature panel for the prediction of prostate cancer progression. Br J Cancer 2024; 131:1748-1761. [PMID: 39402324 PMCID: PMC11589118 DOI: 10.1038/s41416-024-02854-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 09/04/2024] [Accepted: 09/12/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Despite nearly 100% 5-year survival for localised prostate cancer, the survival rate for metastatic prostate cancer significantly declines to 32%. Thus, it is crucial to identify molecular indicators that reflect the progression from localised disease to metastatic prostate cancer. METHODS To search for molecular indicators associated with prostate cancer metastasis, we performed proteomic analysis of rapid autopsy tissue samples from metastatic prostate cancer (N = 8) and localised prostate cancer (N = 2). Then, we utilised multiple independent, publicly available prostate cancer patient datasets to select candidates that also correlate with worse prostate cancer clinical prognosis. RESULTS We identified 154 proteins with increased expressions in metastases relative to localised prostate cancer through proteomic analysis. From the subset of these candidates that correlate with prostate cancer recurrence (N = 28) and shorter disease-free survival (N = 37), we identified a 5-gene signature panel with improved performance in predicting worse clinical prognosis relative to individual candidates. CONCLUSIONS Our study presents a new 5-gene signature panel that is associated with worse clinical prognosis and is elevated in prostate cancer metastasis on both protein and mRNA levels. Our 5-gene signature panel represents a potential modality for the prediction of prostate cancer progression towards the onset of metastasis.
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Affiliation(s)
- Michelle Shen
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | | | | | - Shiqin Liu
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Abel Bermudez
- Department of Radiology, Stanford University, Stanford, CA, USA
| | - Meghan A Rice
- Department of Radiology, Stanford University, Stanford, CA, USA
| | - Kelsey Thompson
- Department of Radiology, Stanford University, Stanford, CA, USA
| | - Chun-Liang Chen
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA
- School of Nursing, UT Health San Antonio, San Antonio, TX, USA
| | - Chia-Nung Hung
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Zhao Zhang
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Tim H Huang
- Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Michael A Liss
- Department of Urology, UT Health San Antonio, San Antonio, TX, USA
| | - Kenneth J Pienta
- Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | - Tanya Stoyanova
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
- Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
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Yin Z, Gao Y, Bu X, Wang J, Yao Z, Liu Q, Zhang Y, Yu G, Ping B. Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis. Leuk Lymphoma 2024; 65:2138-2150. [PMID: 39235111 DOI: 10.1080/10428194.2024.2400228] [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: 05/03/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/06/2024]
Abstract
Venetoclax (VEN), a B-cell lymphoma 2 (BCL-2) selective inhibitor, is widely used for treating acute myeloid leukemia (AML) with promising results. However, the anti-leukemic effect of VEN in relapsed/refractory (R/R)- AML requires improvement. In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Basic research indicates that HHT combined with VEN has a highly synergistic effect against both resistant AML cells and primary cells with/without mesenchymal stem cell (MSC) co-culture in vivo, inhibiting proliferation and colony-forming capacity of AML cells associated with concomitant cell cycle arrest. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.
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Affiliation(s)
- Zhao Yin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Ya Gao
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangdong, P.R. China
| | - Xiaoyin Bu
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P.R. China
| | - Junhui Wang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Zurong Yao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, Guangdong, P.R. China
| | - Yu Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, Guangdong, P.R. China
| | - Guopan Yu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Clinical Medical Research Center of Hematological Diseases of Guangdong Province, Guangzhou, Guangdong, P.R. China
| | - Baohong Ping
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
- Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
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Ulase D, Behrens HM, Röcken C. Stroma AReactive Invasion Front Areas (SARIFA) predict poor survival in adenocarcinomas of the stomach and gastrooesophageal junction: a validation study. Virchows Arch 2024; 485:527-534. [PMID: 38748262 DOI: 10.1007/s00428-024-03826-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/03/2024] [Accepted: 05/09/2024] [Indexed: 09/21/2024]
Abstract
Recently, the presence of "Stroma AReactive Invasion Front Areas" (SARIFA) has been described as a promising adverse prognostic factor in gastric cancer. However, the validity of this approach still needs to be tested. The aim of this study was to independently assess the utility of the proposed method in a well-characterised cohort of primary resected adenocarcinomas of stomach and gastrooesophageal junction (n = 392). SARIFA status was analysed on routine slides of resection specimens. Cases were divided into SARIFA-positive and negative groups and analysed in relation to clinicopathological and survival data. SARIFA positivity was found in 15.1% (n = 59) cases and was significantly associated with Lauren phenotype (p < 0.001), pT (p = 0.001), pN (p = 0.018), UICC stage (p = 0.031), tumour budding (p = 0.002), overall survival (p < 0.001) and cancer-specific survival (p < 0.001). SARIFA-positive tumours had a worse prognosis in the multivariate setting (HR = 1.847, 95% CI: 1.300-2.624, p = 0.001). SARIFA status is an independent prognostic factor in gastric cancer, in particular in locally advanced tumours.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany.
| | - Hans-Michael Behrens
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Building U33, 24105, Kiel, Germany
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Higashide M, Watanabe M, Sato T, Umetsu A, Nishikiori N, Ogawa T, Furuhashi M, Ohguro H. FABP5 Is a Possible Factor for the Maintenance of Functions of Human Non-Pigmented Ciliary Epithelium Cells. Int J Mol Sci 2024; 25:9285. [PMID: 39273233 PMCID: PMC11394871 DOI: 10.3390/ijms25179285] [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: 06/27/2024] [Revised: 08/05/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
To elucidate the possible biological roles of fatty acid-binding protein 5 (FABP5) in the intraocular environment, the cells from which FABP5 originates were determined by using four different intraocular tissue-derived cell types including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cell lines, and the effects of FABP ligand 6, a specific inhibitor for FABP5 and FABP7 were analyzed by RNA sequencing and seahorse cellular metabolic measurements. Among these four different cell types, qPCR analysis showed that FABP5 was most prominently expressed in HNPCE cells, in which no mRNA expression of FABP7 was detected. In RNA sequencing analysis, 166 markedly up-regulated and 198 markedly down-regulated differentially expressed genes (DEGs) were detected between non-treated cells and cells treated with FABP ligand 6. IPA analysis of these DEGs suggested that FABP5 may be involved in essential roles required for cell development, cell survival and cell homeostasis. In support of this possibility, both mitochondrial and glycolytic functions of HNPCE cells, in which mRNA expression of FABP5, but not that of FABP7, was detected, were shown by using a Seahorse XFe96 Bioanalyzer to be dramatically suppressed by FABP ligand 6-induced inhibition of the activity of FABP5. Furthermore, in IPA upstream analysis, various unfolded protein response (UPR)-related factors were identified as upstream and causal network master regulators. Analysis by qPCR analysis showed significant upregulation of the mRNA expression of most of UPR-related factors and aquaporin1 (AQP1). The findings in this study suggest that HNPCE is one of intraocular cells producing FABP5 and may be involved in the maintenance of UPR and AQP1-related functions of HNPCE.
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Affiliation(s)
- Megumi Higashide
- Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Megumi Watanabe
- Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Tatsuya Sato
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
- Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Araya Umetsu
- Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Nami Nishikiori
- Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Toshifumi Ogawa
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
- Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
| | - Hiroshi Ohguro
- Departments of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
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McDermott JG, Goodlett BL, Creed HA, Navaneethabalakrishnan S, Rutkowski JM, Mitchell BM. Inflammatory Alterations to Renal Lymphatic Endothelial Cell Gene Expression in Mouse Models of Hypertension. Kidney Blood Press Res 2024; 49:588-604. [PMID: 38972305 PMCID: PMC11345939 DOI: 10.1159/000539721] [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: 10/16/2023] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
INTRODUCTION Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. METHODS We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. RESULTS Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p < 0.01), 274 significantly enriched pathways (p < 0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. CONCLUSION These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.
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Affiliation(s)
- Justin G. McDermott
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Bethany L. Goodlett
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Heidi A. Creed
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | | | - Joseph M. Rutkowski
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
| | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX 77807
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Grochowski P, Grosser B, Sommer F, Probst A, Waidhauser J, Schenkirsch G, Reitsam NG, Märkl B. The Concept of Stroma AReactive Invasion Front Areas (SARIFA) as a new prognostic biomarker for lipid-driven cancers holds true in pancreatic ductal adenocarcinoma. BMC Cancer 2024; 24:768. [PMID: 38926671 PMCID: PMC11210040 DOI: 10.1186/s12885-024-12519-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a 'difficult-to-treat' entity. To forecast its prognosis, we introduced a new biomarker, SARIFA (stroma areactive invasion front areas), which are areas at the tumour invasion front lacking desmoplastic stroma reaction upon malignant invasion in the surrounding tissue, leading to direct contact between tumour cells and adipocytes. SARIFA showed its significance in gastric and colorectal carcinoma, revealing lipid metabolism alternations that promote tumour progression. METHODS We reviewed the SARIFA status of 166 PDAC cases on all available H&E-stained tumour slides from archival Whipple-resection specimens. SARIFA positivity was defined as SARIFA detection in at least 66% of the available slides. To investigate alterations in tumour metabolism and microenvironment, we performed immunohistochemical staining for FABP4, CD36 and CD68. To verify and quantify a supposed delipidation of adipocytes, adipose tissue was digitally morphometrised. RESULTS In total, 53 cases (32%) were classified as SARIFA positive and 113 (68%) as SARIFA negative. Patients with SARIFA-positive PDAC showed a significantly worse overall survival compared with SARIFA-negative cases (median overall survival: 11.0 months vs. 22.0 months, HR: 1.570 (1.082-2.278), 95% CI, p = 0.018), which was independent from other prognostic markers (p = 0.014). At the invasion front of SARIFA-positive PDAC, we observed significantly higher expression of FABP4 (p < 0.0001) and higher concentrations of CD68+ macrophages (p = 0.031) related to a higher risk of tumour progression. CD36 staining showed no significant expression differences. The adipocyte areas at the invasion front were significantly smaller, with mean values of 4021 ± 1058 µm2 and 1812 ± 1008 µm2 for the SARIFA-negative and -positive cases, respectively (p < 0.001). CONCLUSIONS SARIFA is a promising prognostic biomarker for PDAC. Its assessment is characterised by simplicity and low effort. The mechanisms behind SARIFA suggest a tumour-promoting increased lipid metabolism and altered immune background, both showing new therapeutic avenues.
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Affiliation(s)
| | - Bianca Grosser
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Florian Sommer
- General, Visceral and Transplantation Surgery, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Andreas Probst
- Gastroenterology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Johanna Waidhauser
- Hematology and Oncology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | | | - Nic G Reitsam
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Bruno Märkl
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
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10
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Ghorbani A, Chatanaka MK, Avery LM, Wang M, Brown J, Cohen R, Gorham T, Misaghian S, Padmanabhan N, Romero D, Stengelin M, Mathew A, Sigal G, Wohlstadter J, Horbinski C, McCortney K, Xu W, Zadeh G, Mansouri A, Yousef GM, Diamandis EP, Prassas I. Glial fibrillary acidic protein, neurofilament light, matrix metalloprotease 3 and fatty acid binding protein 4 as non-invasive brain tumor biomarkers. Clin Proteomics 2024; 21:41. [PMID: 38879494 PMCID: PMC11179213 DOI: 10.1186/s12014-024-09492-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/29/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival. METHODS Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays. RESULTS High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas. CONCLUSIONS GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.
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Affiliation(s)
- Atefeh Ghorbani
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Miyo K Chatanaka
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Lisa M Avery
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Department of Biostatistics, The Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Mingyue Wang
- Meso Scale Diagnostics, LLC., Rockville, MD, USA
| | | | - Rachel Cohen
- Meso Scale Diagnostics, LLC., Rockville, MD, USA
| | - Taron Gorham
- Meso Scale Diagnostics, LLC., Rockville, MD, USA
| | | | | | | | | | - Anu Mathew
- Meso Scale Diagnostics, LLC., Rockville, MD, USA
| | - George Sigal
- Meso Scale Diagnostics, LLC., Rockville, MD, USA
| | | | - Craig Horbinski
- Feinberg School of Medicine, Northwestern Medicine, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Katy McCortney
- Feinberg School of Medicine, Northwestern Medicine, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Wei Xu
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Department of Biostatistics, The Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada
| | - Gelareh Zadeh
- MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Alireza Mansouri
- Department of Neurosurgery, Hershey Medical Center, Hershey, PA, USA
- Penn State Cancer Institute, Hershey Medical Center, Hershey, PA, USA
| | - George M Yousef
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
- Laboratory Medicine Program, University Health Network, Toronto, Canada
| | - Eleftherios P Diamandis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
| | - Ioannis Prassas
- Laboratory Medicine Program, University Health Network, Toronto, Canada.
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11
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Ohguro H, Watanabe M, Sato T, Nishikiori N, Umetsu A, Higashide M, Ogawa T, Furuhashi M. FABP4 Is an Indispensable Factor for Regulating Cellular Metabolic Functions of the Human Retinal Choroid. Bioengineering (Basel) 2024; 11:584. [PMID: 38927820 PMCID: PMC11200562 DOI: 10.3390/bioengineering11060584] [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: 05/09/2024] [Revised: 06/02/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells.
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Affiliation(s)
- Hiroshi Ohguro
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (H.O.); (M.W.); (N.N.); (A.U.); (M.H.)
| | - Megumi Watanabe
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (H.O.); (M.W.); (N.N.); (A.U.); (M.H.)
| | - Tatsuya Sato
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Nami Nishikiori
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (H.O.); (M.W.); (N.N.); (A.U.); (M.H.)
| | - Araya Umetsu
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (H.O.); (M.W.); (N.N.); (A.U.); (M.H.)
| | - Megumi Higashide
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (H.O.); (M.W.); (N.N.); (A.U.); (M.H.)
| | - Toshifumi Ogawa
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Masato Furuhashi
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
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12
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Chu Y, Zhang S, Wan W, Yang J, Zhang Y, Nie C, Xing W, Tong S, Liu J, Tian G, Wang B, Ji L. Pathological image profiling identifies onco-microbial, tumor immune microenvironment, and prognostic subtypes of colorectal cancer. APMIS 2024; 132:416-429. [PMID: 38403979 DOI: 10.1111/apm.13387] [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: 09/20/2023] [Accepted: 02/02/2024] [Indexed: 02/27/2024]
Abstract
Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.
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Affiliation(s)
- Yuwen Chu
- School of Electrical & Information Engineering, Anhui University of Technology, Anhui, China
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Shuo Zhang
- School of management, Harbin Institute of Technology, Harbin, China
| | - Wei Wan
- Department of Colorectal and Anal Surgery, Yidu Central Hospital of Weifang, Shandong, China
| | - Jialiang Yang
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Yumeng Zhang
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
- School of Mathematics and Statistics, Hainan Normal University, Haikou, China
| | - Chuanqi Nie
- School of Electrical & Information Engineering, Anhui University of Technology, Anhui, China
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Weipeng Xing
- School of Electrical & Information Engineering, Anhui University of Technology, Anhui, China
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Shanhe Tong
- School of Electrical & Information Engineering, Anhui University of Technology, Anhui, China
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Jinyang Liu
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Geng Tian
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
| | - Bing Wang
- School of Electrical & Information Engineering, Anhui University of Technology, Anhui, China
| | - Lei Ji
- Geneis Beijing Co., Ltd., Beijing, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao, China
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13
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Franzese O, Ancona P, Bianchi N, Aguiari G. Apoptosis, a Metabolic "Head-to-Head" between Tumor and T Cells: Implications for Immunotherapy. Cells 2024; 13:924. [PMID: 38891056 PMCID: PMC11171541 DOI: 10.3390/cells13110924] [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: 04/12/2024] [Revised: 05/18/2024] [Accepted: 05/22/2024] [Indexed: 06/20/2024] Open
Abstract
Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies.
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Affiliation(s)
- Ornella Franzese
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Pietro Ancona
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Nicoletta Bianchi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy;
| | - Gianluca Aguiari
- Department of Neuroscience and Rehabilitation, University of Ferrara, Via F. Mortara 74, 44121 Ferrara, Italy;
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14
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Beton-Mysur K, Kopec M, Brozek-Pluska B. Raman Imaging-A Valuable Tool for Tracking Fatty Acid Metabolism-Normal and Cancer Human Colon Single-Cell Study. Int J Mol Sci 2024; 25:4508. [PMID: 38674093 PMCID: PMC11050638 DOI: 10.3390/ijms25084508] [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: 03/27/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Altered metabolism of lipids is a key factor in many diseases including cancer. Therefore, investigations into the impact of unsaturated and saturated fatty acids (FAs) on human body homeostasis are crucial for understanding the development of lifestyle diseases. In this paper, we focus on the impact of palmitic (PA), linoleic (LA), and eicosapentaenoic (EPA) acids on human colon normal (CCD-18 Co) and cancer (Caco-2) single cells using Raman imaging and spectroscopy. The label-free nature of Raman imaging allowed us to evaluate FAs dynamics without modifying endogenous cellular metabolism. Thanks to the ability of Raman imaging to visualize single-cell substructures, we have analyzed the changes in chemical composition of endoplasmic reticulum (ER), mitochondria, lipid droplets (LDs), and nucleus upon FA supplementation. Analysis of Raman band intensity ratios typical for lipids, proteins, and nucleic acids (I1656/I1444, I1444/I1256, I1444/I750, I1304/I1256) proved that, using Raman mapping, we can observe the metabolic pathways of FAs in ER, which is responsible for the uptake of exogenous FAs, de novo synthesis, elongation, and desaturation of FAs, in mitochondria responsible for energy production via FA oxidation, in LDs specialized in cellular fat storage, and in the nucleus, where FAs are transported via fatty-acid-binding proteins, biomarkers of human colon cancerogenesis. Analysis for membranes showed that the uptake of FAs effectively changed the chemical composition of this organelle, and the strongest effect was noticed for LA. The spectroscopy studies have been completed using XTT tests, which showed that the addition of LA or EPA for Caco-2 cells decreases their viability with a stronger effect observed for LA and the opposite effect observed for PA. For normal cells, CCD-18 Co supplementation using LA or EPA stimulated cells for growing, while PA had the opposite impact.
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Affiliation(s)
| | | | - Beata Brozek-Pluska
- Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland; (K.B.-M.); (M.K.)
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15
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Reitsam NG, Grozdanov V, Löffler CML, Muti HS, Grosser B, Kather JN, Märkl B. Novel biomarker SARIFA in colorectal cancer: highly prognostic, not genetically driven and histologic indicator of a distinct tumor biology. Cancer Gene Ther 2024; 31:207-216. [PMID: 37990064 PMCID: PMC10874891 DOI: 10.1038/s41417-023-00695-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/24/2023] [Accepted: 11/08/2023] [Indexed: 11/23/2023]
Abstract
SARIFA (Stroma AReactive Invasion Front Areas) has recently emerged as a promising histopathological biomarker for colon and gastric cancer. To elucidate the underlying tumor biology, we assessed SARIFA-status in tissue specimens from The-Cancer-Genome-Atlas (TCGA) cohorts COAD (colonic adenocarcinoma) and READ (rectal adenocarcinoma). For the final analysis, 207 CRC patients could be included, consisting of 69 SARIFA-positive and 138 SARIFA-negative cases. In this external validation cohort, H&E-based SARIFA-positivity was strongly correlated with unfavorable overall, disease-specific, and progression-free survival, partly outperforming conventional prognostic factors. SARIFA-positivity was not associated with known high-risk genetic profiles, such as BRAF V600E mutations or microsatellite-stable status. Transcriptionally, SARIFA-positive CRCs exhibited an overlap with CRC consensus molecular subtypes CMS1 and CMS4, along with distinct differential gene expression patterns, linked to lipid metabolism and increased stromal cell infiltration scores (SIIS). Gene-expression-based drug sensitivity prediction revealed a differential treatment response in SARIFA-positive CRCs. In conclusion, SARIFA represents the H&E-based counterpart of an aggressive tumor biology, demonstrating a partial overlap with CMS1/4 and also adding a further biological layer related to lipid metabolism. Our findings underscore SARIFA-status as an ideal biomarker for refined patient stratification and novel drug developments, particularly given its cost-effective assessment based on routinely available H&E slides.
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Affiliation(s)
- Nic G Reitsam
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany.
| | | | - Chiara M L Löffler
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine I, University Hospital Dresden, Dresden, Germany
| | - Hannah S Muti
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
| | - Bianca Grosser
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
| | - Jakob N Kather
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine I, University Hospital Dresden, Dresden, Germany
- Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
- Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Bruno Märkl
- Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Bavarian Cancer Research Center (BZKF), Augsburg, Germany
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16
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Zuo Q, Xu Q, Li Z, Luo D, Peng H, Duan Z. TRIM3 inhibits colorectal cancer cell migration and lipid droplet formation by promoting FABP4 degradation. Histol Histopathol 2024; 39:239-250. [PMID: 37212515 DOI: 10.14670/hh-18-627] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
This study is to investigate the regulation of TRIM3/FABP4 on colorectal cancer (CRC) cell migration and lipid metabolism. After transfection of HCT116, LoVo, or SW480 cells, the expression of FABP4, TRIM3, N-cadherin, Vimentin, E-cadherin, and lipid droplet (LD) formation-related genes was measured by qRT-PCR or western blot assays. Wound healing and Transwell assays were applied to detect CRC cell migration and invasion abilities. The levels of triglyceride (TG) and total cholesterol (TC) were measured and the formation of LDs was observed. Additionally, the relationship between FABP4 and TRIM3 was confirmed by Co-IP and ubiquitination assays. Furthermore, a liver metastasis model of CRC was established to explore the effect of FABP4 on CRC tumor metastasis in vivo. FABP4 was upregulated in CRC cells. Downregulation of FABP4 or upregulation of TRIM3 resulted in repressed cell migration and invasion, decreased TG and TC levels, and reduced numbers of LDs. In nude mice, knockdown of FABP4 reduced metastatic nodules in the liver. Mechanistically, TRIM3 combined FABP4 and decreased its protein expression by ubiquitination. Overexpressed FABP4 reversed the influence of TRIM3 upregulation on CRC cell migration and LD formation. In conclusion, underexpressed TRIM3 suppressed FABP4 ubiquitination and accelerated CRC cell migration and LD formation.
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Affiliation(s)
- Qi Zuo
- Department of Emergency, The First Hospital of Changsha, Changsha, Hunan, PR China
| | - Qimei Xu
- Department of Pathology, The First Hospital of Changsha, Changsha, Hunan, PR China
| | - Zhen Li
- Department of Pathology, The First Hospital of Changsha, Changsha, Hunan, PR China
| | - Dixian Luo
- Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, PR China
| | - Hanwu Peng
- Department of Emergency, The First Hospital of Changsha, Changsha, Hunan, PR China
| | - Zhi Duan
- Department of Pathology, The First Hospital of Changsha, Changsha, Hunan, PR China.
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17
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Li Y, Lee W, Zhao ZG, Liu Y, Cui H, Wang HY. Fatty acid binding protein 5 is a novel therapeutic target for hepatocellular carcinoma. World J Clin Oncol 2024; 15:130-144. [PMID: 38292656 PMCID: PMC10823939 DOI: 10.5306/wjco.v15.i1.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 12/02/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide. Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival, growth, and evolution. Emerging evidence suggests the importance of fatty acid binding proteins (FABPs) in contribution to cancer progression and metastasis; however, how these FABPs are dysregulated in cancer cells, especially in HCC, and the roles of FABPs in cancer progression have not been well defined. AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies. METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma (LIHC) as well as patient cohorts with other cancer types in this study. We investigated genetic alterations of FABPs in various cancer types. mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome, enriched cancer hallmarks and oncogenes previously reported for patients with HCC. We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells. RESULTS We discovered that a gene cluster including five FABP family members (FABP4, FABP5, FABP8, FABP9 and FABP12) is frequently co-amplified in cancer. Amplification, in fact, is the most common genetic alteration for FABPs, leading to overexpression of FABPs. FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues. High FABP5 expression correlates well with worse patient outcomes (P < 0.05). FABP5 expression highly correlates with enrichment of G2M checkpoint (r = 0.33, P = 1.1e-10), TP53 signaling pathway (r = 0.22, P = 1.7e-5) and many genes in the gene sets such as CDK1 (r = 0.56, P = 0), CDK4 (r = 0.49, P = 0), and TP53 (r = 0.22, P = 1.6e-5). Furthermore, FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients (r = 0.58, P = 0; r = 0.58, P = 0; respectively). FABP5high Huh7 cells also expressed higher protein levels of p53, BIRC5, CDK1, CDK2, and CDK4 than FABP5low HepG2 cells. FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells. CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer, especially in HCC, leading to its significant elevated expression in HCC. Its high expression correlates well with worse patient outcome, enriched cancer hallmarks and oncogenes in HCC. FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells. All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - William Lee
- Biomedical Engineering, Texas A&M University, College Station, TX 77843, United States
| | - Zhen-Gang Zhao
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Yi Liu
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao Cui
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao-Yu Wang
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
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18
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Wu X, Yang SY, Zhang YH, Fang JZ, Wang S, Xu ZW, Zhang XJ. Prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma. World J Clin Oncol 2024; 15:45-61. [PMID: 38292659 PMCID: PMC10823936 DOI: 10.5306/wjco.v15.i1.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/03/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Heat shock protein A4 (HSPA4) belongs to molecular chaperone protein family which plays important roles within variable cellular activities, including cancer initiation and progression. However, the prognostic and immunological significance of HSPA4 in lung adenocarcinoma (LUAD) has not been revealed yet. AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD. METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database. The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test. Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors, including HSPA4, in LUAD. Gene set enrichment analysis (GSEA) was conducted to identify the key signaling pathways associated with HSPA4. The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA). RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage, advanced pathologic stage, progression disease status of primary therapy outcome and female subgroups with LUAD. In addition, increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival. GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response, particularly through diminishing the function of cytotoxicity cells and CD8 T cells. The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells, while a negative correlation was observed with cytotoxic cell infiltration levels. CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.
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Affiliation(s)
- Xuan Wu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shen-Ying Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Yi-Hua Zhang
- Graduate School, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Jin-Zhou Fang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shuai Wang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Zhi-Wei Xu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Xiao-Ju Zhang
- Department of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
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Angarola BL, Sharma S, Katiyar N, Gu Kang H, Nehar-Belaid D, Park S, Gott R, Eryilmaz GN, LaBarge MA, Palucka K, Chuang JH, Korstanje R, Ucar D, Anczukow O. Comprehensive single cell aging atlas of mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.20.563147. [PMID: 37961129 PMCID: PMC10634680 DOI: 10.1101/2023.10.20.563147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. We investigate how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory, or cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveal co-localization of aged immune and epithelial cells in situ. Lastly, transcriptional signatures of aging mammary cells are found in human breast tumors, suggesting mechanistic links between aging and cancer. Together, these data uncover that epithelial, immune, and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment, and neoplasia risk.
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Affiliation(s)
| | | | - Neerja Katiyar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Hyeon Gu Kang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - SungHee Park
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Giray N Eryilmaz
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Mark A LaBarge
- Beckman Research Institute at City of Hope, Duarte, CA, USA
| | - Karolina Palucka
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Jeffrey H Chuang
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Duygu Ucar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
- Institute for Systems Genomics, UConn Health, Farmington, CT, USA
| | - Olga Anczukow
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
- Institute for Systems Genomics, UConn Health, Farmington, CT, USA
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Zhang D, Zhao Y, Wang S, Wang X, Sun Y. A Prognostic Model of Angiogenesis and Neutrophil Extracellular Traps Related Genes Manipulating Tumor Microenvironment in Colon Cancer. J Cancer 2023; 14:2109-2127. [PMID: 37497410 PMCID: PMC10367930 DOI: 10.7150/jca.85778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023] Open
Abstract
Colon adenocarcinoma (COAD) is one of the most common carcinomas worldwide. The main causes of cancer-related mortality of COAD are metastases. The fundamental processes for how angiogenesis and neutrophil extracellular traps (NETs) contributing to tumor progression and metastasis are still uncertain. In our study, The Cancer Genome Atlas (TCGA)-COAD dataset (train set) and GSE17536 (test set) were analyzed. Angiogenesis potential index (API) and NETs potential index (NPI) based on angiogenesis and NETs-related genes were respectively built using bioinformatic methods and machine learning algorithms. Subjects were split into groups with low API/NPI or high API/NPI. Survival analysis showed the high API and high NPI patients with the worst survival compared with the others. Between the high API/NPI group and the other groups, differentially expressed genes (DEGs) were found. A four-gene signature (TIMP1, FSL3, CALB2, and FABP4) was included in a risk model based on least absolute shrinkage and selection operator (LASSO) analysis. Additionally, the model displayed a significant association with many immune microenvironment characteristics. Finally, we verified the clinical significance of CALB2 expression and its role to promote the invasion and migration of colon cancer cells in vitro.
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Affiliation(s)
- Dongsheng Zhang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yan Zhao
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Shirui Wang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaowei Wang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
| | - Yueming Sun
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
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Yang J, Liu X, Shao Y, Zhou H, Pang L, Zhu W. Diagnostic, Prognostic, and Immunological Roles of FABP4 in Pancancer: A Bioinformatics Analysis. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3764914. [PMID: 36532833 PMCID: PMC9754845 DOI: 10.1155/2022/3764914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/15/2022] [Accepted: 11/20/2022] [Indexed: 08/27/2023]
Abstract
BACKGROUND Fatty acid binding protein 4 (FABP4) is mainly involved in the regulation of systemic metabolism through various lipid signaling pathways. Metabolic reprogramming is one of the important factors in the development and progression of cancer. It has been recently reported that FABP4 is closely related to the development of cancer and may be involved in tumor invasion and metastasis. METHODS In this study, we explored the expression pattern of FABP4 in pancancer through TCGA and CPTAC. Using TCGA, Kaplan-Meier Plotter, and STRING databases, to explore its diagnostic and prognostic value, and function through GO/KEGG and GSEA. Then, using the TIMER2.0 database, we investigated the correlation between FABP4 expression and immune infiltration in cancers, especially stomach adenocarcinomas (STAD) and colorectal adenocarcinoma (COADREAD). RESULTS Compared with normal tissues, the expression of FABP4 in more than 10 tumor tissues was lower (p < 0.05). Through the receiver operating characteristic (ROC) curve, the diagnostic value was found higher in colorectal cancer, breast cancer, thyroid cancer, and lung cancer, with the area under the curve (AUC) > 0.9. Through the K-M curve, FABP4 was found to correlate to the prognosis of various cancers. The results of gastric cancer and colorectal cancer are consistent. The low-expression group has a better prognosis than the high-expression group, and the expression of FABP4 in the early T and N stages of gastrointestinal tumors is lower. FABP4 highly expressed gene set is mostly enriched in extracellular matrix degradation and cell adhesion functions. Gastrointestinal tumors with high expression of FABP4 may have more immunosuppressive effects on macrophages and have a worse prognosis. CONCLUSION FABP4 can be used as a diagnostic and prognostic biomarker in pancancer, and its high expression in gastrointestinal tumors suggests poor prognosis. This may be correlated to the immune infiltration of macrophages and epithelial-mesenchymal transition.
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Affiliation(s)
- Jing Yang
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu 215228, China
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiaojing Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Department of Radiotherapy, The Friendship Hospital of Ily Kazak Autonomous Prefecture, Ily, Xinjiang 835000, China
| | - Yueqin Shao
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu 215228, China
| | - Hong Zhou
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu 215228, China
| | - Lijun Pang
- Oncology Center, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Wujiang, Jiangsu 215228, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
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