Fatty acid-binding protein 1 is preferentially lost in microsatellite instable colorectal carcinomas and is immune modulated via the interferon γ pathway.
Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Stephanie M
SM
Wood
Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia.
Anthony J
AJ
Gill
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Alexander S
AS
Brodsky
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Shaolei
S
Lu
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Kenneth
K
Friedman
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Galina
G
Karashchuk
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Kara
K
Lombardo
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Dongfang
D
Yang
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Murray B
MB
Resnick
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D053842:Microsatellite Instability; D047495:PPAR gamma / Q000819:agonists; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology
C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007371:Interferon-gamma
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