Dataset Information

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

ABSTRACT: Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.

SUBMITTER: Sudo G

PROVIDER: S-EPMC8486202 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

Sudo Gota G Aoki Hironori H Yamamoto Eiichiro E Takasawa Akira A Niinuma Takeshi T Yoshido Ayano A Kitajima Hiroshi H Yorozu Akira A Kubo Toshiyuki T Harada Taku T Ishiguro Kazuya K Kai Masahiro M Katanuma Akio A Yamano Hiro-O HO Osanai Makoto M Nakase Hiroshi H Suzuki Hiromu H

Cancer science 20210812 10

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was ...[more]

PMID: 34293235

Similar Datasets

Project description:BACKGROUND:Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1β (IL-1β), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1β release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands. METHODS:Purified (> 99%) microglia cultured from neonatal rat cortex and cerebellum were first primed with the putative TLR4/TLR2 agonist SAA (recombinant human Apo-SAA) or the established TLR4 agonist lipopolysaccharide (LPS) followed by addition of ATP. Expression of genes for the NLRP3 inflammasome, IL-1β, tumor necrosis factor-α (TNF-α), and SAA1 was measured by quantitative real-time polymerase chain reaction (q-PCR). Intracellular and extracellular amounts of IL-1β were determined by ELISA. RESULTS:Apo-SAA stimulated, in a time-dependent manner, the expression of NLRP3, IL-1β, and TNF-α in cortical microglia, and produced a concentration-dependent increase in the intracellular content of IL-1β in these cells. A 2-h 'priming' of the microglia with Apo-SAA followed by addition of ATP for 1 h, resulting in a robust release of IL-1β into the culture medium, with a concomitant reduction in its intracellular content. The selective P2X7R antagonist A740003 blocked ATP-dependent release of IL-1β. Microglia prepared from rat cerebellum displayed similar behaviors. As with LPS, Apo-SAA upregulated SAA1 and TLR2 mRNA, and downregulated that of TLR4. LPS was less efficacious than Apo-SAA, perhaps reflecting an action of the latter at TLR4 and TLR2. The TLR4 antagonist CLI-095 fully blocked the action of LPS, but only partially that of Apo-SAA. Although the TLR2 antagonist CU-CPT22 was inactive against Apo-SAA, it also failed to block the TLR2 agonist Pam3CSK4. CONCLUSIONS:Microglia are central to the inflammatory process and a major source of IL-1β when activated. P2X7R-triggered IL-1β maturation and export is thus likely to represent an important contributor to this cytokine pool. Given that SAA is detected in Alzheimer disease and multiple sclerosis brain, together with IL-1β-immunopositive microglia, these findings propose a link between P2X7R, SAA, and IL-1β in CNS pathophysiology.

Dataset Information

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

Publications

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets