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Inhibition of the Alternative Complement Pathway May Cause Secretion of Factor B, Enabling an Early Detection of Pancreatic Cancer

Authors
 Min Jung Lee  ;  Jin-Young Cho  ;  Sumi Bae  ;  Hye Soo Jung  ;  Chang Moo Kang  ;  Sung Hyun Kim  ;  Hye Jin Choi  ;  Choong-Kun Lee  ;  Hoguen Kim  ;  Daewoong Jo  ;  Young-Ki Paik 
Citation
 JOURNAL OF PROTEOME RESEARCH, Vol.23(3) : 985-998, 2024-03 
Journal Title
JOURNAL OF PROTEOME RESEARCH
ISSN
 1535-3893 
Issue Date
2024-03
MeSH
Carcinoma, Pancreatic Ductal* / diagnosis ; Carcinoma, Pancreatic Ductal* / genetics ; Complement Factor B / genetics ; Complement Factor B / metabolism ; Complement Pathway, Alternative ; Early Detection of Cancer ; Humans ; Pancreatic Neoplasms* / diagnosis ; Pancreatic Neoplasms* / genetics ; Pancreatic Neoplasms* / metabolism ; Proto-Oncogene Proteins p21(ras)
Keywords
adrenomedullin ; alternative pathway ; cancer biomarker ; complement factor B ; complement factor H ; pancreatic ductal adenocarcinoma ; proteomics
Abstract
This study aims to elucidate the cellular mechanisms behind the secretion of complement factor B (CFB), known for its dual roles as an early biomarker for pancreatic ductal adenocarcinoma (PDAC) and as the initial substrate for the alternative complement pathway (ACP). Using parallel reaction monitoring analysis, we confirmed a consistent ∼2-fold increase in CFB expression in PDAC patients compared with that in both healthy donors (HD) and chronic pancreatitis (CP) patients. Elevated ACP activity was observed in CP and other benign conditions compared with that in HD and PDAC patients, suggesting a functional link between ACP and PDAC. Protein-protein interaction analyses involving key complement proteins and their regulatory factors were conducted using blood samples from PDAC patients and cultured cell lines. Our findings revealed a complex control system governing the ACP and its regulatory factors, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, adrenomedullin (AM), and complement factor H (CFH). Particularly, AM emerged as a crucial player in CFB secretion, activating CFH and promoting its predominant binding to C3b over CFB. Mechanistically, our data suggest that the KRAS mutation stimulates AM expression, enhancing CFH activity in the fluid phase through binding. This heightened AM-CFH interaction conferred greater affinity for C3b over CFB, potentially suppressing the ACP cascade. This sequence of events likely culminated in the preferential release of ductal CFB into plasma during the early stages of PDAC. (Data set ID PXD047043.) © 2024 American Chemical Society
Full Text
https://pubs.acs.org/doi/10.1021/acs.jproteome.3c00695
DOI
10.1021/acs.jproteome.3c00695
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Chang Moo(강창무) ORCID logo https://orcid.org/0000-0002-5382-4658
Kim, Sung Hyun(김성현) ORCID logo https://orcid.org/0000-0001-7683-9687
Kim, Hogeun(김호근)
Lee, Choong-kun(이충근) ORCID logo https://orcid.org/0000-0001-5151-5096
Choi, Hye Jin(최혜진) ORCID logo https://orcid.org/0000-0001-5917-1400
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/198856
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