Version 2 2024-02-13, 20:21Version 2 2024-02-13, 20:21
Version 1 2024-02-02, 16:17Version 1 2024-02-02, 16:17
journal contribution
posted on 2024-02-13, 20:21authored byMin 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
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.)