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Elevated expression of complement factor I in lung cancer cells associates with shorter survival–Potentially via non-canonical mechanism

Felberg, Anna ; Bieńkowski, Michał ; Stokowy, Tomasz ; Myszczyński, Kamil ; Polakiewicz, Zuzanna ; Kitowska, Kamila ; Sądej, Rafał ; Mohlin, Frida LU ; Kuźniewska, Alicja and Kowalska, Daria , et al. (2024) In Translational Research 269. p.1-13
Abstract

While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS).... (More)

While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Complement system, Immunohistochemistry, Innate immunity, Lung cancer, NSCLC
in
Translational Research
volume
269
pages
13 pages
publisher
Elsevier
external identifiers
  • pmid:38395390
  • scopus:85188212877
ISSN
1931-5244
DOI
10.1016/j.trsl.2024.02.003
language
English
LU publication?
yes
id
b779a96d-6617-400f-b960-2ad01a39f93b
date added to LUP
2024-04-08 09:50:33
date last changed
2024-04-22 12:27:07
@article{b779a96d-6617-400f-b960-2ad01a39f93b,
  abstract     = {{<p>While numerous membrane-bound complement inhibitors protect the body's cells from innate immunity's autoaggression, soluble inhibitors like complement factor I (FI) are rarely produced outside the liver. Previously, we reported the expression of FI in non-small cell lung cancer (NSCLC) cell lines. Now, we assessed the content of FI in cancer biopsies from lung cancer patients and associated the results with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining intensity did not correlate with age, smoking status, tumor size, stage, differentiation grade, and T cell infiltrates, but was associated with progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS). Multivariate Cox analysis of low vs. high FI content revealed HR 0.55, 95 % CI 0.32-0.95, p=0.031 for PFS, HR 0.51, 95 % CI 0.25-1.02, p=0.055 for OS, and HR 0.32, 95 % CI 0.12-0.84, p=0.021 for DSS. Unfavorable prognosis might stem from the non-canonical role of FI, as the staining pattern did not correlate with C4d - the product of FI-supported degradation of active complement component C4b. To elucidate that, we engineered three human NSCLC cell lines naturally expressing FI with CRISPR/Cas9 technology, and compared the transcriptome of FI-deficient and FI-sufficient clones in each cell line. RNA sequencing revealed differentially expressed genes engaged in intracellular signaling pathways controlling proliferation, apoptosis, and responsiveness to growth factors. Moreover, in vitro colony-formation assays showed that FI-deficient cells formed smaller foci than FI-sufficient NSCLC cells, but their size increased when purified FI protein was added to the medium. We postulate that a non-canonical activity of FI influences cellular physiology and contributes to the poor prognosis of lung cancer patients.</p>}},
  author       = {{Felberg, Anna and Bieńkowski, Michał and Stokowy, Tomasz and Myszczyński, Kamil and Polakiewicz, Zuzanna and Kitowska, Kamila and Sądej, Rafał and Mohlin, Frida and Kuźniewska, Alicja and Kowalska, Daria and Stasiłojć, Grzegorz and Jongerius, Ilse and Spaapen, Robbert and Mesa-Guzman, Miguel and Montuenga, Luis M. and Blom, Anna M. and Pio, Ruben and Okrój, Marcin}},
  issn         = {{1931-5244}},
  keywords     = {{Complement system; Immunohistochemistry; Innate immunity; Lung cancer; NSCLC}},
  language     = {{eng}},
  pages        = {{1--13}},
  publisher    = {{Elsevier}},
  series       = {{Translational Research}},
  title        = {{Elevated expression of complement factor I in lung cancer cells associates with shorter survival–Potentially via non-canonical mechanism}},
  url          = {{http://dx.doi.org/10.1016/j.trsl.2024.02.003}},
  doi          = {{10.1016/j.trsl.2024.02.003}},
  volume       = {{269}},
  year         = {{2024}},
}