Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer

Autor: Tsukasa Takayashiki, Shigetsugu Takano, Mamoru Takada, Reiri Shimazaki, Kazuyuki Sogawa, Kosuke Sasaki, Shingo Kagawa, Mamoru Satoh, Fumio Nomura, Satoshi Kuboki, Shinichiro Motohashi, Hideyuki Yoshitomi, Masayuki Ohtsuka, Katsunori Furukawa, Yoji Miyahara, Masaru Miyazaki
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research
Complement factor B
Stromal cell
Regulatory T-cells
endocrine system diseases
Proliferation
Apoptosis
Kaplan-Meier Estimate
Senescence
Pancreatic ductal adenocarcinoma
03 medical and health sciences
Mice
0302 clinical medicine
Pancreatic cancer
Cell Line
Tumor
medicine
Animals
Humans
Cells
Cultured
Cellular Senescence
Cell Proliferation
Secretome
Tumor microenvironment
p21
Tumor-infiltrating lymphocytes
Chemistry
FOXP3
General Medicine
medicine.disease
Prognosis
Secreted protein
digestive system diseases
Pancreatic Neoplasms
030104 developmental biology
Oncology
Cell culture
030220 oncology & carcinogenesis
Cancer cell
Multivariate Analysis
Cancer research
Molecular Medicine
Original Article
RNA Interference
Carcinoma
Pancreatic Ductal
Zdroj: Cellular Oncology (Dordrecht)
ISSN: 2211-3436
2211-3428
Popis: Background The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. Methods We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. Results Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-β-galactosidase (SA-β-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8+ tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8+/Foxp3+ Tregs populations in PDAC tissues. Conclusions Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje