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

Autor: Shimazaki R; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Takano S; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan. stakano@faculty.chiba-u.jp., Satoh M; Division of Clinical Mass Spectrometry, Chiba University Hospital, Chiba, 260-8677, Japan., Takada M; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Miyahara Y; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Sasaki K; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Yoshitomi H; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Kagawa S; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Furukawa K; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Takayashiki T; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Kuboki S; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Sogawa K; Department of Biochemistry, School of Life and Environmental Science, Azabu University, 252-5201, Kanagawa, Japan., Motohashi S; Department of Medical Immunology, Graduate School of Medicine, Chiba University, 260-8677, Chiba, Japan., Nomura F; Division of Clinical Mass Spectrometry, Chiba University Hospital, Chiba, 260-8677, Japan., Miyazaki M; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan., Ohtsuka M; Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260- 8677, Japan.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2021 Aug; Vol. 44 (4), pp. 937-950. Date of Electronic Publication: 2021 Jun 01.
DOI: 10.1007/s13402-021-00614-z
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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