The Complement C3a-C3a Receptor Axis Regulates Epithelial-to-Mesenchymal Transition by Activating the ERK Pathway in Pancreatic Ductal Adenocarcinoma

• Published in: Anticancer research Vol. 42; no. 3; pp. 1207 - 1215
• Main Authors: Suzuki, Rei, Okubo, Yoshinori, Takagi, Tadayuki, Sugimoto, Mitsuru, Sato, Yuki, Irie, Hiroki, Nakamura, Jun, Takasumi, Mika, Kato, Tsunetaka, Hashimoto, Minami, Kobashi, Ryouichiro, Hikichi, Takuto, Ohira, Hiromasa
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.03.2022
• Subjects: Adenocarcinoma; Aged; Aged, 80 and over; Arginine - analogs & derivatives; Arginine - pharmacology; Benzhydryl Compounds - pharmacology; Cancer; Carcinoma, Pancreatic Ductal - enzymology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Complement C3 - metabolism; Complement component C3; Complement component C3a; Complement Inactivating Agents - pharmacology; Complement receptors; Enzyme Activation; Epithelial-Mesenchymal Transition - drug effects; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Kinases; Male; Mesenchyme; Metabolic pathways; Metastases; Middle Aged; Neoplasm Invasiveness; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Receptors; Receptors, Complement - antagonists & inhibitors; Receptors, Complement - genetics; Receptors, Complement - metabolism; Serum levels; Signal Transduction; Tissues; Tumors; Pancreatic adenocarcinoma; complement C3a; complement C3a receptor; metastasis; epithelial-to-mesenchymal transition
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.15587

We aimed to clarify the role of complement C3a and its receptor C3aR in progression of pancreatic ductal adenocarcinoma (PDAC). We evaluated the serum levels of C3 and C3a in patients with PDAC. C3aR expression in tissue was assessed using a tissue microarray. To confirm the protumoral effects of C3a in PDAC, we conducted in vitro experiments using PDAC cell lines (Panc-1 and MiaPaca-2) that exhibit high C3aR expression. Serum levels of both C3 and C3a were higher in 26 patients with PDAC than in 28 nontumor-bearing controls. In the tissue microarray, we observed increased expression of C3aR in PDAC cells, especially in cases with metastatic lesions. In vitro experiments showed that C3a facilitated tumor cell proliferation, migration and invasion by activating the extracellular-regulated kinase signaling pathway and inducing epithelial-to-mesenchymal transition. Inhibition of the C3a-C3aR axis by pharmacological blockade and short-hairpin RNA-mediated knockdown of C3aR alleviated its protumoral effect. These findings provide a new approach for the development of treatments targeting the C3a-C3aR axis.