Upregulation of transferrin receptor-1 induces cholangiocarcinoma progression via induction of labile iron pool

Abstract

Labile iron pool is a cellular source of ions available for Fenton reactions resulting in oxidative stress. Living organisms avoid an excess of free irons by a tight control of iron homeostasis. We investigated the altered expression of iron regulatory proteins and iron discrimination in the development of liver fluke-associated cholangiocarcinoma. Additionally, the levels of labile iron pool and the functions of transferrin receptor-1 on cholangiocarcinoma development were also identified. Iron deposition was determined using the Prussian blue staining method in human cholangiocarcinoma tissues. We investigated the alteration of iron regulatory proteins including transferrin, transferrin receptor-1, ferritin, ferroportin, hepcidin, and divalent metal transporter-1 in cholangiocarcinoma tissues using immunohistochemistry. The clinicopathological data of cholangiocarcinoma patients and the expressions of proteins were analyzed. Moreover, the level of intracellular labile iron pool in cholangiocarcinoma cell lines was identified by the RhoNox-1 staining method. We further demonstrated transferrin receptor-1 functions on cell proliferation and migration upon small interfering RNA for human transferrin receptor 1 transfection. Results show that Iron was strongly stained in tumor tissues, whereas negative staining was observed in normal bile ducts of healthy donors. Interestingly, high iron accumulation was significantly correlated with poor prognosis of cholangiocarcinoma patients. The expressions of iron regulatory proteins in human cholangiocarcinoma tissues and normal liver from cadaveric donors revealed that transferrin receptor-1 expression was increased in the cancer cells of cholangiocarcinoma tissues when compared with the adjacent normal bile ducts and was significantly correlated with cholangiocarcinoma metastasis. Labile iron pool level and transferrin receptor-1 expression were significantly increased in KKU-214 and KKU-213 when compared with cholangiocyte cells (MMNK1). Additionally, the suppression of transferrin receptor-1 expression significantly decreased intracellular labile iron pool, cholangiocarcinoma migration, and cell proliferation when compared with control media and control small interfering RNA. In Conclusion, high expression of transferrin receptor-1 resulting in iron uptake contributes to increase in the labile iron pool which plays roles in cholangiocarcinoma progression with aggressive clinical outcomes.

CD71+ Population Enriched by HPV-E6 Protein Promotes Cancer Aggressiveness and Radioresistance in Cervical Cancer Cells

“…Our data suggested that inhibition of CD71 suppressed the self-renewal ability, cell survival after irradiation treatment, cell proliferation, and in vitro and in vivo tumorigenicity of cervical cancer cells. Downregulation of CD71 in a cholangiocarcinoma cell line with siRNA has also been reported to inhibit cell migration, proliferation, and cell survival (18), and suppression of CD71 using siRNA in ESCC cells reduces their colony-forming ability and arrests cells in the S-phase (19). In this study, we demonstrated that downregulation of CD71 in HPV16-positive SiHa cells and HPV18-E6-overexpressing 18E6-5 cells suppressed self-renewal ability and cell proliferation.…”

“…Our findings provided additional evidence indicating that CD71 protein is highly expressed in cervical cancer. Increased expression of CD71 has also been reported in many other cancers, including astrocytic brain tumors, breast cancer, cholangiocarcinoma, ESCC, pancreatic cancer, and renal cell carcinoma (17)(18)(19)(20)(21)(22). Furthermore, enhanced CD71 expression has been reported to be correlated with poor clinical outcomes in patients with estrogen receptor-positive breast cancer and glioblastoma, suggesting that CD71 might serve as a therapeutic target (21,22).…”

“…CD71, also known as transferrin receptor, is a homodimeric transmembrane glycoprotein that binds to iron-bound transferrin and serves as a mediator for the delivery of extracellular iron into cells via endocytosis (15,16). Overexpression of CD71 has been reported in certain types of solid tumors, including breast cancer, renal cell carcinoma, cholangiocarcinoma, esophageal squamous cell carcinoma (ESCC), pancreatic cancer, and glioblastoma (17)(18)(19)(20)(21)(22). High levels of CD71 are also detected in leukemic cells of poorly differentiated acute myeloid leukemia (AML) compared with the levels in partially differentiated AML (23).…”

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

“…Contribution to CCA progression and poorer clinical outcomes. [64] Ferritin high expression Negative prognostic index for CCA patients. [65] Fpn reduced mRNA levels Reduction of iron release, in tumor cells of CCA patients sample compared to matched surrounding liver, suggests that elevated iron content is a negative prognostic factor.…”

Peer Review #1 of "Antifibrotic effect of xanthohumol in combination with praziquantel is associated with altered redox status and reduced iron accumulation during liver fluke-associated cholangiocarcinogenesis (v0.2)"

“…TfR-1 knockdown has been shown to reduce iron uptake by 80% in human hepatoma cell line (Herbison et al 2009). Moreover, the aberrant expression of TfR-1 substantially contributed to the regulation of systemic iron levels and can play key roles in CCA development (Jamnongkan et al 2017). TfR-1 has been reported to be a major molecule that responded to iron uptake mediated by insulin through hypoxia conditions (Biswas et al 2013).…”