Transferrin Receptor Promotes Endometrial Cancer Proliferation by Activating the Iron-Dependent PI3K/AKT/mTOR Signaling Pathway
Yufei Yang
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Writing - original draft, Methodology, Investigation, Conceptualization
Search for more papers by this authorYing Ning
Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Project administration, Writing - review & editing
Search for more papers by this authorYu Chen
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Formal analysis, Investigation
Search for more papers by this authorTian Tian
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorXinyan Gao
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorYan Kong
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorCorresponding Author
Ke Lei
Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
Correspondence:
Ke Lei ([email protected])
Zhumei Cui ([email protected])
Contribution: Project administration, Writing - review & editing
Search for more papers by this authorCorresponding Author
Zhumei Cui
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Correspondence:
Ke Lei ([email protected])
Zhumei Cui ([email protected])
Contribution: Funding acquisition, Supervision, Writing - review & editing
Search for more papers by this authorYufei Yang
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Writing - original draft, Methodology, Investigation, Conceptualization
Search for more papers by this authorYing Ning
Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Project administration, Writing - review & editing
Search for more papers by this authorYu Chen
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Formal analysis, Investigation
Search for more papers by this authorTian Tian
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorXinyan Gao
Department of Clinical Medicine, Qingdao University, Qingdao, China
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorYan Kong
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Contribution: Investigation, Validation
Search for more papers by this authorCorresponding Author
Ke Lei
Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
Correspondence:
Ke Lei ([email protected])
Zhumei Cui ([email protected])
Contribution: Project administration, Writing - review & editing
Search for more papers by this authorCorresponding Author
Zhumei Cui
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China
Correspondence:
Ke Lei ([email protected])
Zhumei Cui ([email protected])
Contribution: Funding acquisition, Supervision, Writing - review & editing
Search for more papers by this authorFunding: This work was supported by National Natural Science Foundation of China (82472719).
ABSTRACT
Aberrant iron metabolism is frequently observed in cancers, including endometrial cancer (EC). However, the role of transferrin receptor (TFRC), a key regulator of iron metabolism, remains unclear in endometrial cancer. We found transferrin receptor expression was significantly upregulated in endometrial cancer tissues compared to adjacent nontumor tissues, and high transferrin receptor levels were associated with poor prognosis. Functional studies revealed that transferrin receptor knockdown impaired endometrial cancer cell proliferation in vitro and in vivo, while transferrin receptor overexpression enhanced endometrial cancer cell proliferation. Mechanistically, transferrin receptor activated the PI3K/AKT/mTOR signaling pathway, as its knockdown suppressed the pathway, and rapamycin, an mTOR inhibitor, reversed transferrin receptor-induced pathway activation and proliferation. Modulation of the labile iron pool by ferric ammonium citrate (FAC) or deferoxamine (DFO) rescued transferrin receptor-induced biological effects. Additionally, AURKA was identified as a regulator of transferrin receptor expression. These findings demonstrate the oncogenic role of transferrin receptor in endometrial cancer and suggest that targeting iron homeostasis and the PI3K/AKT/mTOR pathway may represent potential therapeutic strategies for endometrial cancer.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting Information
| Filename | Description |
|---|---|
| cas70015-sup-0001-FigureS1.docxWord 2007 document , 259 KB |
Figure S1. TFRC promotes the proliferation of EC cells in vitro. |
| cas70015-sup-0002-FigureS2.docxWord 2007 document , 321.5 KB |
Figure S2. TFRC promotes the proliferation of EC cells in vitro. |
| cas70015-sup-0003-TableS1.docxWord 2007 document , 16.6 KB |
Table S1. ShRNA sequences used in the study. |
| cas70015-sup-0004-TableS2.docxWord 2007 document , 16.5 KB |
Table S2. Primer sequences used in the study. |
| cas70015-sup-0005-TableS3.docxWord 2007 document , 21.5 KB |
Table S3. Correlation between tumor TFRC expression and clinicopathologic characteristics in UCEC patients. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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