Estrogen-Induced Extracellular Calcium Influx Promotes Endometrial Cancer Progress by Regulating Lysosomal Activity and Mitochondrial ROS

Frontiers in Medicine

article

Boqiang Shen¹  Juan Hao¹  Yanying Lin²  Xingchen Li¹  Xiao Yang¹  Ting Huang¹  Jiaqi Wang¹  Yuanyuan Jia¹  Jingyi Zhou¹  Jianliu Wang¹ 

[1] Department of Obstetrics and Gynecology, Peking University People's Hospital;Center of Reproductive Medicine, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University

关键词: endometrial cancer (EC);    estrogen;    serum calcium;    calcium homeostasis;    prognosis (carcinoma);   

DOI  :  10.3389/fmed.2022.835700

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Objective Calcium is present in serum mainly in filterable and bound forms, and Ca 2+ is a major key to modulate signaling pathways that control oncogenesis and oncochannels associated with several types of cancer. However, the biological significance of serum calcium and its related mechanism with estrogen in endometrial cancer (EC) still remains elusive. This study aims to ascertain the relationship between serum calcium and clinicopathology in EC. Methods Retrospective assessment of a total of 502 patients diagnosed with EC after surgery in Peking University People's Hospital from 2010 to 2018. Preoperative serum ionized calcium and the albumin corrected calcium was calculated in quartiles for various postoperative clinicopathological characteristics, logistic regression adjusted for potential confounders. Intracellular calcium homeostasis change induced by estrogen was detected by confocal analysis. Downstream pathways were analyzed by transcriptome and proteomics. Mitochondrial Ca 2+ and ROS (reactive oxygen species) level was detected by confocal and flow cytometry. Lysosomal morphological and membrane changes were verified by confocal or Western blot assays. Results High level of albumin-corrected serum calcium was significantly correlated with EC clinicopathological characteristics progression include lymph vascular space invasion, lymph nodes metastasis, myometrial invasion, and cervical invasion. Calcium homeostasis regulated by estrogen in EC cells derived from extracellular calcium influx but not the release of the endoplasmic reticulum. Proteomic and bioinformatic analysis revealed the calcium influx might be involved in the regulation of autophagy and mitochondrial-related pathways. Mechanistic investigation demonstrated that calcium influx acted on the function of mitochondrial ROS and lysosomal activity. Conclusion Our findings revealed that serum calcium level was significantly related to poor outcomes. The extracellular calcium influx induced by estrogen was targeted to mitochondrial ROS and lysosome activity, which should be oriented to improve EC therapeutic strategies.

【 授权许可】

CC BY