Abstract
ObjectiveCalcium is present in serum mainly in filterable and bound forms, and Ca2+ 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.MethodsRetrospective 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 Ca2+ 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.ResultsHigh 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.ConclusionOur 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.
Highlights
Endometrial cancer (EC) is a common female reproductive system tumor originating from the endometrium epithelium
The estrogen receptor (ER) expression on prognosis and the estrogen on the risk of acquiring disease have been extensively researched, we have previously demonstrated that non-nuclear ER to account for estrogen action in the plasma membrane and calcium mobilization [7], few studies have evaluated the importance of other blood-based biomarkers like the calcium levels
We identified 580 cases diagnosed with EC after bringing in the exclusion criterion (Figure 1) due to irrelevant malignant history or missing data (N = 78)
Summary
Endometrial cancer (EC) is a common female reproductive system tumor originating from the endometrium epithelium. Research shows that in 2021, the number of new cases of endometrial cancer in the United States is the fourth in female malignant tumors and the sixth in death [1]. Cancer survival has improved since the mid-1970s for all of the most common cancers except uterine cervix and uterine corpus, mainly reflecting the absence of significant treatment advances for these cancers [1]. EC lags behind nearly every primary cancer type in terms of developing targeted therapy. Predictive biomarkers have not been identified [2].
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