Extracellular Calcium-Sensing Receptor (CaSR) Is Substantially Increased in Mesothelioma and, When Activated, Causes Apoptosis in Mesothelioma Cell Lines
Bibliographic record
Abstract
Increases in CaSR expression are reported in breast and prostate cancer and parathyroid adenoma. Currently, it is unknown whether CaSR is expressed in malignant mesothelioma. To understand any functional consequences of CaSR expression in normal mesothelia and mesothelioma, we examined paraffin-embedded sections and the normal mesothelial cell line (Met5a) in comparison with drug-resistant mesothelioma cell lines (H28 and H2052). Immunohistochemistry was used to assess CaSR expression in human tissue; RT-PCR and Western blotting were used to determine CaSR expression in the cell lines. To understand if CaSR activation stimulated apoptosis, we compared rates of TUNEL staining after challenge with CaSR agonists in low calcium or after siRNA reduction of the CaSR. Histologic sections showed that malignant mesothelioma (n = 6) had stronger CaSR immunostaining than controls (n = 6; P < .05). In vitro, both control mesothelia (Met5a) and mesothelioma (H28, H2052) expressed amplicons for the CaSR. The Met5a cells expressed no CaSR protein; however, the H2052 cells showed 6-fold more CaSR protein than H28 cells. When the H2052 cells were incubated with 0.5 mmol/L Ca2+, they showed a total of 7% ± 4% of positive cells by TUNEL (5 fields/about80 cells/field). In contrast, 3 mmol/L Ca2+ addition to H2502 increased the TUNEL-positive cells to 34% ± 9% (P < .05; n = 6). Treatment of the H2052 cells with the CaSR agonist’s neomycin sulfate, GdCl3, or polyarginine for 8 hours in low calcium (0.5 mmol/L) showed similar TUNEL results to high calcium. Transient transfection of siRNA CaSR into H2052 cells treated with 3 mmol/L Ca2+ showed significantly less TUNEL staining (12% ± 5% of total cells; P < .05; n = 3) than the scrambled group (25% ± 8% of total cells). Together, these results suggest CaSR stimulation by calcium or other polyvalent CaSR agonists stimulates apoptosis in mesothelioma cells. The substantial expression of CaSR in mesothelioma may represent a novel therapeutic venue against mesothelioma.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".