High Expression of Orai1 Enhances Cell Proliferation and is Associated with Poor Prognosis in Human Colorectal Cancer

Ren

et al. 2018

Cell Physiol Biochem

Background/Aims: Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite the development and application of novel agents, MM still undergoes an aggressive and incurable course in the vast majority of patients. Ca²⁺ is one of the critical regulators of cell migration. Ca²⁺ influx is essential for the migration of various types of cells including tumor cells. However, the role of store-operated calcium entry (SOC) channels, the only Ca²⁺ channels of non-excitable cells, has not yet been reported in MM cell survival. Methods: We evaluated the expression of Stim1 and Orai1 (two key regulators of SOC) in MM tissues and cell lines by immunohistochemical assay, quantitative real-time PCR assay and western blot. MM cell lines were pretreated with pharmacological blockers and siRNAs, and then MM cell proliferation, cell cycle arrest, and apoptosis were examined by FACS (flow cytometry) assay, and Annexin V-FITC/PI staining. The correlation between the expression of Stim1 (or Orai1) level and outcome in MM were assessed by using Progress Free Survival (PFS). Results: Stim1 and Orai1 were both abundantly expressed in MM tissue and MM cell lines. Inhibition of SOCE reduced MM cell viability, and induced cell cycle arrest and apoptosis. Stim1 or Orai1 silencing also reduced cell viability, caused cell apoptosis and cell cycle arrest in MM cell lines. Over-expression of Stim1/Orai1 in MM patients was closely associated with the clinical outcome of MM. Conclusion: The Stim1/Orai1-mediated signaling participates in the pathogenesis of MM, which represents an attractive target for future therapeutic intervention.

Section: Discussionmentioning

confidence: 99%

Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis

Ren

et al. 2018

Cell Physiol Biochem

“…[ 3 – 5 ] High morbidity of metastasis and relapse were considered as main contributors to unsatisfactory long-term prognosis for CRC patients underwent standard treatments. [ 6 , 7 ] It has been revealed both inflammation and immunity dysregulation was closely associated with proliferation and migration of tumor cells. [ 8 – 10 ] However, there was no sufficient data focusing on the significance of biomarker involved both inflammation and immunity in CRC patients.…”

Section: Introductionmentioning

confidence: 99%

Increased serum pentraxin-3 level predicts poor prognosis in patients with colorectal cancer after curative surgery, a cohort study

Liu¹,

Zhao

Guo³

2018

Medicine

Pentraxin-3 (PTX3) is a glycoprotein involved in inflammation and immune regulation of cancer. The aim of this study was to evaluate the serum PTX3 level in patients with colorectal cancer (CRC) and analyze its prognostic significance.A total of 263 consecutive patients underwent radical resection for primary CRC and 126 healthy controls were enrolled in this study. Serum PTX3 level was measured within the day before surgery though enzyme-linked immunosorbent assays, comparing with the level of healthy control. Baseline demographic and clinical characteristics were recorded. The association between serum PTX3 level and survival outcome was analyzed by the Kaplan–Meier with Log-Rank test and Cox regression methods.Mean serum PTX3 level in CRC patients was higher than that of healthy control (13.8 ± 3.2ng/mL versus 3.3 ± 1.2ng/mL, P < .001). Finally, 55 (20.9%) patients out of all 263 patients studied had died during following-up period. All patients were divided into 2 groups using the optimal cutoff value (12.6 ng/mL) of PTX3 level using a sensitivity of 68.0% and a specificity of 71.7% as optimal conditions from receiver operating curve analysis. Patients with a PTX3≥12.6ng/mL had poorer 5 years overall survival rate (76.6% versus 67.8%, P = .025) patients with a PTX3 < 12.6ng/mL in univariate analysis and serum PTX3 level also been confirmed as an independent predictor for survival for CRC in multivariate analysis (Hazard ratio, 1.468; 95% [confidence interval] CI, 1.081–1.976; P < .001).Serum PTX3 level can serve as an independent prognostic biomarker for CRC patients after curative resection.

“…Next, we evaluated the possible role of σ2R/TMEM97 in the ability of MDA-MB-231 cells to migrate. Migration was assessed using the wound-healing assay as described elsewhere [2]. This protocol revealed that SM21 (100 nM) evoked a rapid close up of the scratch at 12 h; meanwhile, small gaps between cells could still be observed under control conditions at that time point (Figure 2e; middle panels versus left hand side panels and the beside bar graph).…”

Section: σ2r/tmem97 Ligands Alter Tnbc Cell Proliferation and Migrationmentioning

confidence: 99%

“…Fura-2 emission was acquired at 515 nm of wavelength using a cooled digital CCD camera (Hisca CCD C-6790, Hamamatsu, Japan), and using the Aquacosmos 2.5 software (Hamamatsu Photonics, Hamamatsu, Japan). The resulting traces were normalized with respect to the fluorescence emitted by the cells under resting conditions (F n /F 0 ) [2]. Cells were temporarily maintained in a Ca 2+ -free HBS (EGTA was added, 75 µM), and subsequently, 2 µM of TG was administered to evoke the depletion of the intracellular Ca 2+ stores.…”

Section: Measurement Of Cytosolic Free-ca 2+ Concentrationmentioning

confidence: 99%

“…Store operated Ca 2+ entry (SOCE) is considered as a major Ca 2+ -entry mechanism in nonelectrically excited cells; it is regulated by emptying of the intracellular Ca 2+ stores, such as the endoplasmic reticulum (ER). Enhanced SOCE has been reported in different cancer types, including human colorectal cancer, osteosarcoma, and ovary carcinoma [1,2]. In addition, SOCE remodeling, due to changes in the expression of its key molecular components, has been also evidenced in several types of cancer, such as colorectal cancer and oral/oropharyngeal squamous cell carcinoma [3].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NO1, a New Sigma 2 Receptor/TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines

Cantonero

Camello

Abate

et al. 2020

Cancers

(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other σ2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation.