Calcium signaling and epigenetics: A key point to understand carcinogenesis

Izquierdo-Torres, Eduardo; Hernández‐Oliveras, Andrés; Fuentes-García, Gabriela; Zarain‐Herzberg, Ángel

doi:10.1016/j.ceca.2020.102285

Cited by 19 publications

(21 citation statements)

References 159 publications

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“…Calcium ions are one of the most important cellular messengers in biology and have been implicated many hallmarks of cancer [41]. Several drugs have been reported to block CNG channels including calcium channel blockers currently used in clinical practice in the management of high blood pressure, angina and cardiac arrhythmias, including dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil) and benzothiazepines (e.g., diltiazem) as well as the local anaesthetic tetracaine and calmodulin antagonists [32,42,43].…”

Section: Discussionmentioning

confidence: 99%

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Hepburn

Lazzarini

Veeratterapillay

et al. 2021

Cancers

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Cisplatin-based neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy for muscle-invasive bladder cancer (MIBC) patients. Despite a 5–10% survival benefit, some patients do not respond and experience substantial toxicity and delay in surgery. To date, there are no clinically approved biomarkers predictive of response to NAC and their identification is urgently required for more precise delivery of care. To address this issue, a multi-methods analysis approach of machine learning and differential gene expression analysis was undertaken on a cohort of 30 MIBC cases highly selected for an exquisitely strong response to NAC or marked resistance and/or progression (discovery cohort). RGIFE (ranked guided iterative feature elimination) machine learning algorithm, previously demonstrated to have the ability to select biomarkers with high predictive power, identified a 9-gene signature (CNGB1, GGH, HIST1H4F, IDO1, KIF5A, MRPL4, NCDN, PRRT3, SLC35B3) able to select responders from non-responders with 100% predictive accuracy. This novel signature correlated with overall survival in meta-analysis performed using published NAC treated-MIBC microarray data (validation cohort 1, n = 26, Log rank test, p = 0.02). Corroboration with differential gene expression analysis revealed cyclic nucleotide-gated channel, CNGB1, as the top ranked upregulated gene in non-responders to NAC. A higher CNGB1 immunostaining score was seen in non-responders in tissue microarray analysis of the discovery cohort (n = 30, p = 0.02). Kaplan-Meier analysis of a further cohort of MIBC patients (validation cohort 2, n = 99) demonstrated that a high level of CNGB1 expression associated with shorter cancer specific survival (p < 0.001). Finally, in vitro studies showed siRNA-mediated CNGB1 knockdown enhanced cisplatin sensitivity of MIBC cell lines, J82 and 253JB-V. Overall, these data reveal a novel signature gene set and CNGB1 as a simpler proxy as a promising biomarker to predict chemoresponsiveness of MIBC patients.

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Section: Discussionmentioning

confidence: 99%

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Hepburn

Lazzarini

Veeratterapillay

et al. 2021

Cancers

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“…In addition, previous studies reported the key role of intracellular calcium remodeling in colorectal cancer process that includes cellular proliferation, migration, invasion and metastasis [ 34 , 35 ]. As during cellular transformation, disturbances of intracellular Ca 2+ occur due to altered expression of Ca 2+ channel proteins which control the process of Ca 2+ pump [ 36 ]. One of these Ca 2+ channel proteins is SERCA2 which is important for ER Ca 2+ stores refill to maintain efficient protein folding and maturation, whereas overexpression causing ER Ca 2+ stores overload that leads to ER stress observed in various cancers [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the correlation between the expression of TSP50, SERCA2 and IL-8 in CRC, significant positive correlation was found between the three biomarkers’ expression in neoplastic epithelial cells. This finding could be explained by the fact that both inflammatory process and tumorigenesis are related to disruption of Ca 2+ homeostasis which is involved in DNA and gene methylation [ 36 ]. TSP50 gene abnormal methylation and the subsequent TSP50 protein expression in tumorous epithelial and stromal cells may be related to SERCA2 expression and intracellular Ca 2+ alteration.…”

Section: Discussionmentioning

confidence: 99%

Expression of TSP50, SERCA2 and IL-8 in Colorectal Adenoma and Carcinoma: Correlation to Clinicopathological Factors

Youssef¹,

Radi²,

El-Azeem³

2021

Pathol. Oncol. Res.

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Background: Colorectal cancer (CRC) is the third most common type of cancer, it is considered a genetically heterogeneous disease with different molecular pathways being involved in its initiation and progression. Testes-specific protease 50 (TSP50) gene is a member of cancer/testis antigens that encodes for threonine protease enzyme. Overexpression of TSP50 was found to enhance the progression and invasion of breast cancer and other malignant tumors. SERCA2 is widely expressed in several body tissues; its aberrant expression has been involved in many cancers. IL-8 is an inflammatory cytokine. Alongside its role in inflammation, its expression was reported to induce the migration of tumor cells.Aim: Study the expression of TSP50, SERCA2 and IL-8 in colorectal adenoma (CRA), CRC and normal colonic tissues to compare the expression of these biomarkers in relation to clinicopathological parameters and prognostic factors.Results: TSP50, SERCA2 and IL-8 expression varied between normal colonic tissues, CRA and CRC. Significant statistical association was detected between the three biomarkers’ overexpression and degree of dysplasia in CRA. Also, significant statistical relation was found between the three biomarkers’ overexpression and presence of lympho-vascular invasion, advanced TNM staging and high intra-tumoral inflammatory infiltrate. Multivariable analysis showed that the overexpression of the three biomarkers is significantly associated with worse prognosis.Conclusion: The expression of TSP50, SERCA2 and IL-8 was different between the normal tissue and neoplastic colorectal tissue on one hand and between CRA and CRC on the other. Increased expression of these biomarkers in neoplastic epithelial cells of colorectal carcinoma is associated with adverse prognostic factors and could be considered as independent prognostic factors.

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“…Due to the huge amount of Ca 2+ -dependent events occurring in cells, alteration of its signaling pathways contributes to the development of multiple human disorders. Therefore, the study of Ca 2+ signaling is essential for understanding the pathophysiology of many diseases, including diabetes, carcinogenesis, cardio- and cerebrovascular diseases including endothelial dysfunction, as well as neurodegenerative disorders [ 4 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

et al. 2022

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Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

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Calcium signaling and epigenetics: A key point to understand carcinogenesis

Cited by 19 publications

References 159 publications

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Expression of TSP50, SERCA2 and IL-8 in Colorectal Adenoma and Carcinoma: Correlation to Clinicopathological Factors

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

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