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1
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Zhou Z, Feng D, Yang Y, Gao P, Wang L, Wu Z. Pan-cancer analysis reveals the prognostic gene CASR suppresses tumor progression and epithelial-mesenchymal transition in renal clear cell carcinoma. Cell Calcium 2023; 116:102803. [PMID: 37804688 DOI: 10.1016/j.ceca.2023.102803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 10/09/2023]
Abstract
Calcium-sensing receptor (CASR), primarily found in the parathyroid gland and other tissues, plays a crucial role in sensing and regulating extracellular calcium, which was also aberrantly expressed in human tumors. Nevertheless, a comprehensive analysis of CASR in pan-cancer has yet to be conducted. To gain a better understanding of CASR in pan-cancer, data profiles on CASR cancers were collected from TCGA database. The expression level, clinical significance, prognostic value, and potential mechanisms of CASR in pan-cancer were analyzed via multiple public databases. The functional assays were conducted using human kidney renal clear cell carcinoma (KIRC) cell lines, clinical samples, and nude mice. Our research revealed that the abnormal expression of CASR was found in a variety of tumors. The expression and mutation of CASR were significantly associated with tumor prognosis and stage. Pathway analyses suggested that CASR was involved in the epithelial-mesenchymal transition (EMT) progress. Besides, CASR expression was correlated with immune inhibitory genes and immunotherapy in cancers. Particularly in KIRC, we established that CASR mRNA and protein levels were downregulated in clinical samples and cell lines. Moreover, a Cox regression analysis revealed that CASR was an independent prognostic factor in both TCGA-KIRC samples and clinical samples from our center. In vitro and in vivo experiments revealed that blocking CASR with lentivirus could suppress tumor growth and invasion, and EMT progress in KIRC cells. In summary, our study provides a comprehensive bioinformatic analysis of CASR in pan-cancer, offering deeper insights into its function and the EMT mechanism in KIRC, warranting further investigation.
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Affiliation(s)
- Zijian Zhou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Dexiang Feng
- Department of Urology, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou 215123, PR China
| | - Yuanyuan Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Peng Gao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China; Institute of Urology, Fudan University, Shanghai 200040, PR China
| | - Lujia Wang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China; Institute of Urology, Fudan University, Shanghai 200040, PR China.
| | - Zhong Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China; Institute of Urology, Fudan University, Shanghai 200040, PR China.
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2
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Kumar A, Singh AK, Singh H, Thareja S, Kumar P. Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:3. [PMID: 36308643 DOI: 10.1007/s12032-022-01864-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/29/2022] [Indexed: 01/17/2023]
Abstract
Thymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/β catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells.
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Affiliation(s)
- Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India.
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Aslam A, Ahmad J, Baghdadi MA, Idris S, Almaimani R, Alsaegh A, Alhadrami M, Refaat B. Chemopreventive effects of vitamin D 3 and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166040. [PMID: 33338596 DOI: 10.1016/j.bbadis.2020.166040] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/07/2020] [Accepted: 12/09/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca2+)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca2+-mediated apoptosis in vivo and in vitro. METHODS Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD3 (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD3, Pcal and/or 5-FU were applied in the HT29 colon cancer cells. RESULTS The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca2+ concentrations and Ca2+-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca2+ levels and Ca2+-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca2+-related molecules at the gene and protein levels in vivo and in vitro. CONCLUSIONS VD3 was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca2+-related molecules involved in tumour suppression.
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Affiliation(s)
- Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | | | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Riyad Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | - Aiman Alsaegh
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mai Alhadrami
- Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
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Xie P, Mo JL, Liu JH, Li X, Tan LM, Zhang W, Zhou HH, Liu ZQ. Pharmacogenomics of 5-fluorouracil in colorectal cancer: review and update. Cell Oncol (Dordr) 2020; 43:989-1001. [PMID: 32474853 DOI: 10.1007/s13402-020-00529-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/20/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a disease with high morbidity and mortality rates. 5-fluorouracil (5-FU) is the first-line recommended drug for chemotherapy in patients with CRC, and it has a good effect on a variety of other solid tumors as well. Unfortunately, however, due to the emergence of drug resistance the effectiveness of treatment may be greatly reduced. In the past decade, major progress has been made in the field of 5-FU drug resistance in terms of molecular mechanisms, pre-clinical (animal) models and clinical trials. CONCLUSIONS In this article we systematically review and update current knowledge on 5-FU pharmacogenomics related to drug uptake and activation, the expression and activity of target enzymes (DPD, TS and MTHFR) and key signaling pathways in CRC. Furthermore, a summary of drug combination strategies aimed at targeting specific genes and/or pathways to reverse 5-FU resistance is provided. Based on this, we suggest that causal relationships between genes, pathways and drug sensitivity should be systematically considered from a multidimensional perspective. In the design of research methods, emerging technologies such as CRISPR-Cas, TALENS and patient-derived xenograft models should be applied as far as possible to improve the accuracy of clinically relevant results.
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Affiliation(s)
- Pan Xie
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Jun-Luan Mo
- Shenzhen Center for Chronic Disease Control, 518020, Shenzhen, People's Republic of China
| | - Jin-Hong Liu
- Shenzhen Center for Chronic Disease Control, 518020, Shenzhen, People's Republic of China
| | - Xi Li
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Li-Ming Tan
- Department of Pharmacy, The Second People's Hospital of Huaihua City, 418000, Huaihua, People's Republic of China
| | - Wei Zhang
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China. .,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China.
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5
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Renal Ca 2+ and Water Handling in Response to Calcium Sensing Receptor Signaling: Physiopathological Aspects and Role of CaSR-Regulated microRNAs. Int J Mol Sci 2019; 20:ijms20215341. [PMID: 31717830 PMCID: PMC6862519 DOI: 10.3390/ijms20215341] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/17/2019] [Accepted: 10/23/2019] [Indexed: 12/31/2022] Open
Abstract
Calcium (Ca2+) is a universal and vital intracellular messenger involved in a diverse range of cellular and biological processes. Changes in the concentration of extracellular Ca2+ can disrupt the normal cellular activities and the physiological function of these systems. The calcium sensing receptor (CaSR) is a unique G protein-coupled receptor (GPCR) activated by extracellular Ca2+ and by other physiological cations, aminoacids, and polyamines. CaSR is the main controller of the extracellular Ca2+ homeostatic system by regulating parathyroid hormone (PTH) secretion and, in turn, Ca2+ absorption and resorption. Recent advances highlight novel signaling pathways activated by CaSR signaling involving the regulation of microRNAs (miRNAs). miRNAs are naturally-occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. We previously described that high luminal Ca2+ in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking through CaSR activation. Moreover, we demonstrated that CaSR signaling reduces AQP2 abundance via AQP2-targeting miRNA-137. This review summarizes the recent data related to CaSR-regulated miRNAs signaling pathways in the kidney.
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Wang W, Yu S, Huang S, Deng R, Ding Y, Wu Y, Li X, Wang A, Wang S, Chen W, Lu Y. A Complex Role for Calcium Signaling in Colorectal Cancer Development and Progression. Mol Cancer Res 2019; 17:2145-2153. [PMID: 31366605 DOI: 10.1158/1541-7786.mcr-19-0429] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/27/2019] [Accepted: 07/29/2019] [Indexed: 11/16/2022]
Abstract
Clinical data suggest that many malignant cancers are associated with hypercalcemia. Hypercalcemia can facilitate the proliferation and metastasis of gastric and colon tumors, and has been considered a hallmark of end-stage disease. However, it has also been reported that dietary calcium or vitamin D supplementation could reduce the risk of many types of cancers. In particular, the intestines can absorb considerable amounts of calcium via Ca2+-permeable ion channels, and hypercalcemia is common in patients with colorectal cancer. Thus, this review considers the role of calcium signaling in the context of colorectal cancer and summarizes the functions of specific regulators of cellular calcium levels in the proliferation, invasion, metastasis, cell death, and drug resistance of colorectal cancer cells. The data reveal that even a slight upregulation of intracellular Ca2+ signaling can facilitate the onset and progression of colorectal cancer, while continuous Ca2+ influx and Ca2+ overload may cause tumor cell death. This dual function of Ca2+ signaling adds nuance to the debate over the hallmarks of colorectal cancer, and may even provide new directions and strategies for clinical interventions.
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Affiliation(s)
- Wei Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Suyun Yu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Shuai Huang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Rui Deng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Yushi Ding
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Yuanyuan Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China.,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Shijun Wang
- Shandong Co-Innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Shandong, P.R. China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China. .,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, P.R. China. .,Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, P.R. China
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7
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Li C, Qin F, Xue M, Lei Y, Hu F, Xu H, Sun G, Wang T, Guo M. miR-429 and miR-424-5p inhibit cell proliferation and Ca 2+ influx by downregulating CaSR in pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 2018; 316:C111-C120. [PMID: 30462536 DOI: 10.1152/ajpcell.00219.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cytosolic free Ca2+ concentration is a key factor in pulmonary vasoconstriction and vascular remodeling of pulmonary artery smooth muscle cells (PASMCs). These processes contribute to pulmonary arterial hypertension and are influenced by expression of calcium-sensing receptor (CaSR). Although regulation of CaSR expression is precisely controlled, the contribution of microRNAs (miR) is incompletely understood. Here, we demonstrate that miR-429, miR-424-5p, miR-200b-3p, and miR-200c-3p regulate CaSR by targeting specific 3'-untranslated region, suggesting that these miRNAs function as CaSR inhibitors in PASMCs. Moreover, miR-429 and miR-424-5p inhibit proliferation of PASMCs by downregulating CaSR, resulting in reduced Ca2+ influx under both normoxia and hypoxia. These findings indicate miR-429 and miR-424-5p target CaSR and may function as Ca2+ influx suppressors in pulmonary arterial hypertension-associated diseases.
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Affiliation(s)
- Chuang Li
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
| | - Fang Qin
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
| | - Mengmeng Xue
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
| | - Yucong Lei
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
| | - Fen Hu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei , People's Republic of China
| | - Hui Xu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei , People's Republic of China
| | - Guihong Sun
- School of Basic Medical Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
| | - Tao Wang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei , People's Republic of China
| | - Mingxiong Guo
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan, Hubei , People's Republic of China
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Iamartino L, Elajnaf T, Kallay E, Schepelmann M. Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives. World J Gastroenterol 2018; 24:4119-4131. [PMID: 30271078 PMCID: PMC6158479 DOI: 10.3748/wjg.v24.i36.4119] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
The extracellular calcium-sensing receptor (CaSR) is best known for its action in the parathyroid gland and kidneys where it controls body calcium homeostasis. However, the CaSR has different roles in the gastrointestinal tract, where it is ubiquitously expressed. In the colon, the CaSR is involved in controlling multiple mechanisms, including fluid transport, inflammation, cell proliferation and differentiation. Although the expression pattern and functions of the CaSR in the colonic microenvironment are far from being completely understood, evidence has been accumulating that the CaSR might play a protective role against both colonic inflammation and colorectal cancer. For example, CaSR agonists such as dipeptides have been suggested to reduce colonic inflammation, while dietary calcium was shown to reduce the risk of colorectal cancer. CaSR expression is lost in colonic malignancies, indicating that the CaSR is a biomarker for colonic cancer progression. This dual anti-inflammatory and anti-tumourigenic role of the CaSR makes it especially interesting in colitis-associated colorectal cancer. In this review, we describe the clinical and experimental evidence for the role of the CaSR in colonic inflammation and colorectal cancer, the intracellular signalling pathways which are putatively involved in these actions, and the possibilities to exploit these actions of the CaSR for future therapies of colonic inflammation and cancer.
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Affiliation(s)
- Luca Iamartino
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Taha Elajnaf
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Enikö Kallay
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
| | - Martin Schepelmann
- Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna 1090, Austria
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9
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Hendy GN, Canaff L. Calcium-Sensing Receptor Gene: Regulation of Expression. Front Physiol 2016; 7:394. [PMID: 27679579 PMCID: PMC5020072 DOI: 10.3389/fphys.2016.00394] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 08/23/2016] [Indexed: 12/13/2022] Open
Abstract
The human calcium-sensing receptor gene (CASR) has 8 exons, and localizes to chromosome 3q. Exons 1A and 1B encode alternative 5′-untranslated regions (UTRs) that splice to exon 2 encoding the AUG initiation codon. Exons 2–7 encode the CaSR protein of 1078 amino acids. Promoter P1 has TATA and CCAAT boxes upstream of exon 1A, and promoter P2 has Sp1/3 motifs at the start site of exon 1B. Exon 1A transcripts from the P1 promoter are reduced in parathyroid tumors and colon carcinomas. Studies of colon carcinomas and neuroblastomas have emphasized the importance of epigenetic changes—promoter methylation of the GC-rich P2 promoter, histone acetylation—as well as involvement of microRNAs in bringing about CASR gene silencing and reduced CaSR expression. Functional cis-elements in the CASR promoters responsive to 1,25-dihydroxyvitamin D [1,25(OH)2D], proinflammatory cytokines, and the transcription factor glial cells missing-2 (GCM2) have been characterized. Reduced levels of CaSR and reduced responsiveness to active vitamin D in parathyroid neoplasia and colon carcinoma may blunt the “tumor suppressor” activity of the CaSR. The hypocalcemia of critically ill patients with burn injury or sepsis is associated with CASR gene upregulation by TNF-alpha and IL-1beta via kappaB elements, and by IL-6 via Stat1/3 and Sp1/3 elements in the CASR gene promoters, respectively. The CASR is transactivated by GCM2—the expression of which is essential for parathyroid gland development. Hyperactive forms of GCM2 may contribute to later parathyroid hyperactivity or tumorigenesis. The expression of the CaSR—the calciostat—is regulated physiologically and pathophysiologically at the gene level.
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Affiliation(s)
- Geoffrey N Hendy
- Experimental Therapeutics and Metabolism, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University Montréal, QC, Canada
| | - Lucie Canaff
- Experimental Therapeutics and Metabolism, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University Montréal, QC, Canada
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10
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Tang L, Cheng CY, Sun X, Pedicone AJ, Mohamadzadeh M, Cheng SX. The Extracellular Calcium-Sensing Receptor in the Intestine: Evidence for Regulation of Colonic Absorption, Secretion, Motility, and Immunity. Front Physiol 2016; 7:245. [PMID: 27458380 PMCID: PMC4914593 DOI: 10.3389/fphys.2016.00245] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 06/03/2016] [Indexed: 12/14/2022] Open
Abstract
Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.
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Affiliation(s)
- Lieqi Tang
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Catherine Y Cheng
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Xiangrong Sun
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Alexandra J Pedicone
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
| | - Mansour Mohamadzadeh
- Department of Medicine, Center for Inflammation and Mucosal Immunology, University of Florida Gainesville, FL, USA
| | - Sam X Cheng
- Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida Gainesville, FL, USA
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The calcium-sensing receptor and the hallmarks of cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1398-407. [DOI: 10.1016/j.bbamcr.2015.11.017] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Revised: 11/17/2015] [Accepted: 11/18/2015] [Indexed: 02/07/2023]
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XIE RUI, TANG BO, YONG XIN, LUO GANG, YANG SHIMING. Roles of the calcium sensing receptor in digestive physiology and pathophysiology (Review). Int J Oncol 2014; 45:1355-62. [DOI: 10.3892/ijo.2014.2560] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/30/2014] [Indexed: 11/06/2022] Open
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13
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Prognostic significance of calcium-sensing receptor in breast cancer. Tumour Biol 2014; 35:5709-15. [DOI: 10.1007/s13277-014-1756-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 02/13/2014] [Indexed: 10/25/2022] Open
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Singh N, Aslam MN, Varani J, Chakrabarty S. Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: Promotion of a more differentiated, less malignant and indolent phenotype. Mol Carcinog 2013; 54:543-53. [PMID: 26076051 DOI: 10.1002/mc.22123] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 11/26/2013] [Indexed: 12/22/2022]
Abstract
The calcium sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor. Cancer cells that do not express CaSR (termed CaSR null) are highly malignant while acquisition of CaSR expression in these cells circumvents the malignant phenotype. We hypothesize that chemopreventive agents mediate their action through the induction of CaSR. Here, we compare the effectiveness of Ca(2+), vitamin D, and Aquamin (a marine algae product containing Ca(2+), magnesium and detectable levels of 72 additional minerals) on the induction of CaSR in the CBS and HCT116 human colon carcinoma cell lines and the corresponding CaSR null cells isolated from these lines. All three agonists induced CaSR mRNA and protein expression and inhibited cellular proliferation in the parental and CaSR null cells. Aquamin was found to be most potent in this regard. Induction of CaSR expression by these agonists resulted in demethylation of the CaSR gene promoter with a concurrent increase in CaSR promoter reporter activity. However, demethylation per se did not induce CaSR transcription. Induction of CaSR expression resulted in a down-regulated expression of tumor inducers and up-regulated expression of tumor suppressors. Again, Aquamin was found to be most potent in these biologic effects. This study provides a rationale for the use of a multi-mineral approach in the chemoprevention of colon cancer and suggests that induction of CaSR may be a measure of the effectiveness of chemopreventive agents.
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Affiliation(s)
- Navneet Singh
- Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois
| | - Muhammad N Aslam
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - James Varani
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Subhas Chakrabarty
- Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois
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